PET Agents for Primary Brain Tumor Imaging

Anja G van der Kolk, MD, PhD1,2 Dylan Henssen, MD, PhD1 Harry W Schroeder III, MD, PhD3 Lance T Hall, MD3

1Department of Medical Imaging, Radboudumc, Nijmegen, the Netherlands; 2Donders Center for Cognitive Neuroscience, Nijmegen University, Nijmegen, the Netherlands; 3Department of Radiology and Imaging Sciences, Emory University, Atlanta, GA, USA

Abstract: The role of molecular imaging with positron emission tomography (PET) for diagnosis, treatment planning and post-treatment monitoring of brain tumors has grown substantially in the last decades. In the last 25 years, almost 50 different PET agents have been developed and tested in human clinical studies. While some of these PET agents are yet to make their way into clinical practice, others have already established pivotal roles in brain tumor imaging. Although all these agents share an affinity for brain tumor cells, they target different tumor-altered molecular pathways within these cells: some agents are taken up by the cell through overexpressed transporters and become trapped, altered, or incorporated into upregulated metabolic pathways, while other agents bind to overexpressed receptors or to cells present in the tumor microenvironment. In this monograph, we explore the major genetic and molecular changes characteristic of brain tumors, how they are used by PET agents to gain access to tumor cells and their environment, and how this translates to uptake in clinical practice. Gaining insight in these processes is essential for correct image interpretation and helps to understand why some agents are more successful than others.

Keywords: brain tumors; glioma; molecular imaging; PET; uptake mechanisms

Author for correspondence: Anja G van der Kolk, Department of Medical Imaging, Radboudumc, Nijmegen, the Netherlands;

Cite as: van der Kolk AG, Henssen D, Schroeder HW III, Hall LT. PET Agents for Primary Brain Tumor Imaging. Brisbane (AU): Exon Publications; 2023. Online first 20 Nov 2023.


PET Agents for Primary Brain Tumor Imaging. Brisbane (AU): Exon Publications. ISBN: 978-0-6458663-0-8. Doi:

Copyright: The Authors.

License: This open access article is licensed under Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)


Primary brain tumors are devastating tumors with high morbidity and mortality, even after optimal treatment consisting of surgery and chemoradiation (1). Imaging and histological assessment of mutation status play indispensable roles in the diagnostic workup, treatment, and follow-up of these tumors. Although MRI (magnetic resonance imaging) is the primary imaging technique for both initial diagnosis and subsequent follow-up, structural sequences often fall short in distinguishing between WHO (World Health Organization) types and grades (2). Image contrast in MRI relies primarily on imaging (protons in) water, which is the most abundant substance in the human body and, consequently, not very specific for any type of tissue in particular. In addition, some advanced imaging techniques such as diffusion and perfusion MRI may lack specificity in tumor assessment. These limitations reduce the value of conventional MRI in primary brain tumor assessment.

Molecular imaging techniques like molecular MRI and positron emission tomography (PET) on the other hand generate image contrast by visualizing or measuring specific molecular characteristics of tissues. Since tumors are characterized by various grades of molecular dysregulation that depend on and are often specific for the type of tumor, these imaging techniques could be more tumor-specific than conventional MRI. Indeed, molecular MRI sequences like MR spectroscopy and chemical exchange saturation transfer have shown promise in better delineating brain tumors and differentiating between brain tumor types. However, current limitations in spatial and spectral resolution significantly affect the success rate of metabolic MRI (3). PET has been the classic molecular imaging technique over the last decades, and has a strong track record for cancer imaging in the body. Instead of measuring the static presence of molecules like in MR spectroscopy, PET images represent a dynamic process of PET agent uptake that is characteristic of the particular tissue. In addition, PET agents can be designed to target tissue-specific metabolic pathways and molecules. Compared to MRI, these advantages together could result in higher brain tumor specificity by providing a more complete picture of the molecular phenotype of brain tumors.


Over the last 25 years, more than 50 different PET agents have been evaluated for primary brain tumor imaging in humans. Most agents have been designed to target certain molecules, such as transporters or receptors, that are associated with specific metabolic pathways that are known to be upregulated or even thought to be unique in brain tumor tissue. Notwithstanding their high target specificity, success rates of these agents have varied widely because uptake is a dynamic process that depends on more than just target binding; it also involves crossing the blood-brain barrier (BBB) and becoming retained (or not) in the tumor cell through simple trapping or by metabolic incorporation. These processes depend heavily on the structure of the specific PET agent and which receptor or transporter it targets. An additional complicating factor is the growing insight that current target molecules and associated pathways may be less tumor-specific than previously thought.

Understanding the underlying mechanisms of PET agent transport, binding or uptake, and trapping is important for correct interpretation of PET images in clinical practice, and to aid in choosing the most appropriate agent for the particular tumor type or individual patient case. In this monograph, we explore the major genetic and molecular changes characteristic of brain tumors, how they are used by PET agents to gain access to tumor cells and their environment, and how this translates to uptake in clinical practice. Several in-depth discussions on the value of specific groups of PET agents in clinical diagnosis and follow-up of brain tumors can be found in the literature (47); a concise overview of clinical trial results is given in Table 1.

TABLE 1 Concise overview of clinical trial results of PET agents for brain tumor imaging

PET agent Highlights in imaging Uptake vs. molecular markers Limitations Trials* Figure
Nutrient-based agents
18F-FDG Improves tumor grade differentiation
Identifies malignant transformation in LGG
Particularly useful in evaluating lymphomas
Pos. correlation with MGMT methylation Significant background uptake
Low specificity (e.g. inflammation)
2, 3
18F-Me-4FDG High uptake in HGG Unknown Role BBB permeability unclear - 2, 3
11C-MET Improves tumor delineation
Improves tumor type differentiation
Increased uptake → worse prognosis
Pos. correlation with:
- Tumor cell density
- MGMT promotor methylation
- 1p19q co-deletion
Neg. correlation with IDH mutation
Less successful in grade differentiation
Low specificity (e.g. inflammation)
Short half-life (11C)
2, 4
11C-TYR Uptake in variety of brain tumors No correlation with Ki-67 Questionable whether really reflecting protein synthesis & cell progression
Short half-life (11C)
- 2
11C-MCYS High uptake in recurrent glioblastoma Unknown Significant background uptake
Short half-life (11C)
- 2
18F-FDOPA Higher sensitivity than 18F-FDG
Improves LGG-HGG differentiation
Increased uptake → worse prognosis
Pos. correlation with Ki-67
Pos. correlation with IDH mutation
Variable success in individual tumor grade differentiation
Conflicting results in recurrent tumors
Physiologic uptake in striatum limits tumor delineation in this area
18F-FAMT Higher T/N ratio than 18F-FDG
Improves LGG-HGG differentiation
No correlation with Ki-67 Added value over other amino acid PET agents unknown - 2
18F-FIMP Higher accumulation in higher-grade gliomas
Possibly better retention in cytoplasm
Clear images compared to 11C-MET & 18F-FDG
Unknown Assimilation mechanisms not entirely clear - 2
18F-FET Correctly identifies more malignant areas
High uptake in recurrent glioblastoma improves tumor delineation
Unknown Moderate background uptake
Less successful in grade differentiation
2, 6
18F-OMFD Uptake in variety of brain tumors
Improves tumor delineation
Unknown Unknown - 2
18F-FGln Uptake in high-grade astrocytomas only
High specificity (no uptake in inflammation)
Unknown Unknown - 2
11C-ACBC Higher sensitivity than 18F-FDG Unknown Unsuccessful in grade differentiation - 2
18F-FACBC Affinity for most malignant tumor areas
Lower background uptake than 11C-MET
Improves LGG-HGG differentiation
Pos. correlation with Ki-67 Unknown NCT04111588 2, 4
18F-FSPG High uptake in recurrent glioma
Differences in uptake curves of good vs poor outcomes in oligodendroglioma
Unknown Role BBB permeability unclear NCT02370563 2
D-cis-18F-FPro Uptake associated with cell death Unknown Uptake mechanism unclear
Role BBB permeability unclear
- 2
11C-MeAIB Higher T/N ratio than 11C-MET
Differentiates low- from high-grade gliomas
Pos. correlation with proliferation markers in cell lines Role BBB permeability unclear - 2
11C-AMT Uptake in LGG and HGG
Improves tumor type differentiation
Uptake predicts survival
Improves tumor delineation
Shows uptake in DNET (unique)
Pos. correlation with IDO (LGG)
Pos. correlation with LAT1 (HGG)
Image interpretation depends on kinetic analyses (dynamic PET imaging) - 2
18F-FBPA Feasibility assessment of BNCT in glioma & meningioma
Increased uptake → worse prognosis
Unknown Additional value over 18F-FDG unclear - 2
18F-FBY Solely indicative for LAT1 overexpression due to fast excretion
Can be used for treatment (19F-FBY)
Unknown Unknown - 2
11C-choline Fast imaging due to rapid clearance
Very low background uptake
Uptake in variety of brain tumors
Pos. correlation with Ki-67 Conflicting results regarding LGG-HGG differentiation
Low specificity (e.g. inflammation)
NCT01165632 2
18F-FCHO Fast imaging due to rapid clearance
Very low background uptake
Uptake meningioma > glioblastoma
Uptake grade II-III glioma highly variable
Unknown Low specificity (e.g. inflammation) - 2
11C-acetate Improves grade IV vs. lower grade differentiation Unknown Unknown - 2
13N-ammonia Improves LGG-HGG differentiation
Sensitivity in LGG → astrocytoma component
Unknown Unsuccessful in individual tumor grade differentiation
Unclear if uptake reflects ↑ metabolism or BBB breakdown
- 2
18F-DASA-23 High T/N ratio
PKM2 also therapeutic target
Unknown Unclear transport mechanism NCT03539731 2
Nucleoside-based agents
11C-TdR Improves tumor grade differentiation Unknown High background uptake due to BBB-penetrating radioactive metabolites - 5
18F-FMAU Little brain parenchymal uptake
Improves visualization of recurrent glioma
Unknown Unknown NCT04752267 5
18F-FLT High sensitivity for HGG
Heterogeneous uptake in LGG
Improves HGG differentiation
Pos. correlation with Ki-67 (even more than 11C-MET) Significant role transport through BBB
Less successful in LGG differentiation
NCT04309552 5, 6
11C-4DST High sensitivity for HGG
Improves tumor grade differentiation
Pos. correlation with Ki-67 LGG detection worse than 11C-MET
High background uptake suggests radioactive metabolites
- 5
Receptor-based agents
68Ga-PSMA High uptake in HGG
Improves tumor recurrence detection
Unknown Role BBB permeability unclear NCT05798273
18F-DCFPyL Binds PSMA in glioblastoma microvessels
Binds PSMA on grade III astrocytoma cells
Unknown Role BBB permeability unclear - 7
89Zr-Df-IAB2M High sensitivity for HGG & grade I astrocytoma Trend for correlation with PSMA Unknown - 7
18F-galacto-RGD Heterogeneous uptake within tumor Pos. correlation with Integrin αvβ3 Possibly low affinity for Integrin αvβ3 NCT01939574 7
18F-FPPRGD2 Improves tumor delineation
Improves LGG-HGG differentiation
Unknown Unknown NCT02441972 7
18F-RGD Uptake predicts treatment sensitivity Unknown Unknown - 7
68Ga-PRGD2 Higher T/N ratio than 18F-FDG Unknown Unknown NCT01801371
68Ga-DOTATATE High uptake in meningiomas
Improves tumor delineation
Higher sensitivity vs. contrast-enhanced MRI
Increased uptake → faster growth
Pos. correlation with SSTR2 Unknown NCT04081701 7
68Ga-DOTATOC High uptake in meningiomas
Improves tumor delineation
Higher sensitivity vs. contrast-enhanced MRI
Increased uptake → faster growth
Pos. correlation with SSTR2 Uptake HGG correlated with BBB permeability instead of SSTR2 expression NCT03583528 7
68Ga-DOTANOC Increased uptake in HGG Unknown Uptake HGG correlated with BBB permeability instead of SSTR2 expression - 7
68Ga-BBN Focus on patient stratification for secondary treatment with GRPR-targeted agents
Prominent uptake in contrast-enhancing tumors irrespective of WHO grade
Pos. correlation with GRPR Role BBB permeability unclear NCT03407781
11C-PD153035 Focus on patient stratification for secondary treatment with EGFR-targeted agents Pos. correlation with EGFR Unknown - 7
18F-CPFPX Increased uptake in tissue surrounding glioblastoma Unknown Elusive function A1AR in oncogenesis
Role of BBB permeability unclear
- 7
18F-FLUDA May be able to differentiate primary CNS lymphoma from glioblastoma Unknown Role of BBB permeability unclear - 7
11C-PK11195 Improves LGG-HGG differentiation Unknown Unclear role of TSPO in oncogenesis - 7
18F-DPA-714 Visualizes inflammatory cells within the tumor microenvironment Pos. correlation with no. of glioma-associated myeloid cells Unclear role of TSPO in oncogenesis NCT05672082
18F-FDHT Very low background uptake Unknown Role BBB permeability unclear
Uptake intensity relatively low
- 7
11C-TGN-020 High uptake grade III-IV astrocytoma
Improves tumor grade differentiation
Pos. correlation with AQP1 and -4 Unknown - 7, 9
68Ga-citrate Very low background uptake Unknown Unknown - 7
68Ga(-DOTA)-FAPI Low background activity
Improves LGG-HGG differentiation
Unknown Role of BBB permeability unclear NCT04554719
18F-FAPI Long background activity Unknown Role of BBB permeability unclear - 7
68Ga-Pentixafor High uptake in CNS lymphoma and glioblastoma
Therapeutic potential (177Lu/90Y)
Conflicting results Role of BBB permeability unclear
Inconsistent correlation between uptake and CXCR4 expression
- 7
TME-based and miscellaneous agents
18F-EF5 Heterogeneous uptake in glioblastoma
Uptake corresponds to areas of hypoxia
Unknown Relatively difficult to synthesize - 8
62Cu2+-ATSM Improves grade IV vs. lower grade differentiation
Specific sensitivity to astrocytoma component
Pos. correlation with HIF-1 Agent might not reflect hypoxia but another metabolic upregulation - 8
18F-FAZA Faster clearance vs. 18F-FMISO
Improved T/N ratios vs. 18F-FMISO
Very high uptake in high-grade gliomas
Pos. correlation with VEGF
No correlation with HIF-1
Influence of BBB permeability unclear NCT05047913 8
18F-FRP170 High uptake in HGG
(between necrotic center and outer contrast-enhancing tumor layer)
Pos. correlation with HIF-1
No correlation with Ki-67
Unknown - 8
18F-FMISO High uptake in glioblastoma
Improved tumor grade differentiation
Uptake predicts survival
(Variable) Pos. correlation with:
- HIF-1
Less consistent uptake in grade II-III gliomas
Slow target tissue accumulation & clearance of healthy tissue
124I-CLR1404 High T/N ratio in recurrent astrocytoma Unknown Unknown - 8
18F-ML-10 Focus on treatment assessment
Changes in uptake pattern during treatment
Unknown No correlation with progression
Relatively low specificity
Difficulties in image interpretation due to tumor heterogeneity
- 8
64CuCl2 High uptake in glioblastomas
No uptake in grade II astrocytomas
Unknown Unclear whether it can cross BBB
Role Ctr1 in oncogenesis not completely elucidated
- 8
82Rb-Chloride Differentiates between low- and high-grade tumors Unknown Relatively nonspecific agent
Role of BBB permeability unclear
- 8
18F-FDS High uptake spindle cell carcinoma pituitary Unknown Role BBB permeability unclear - N/A
18F-FP-CIT Improves meningioma vs. other tumor type differentiation Unknown Contradictory results on presence of β-amyloid within meningioma - N/A
11C-PiB High uptake in meningioma Unknown Role DAT in oncogenesis unknown - N/A

*Active trials using the specific PET agent for brain tumor imaging, as reported on

Abbreviations: A1AR, A1 adenosine receptor; AQP, aquaporin; BBB, blood-brain barrier; BNCT, boron neutron capture therapy; Ctr1, copper transporter 1; DAT, dopamine active transporter; DNET, dysembryoplastic neuroepithelial tumor; EGFR, epidermal growth factor receptor; GRPR, gastrin releasing peptide receptor; HGG, high-grade glioma; HIF, hypoxia-inducible factors; IDH, isocitrate dehydrogenase; IDO, indoleamine 2,3-dioxygenase; Ki-67, cellular proliferation activity index; LAT, large neutral amino acid transporter; LGG, low-grade glioma; MGMT, O6-methylguanine-DNA-methyltransferase; MRI, magnetic resonance imaging; N/A, not applicable; PET, positron emission tomography; PSMA, prostate-specific membrane antigen; SSTR, somatostatin receptor; SUV, standardized uptake value; TME, tumor microenvironment; T/N ratio, tumor-to-normal-tissue ratio; TSPO, translocator protein; VEGF, vascular endothelial growth factor; WHO, World Health Organization.


Brain tumor cells are characterized by increased, uncontrolled proliferation and a tendency to invade healthy tissues, sometimes accompanied by spread to distant sites. These features result from combinations of genetic changes, like mutations and deletions, which vary between different tumor types and often even within the same tumor (8, 9). Many genetic changes have been recognized to play a role in brain tumor development, the most important of which will be briefly described below (Table 2).

TABLE 2 Occurrence and effects of common (genetic) changes in brain tumors; see also Figure 1

(Genetic) change Effect Additional info Brain tumor type*
PTEN mutation / deletion Increased energy metabolism & angiogenesis by stimulating PI3K-AKT-mTORC signaling pathway PI3K-AKT-mTORC signaling pathway also stimulated by ↑ tumoral secretion of growth factors (PDGF, EGF, TNF-α) Glioblastoma, IDH-wildtype
Glioblastoma, IDH-mutant (minimal)
TP53 mutation (most common) / inactivation of p53 protein Increased energy metabolism & angiogenesis by stimulating PI3K-AKT-mTORC signaling pathway
DNA damage repair dysregulation, cell cycle progression and apoptosis
Occurs in virtually all tumor types Astrocytoma grade II, III
Oligodendroglioma grade II, III
Pleomorphic xanthoastrocytoma grade II, III (minimal)
Glioblastoma, IDH-wildtype
Glioblastoma, IDH-mutant
EGFR mutation / amplification Increased energy metabolism & angiogenesis by upregulating PI3K-AKT-mTORC signaling pathway through increased signaling of EGFR PI3K-AKT-mTORC signaling pathway also stimulated by ↑ tumoral secretion of growth factors (PDGF, EGF, TNF-α) Glioblastoma, IDH-wildtype
Glioblastoma, IDH-mutant (minimal)
NF1 mutation Cell cycle progression by activating Ras independent of growth factors Ras-Raf-MEK-ERK(MAPK) signaling pathway also stimulated by ↑ tumoral secretion of growth factors (PDGF, EGF, TNF-α) Glioblastoma, IDH-wildtype
BRAF mutation Cell cycle progression by activating Raf independent of growth factors Ras-Raf-MEK-ERK(MAPK) signaling pathway also stimulated by ↑ tumoral secretion of growth factors (PDGF, EGF, TNF-α) Pilocytic astrocytoma
Pleomorphic xanthoastrocytoma grade II, III
Glioblastoma, IDH-wildtype (minimal)
COX2 overexpression Stimulates Ras-Raf-MEK-ERK(MAPK) signaling pathway through EGFR - Astrocytoma grade II, III
Glioblastoma, IDH-wildtype (?)
Glioblastoma, IDH-mutant (?)
MYC overexpression Stimulates many molecular pathways by increased gene transcription
Regulates and stimulates proliferation of highly malignant tumor cell subtype (tumor stem-like cell)
MYC protein functions as general transcription factor for variety of genes associated with normal development; sustained- or over-expression found in virtually all tumor types & seen as major driving force in oncogenesis Medulloblastoma
Glioblastoma, IDH-mutant
Glioblastoma, IDH-wildtype (?)
INK4/ARF (tumor suppressor locus) mutation / deletion Inactivates p53 protein by reduced ARF synthesis
Inactivates Rb1 protein by reduced INK4a and INK4b synthesis
ARF normally inhibits MDM2 from impeding p53 function
INK4a and INK4b normally inhibit CDK4/6 and Cyclin D activity
Astrocytoma grade II, III (less)
Pleomorphic xanthoastrocytoma grade II, III
Glioblastoma, IDH-wildtype
MDM2 / MDM4 gene overexpression Inhibits activity of p53 protein & stimulates its degradation - Glioblastoma, IDH-mutant (minimal)
Glioblastoma, IDH-wildtype
Rb1 mutation / ↑ expression Rb1 regulators Cyclin D, CDK4 & CDK6 (more common) Cell cycle progression by Increases gene transcription Rb1 (tumor suppressor protein) normally inhibits CDKs, stabilizes chromosome structure & binds E2F transcription factors → inhibits gene transcription & subsequent cell cycle progression; Cyclin D, CDK4 and CDK6 cause detachment of E2F from Rb. Glioblastoma, IDH-wildtype
MGMT promoter methylation Decreased DNA repair due to ↓ DNA repair protein MGMT because of impossible gene transcription ‘Positive’ methylation status → oncogenic genetic alterations will survive, but DNA damage caused by chemotherapeutical agents will also evade repair → chemotherapy-induced Astrocytoma grade II, III
Oligodendroglioma grade II, III
Glioblastoma, IDH-wildtype
Glioblastoma, IDH-mutant
IDH1/2 (neomorph) mutation Increased energy metabolism & angiogenesis by mTORC activation (and blocking of cellular differentiation) due to ↑ production of (accumulating) 2HG Mutations result in IDH protein with new function, converting α-KG to 2HG; tumor cell will compensate for altered flux of α-KG by increasing glutaminolysis; IDH-mutated tumors often associated with younger age at diagnosis & better prognosis Astrocytoma grade II, III
Oligodendroglioma grade II, III
Glioblastoma, IDH-mutant
ATRX mutation cellular survival & telomere conservation by upregulating ATRX causing ↑ alternative lengthening of telomeres Often seen together with IDH mutations; amount of cell divisions normally limited by length of telomeres, where successive cell divisions shorten telomeres, leading to cellular ‘ageing’ and death. Astrocytoma grade II, III
Glioblastoma, IDH-mutant
TERT mutation cellular survival & telomere conservation by upregulating TERT causing ↑ telomerase activity Often seen together with IDH mutations; amount of cell divisions normally limited by length of telomeres, where successive cell divisions shorten telomeres, leading to cellular ‘ageing’ and death. Meningioma
Oligodendroglioma grade II, III
Glioblastoma, IDH-wildtype
Glioblastoma, IDH-mutant (less)
1p19q co-deletion Unknown Key molecular feature of oligodendroglioma in 2016 WHO classification of brain tumors Oligodendroglioma grade II, III

*Based on the WHO 2016 classification, considering most studies discussed in this book chapter were published before the 2021 WHO update.

Abbreviations: 2HG, 2-hydroxyglutarate; α-KG, alpha-ketoglutarate; AKT, protein kinase B; ARF, ADP ribosylation factor; ATRX, alpha thalassemia / mental retardation syndrome X-linked; CDK, cyclin-dependent kinase; COX, cyclooxygenase; DNA, deoxyribonucleic acid; EGF, epidermal growth factor and EGFR, its receptor; ERK, extracellular signal-regulated kinases; IDH, isocitrate dehydrogenase; MAPK, mitogen-activated protein kinase; MDM, E3 ubiquitin-protein ligase; MGMT, O6-methylguanine-DNA-methyltransferase; mTORC, mechanistic target of rapamycin complex 1; NF, neurofibromatosis; PDGF, platelet-derived growth factor; PI3K, phosphatidylinositol 3-kinase; PTEN, phosphatase and tensin homolog; Rb, retinoblastoma protein; TERT, telomerase reverse transcriptase; TNF-α, tumor necrosis factor alpha; WHO, world health organization.

PI3K-AKT-mTORC signaling pathway

Both increased tumoral secretion of growth factors, for example, PDGF (platelet-derived growth factor), EGF (epidermal growth factor) and TNF-α (tumor necrosis factor-alpha), as well as mutation or deletion of the tumor suppressor gene PTEN (phosphatase and tensin homolog) will stimulate this pathway leading to increased energy metabolism and angiogenesis. Two other genetic alterations that affect this pathway are loss or inhibition of the p53 protein (see below) that normally stimulates expression of PTEN, and mutation of the EGF receptor (EGFR) gene with subsequent increased signaling of EGFR and pathway upregulation (10).

Ras-Raf-MEK-ERK(MAPK) signaling pathway

In addition to the increased growth factor secretion, several genetic alterations also directly affect the MAPK (mitogen-activated protein kinase) pathway and lead to cell cycle progression: NF1 (neurofibromatosis-1) mutations activate Ras independent of growth factors, while BRAF (B-Raf proto-oncogene) mutations exert the same effect on Raf. More indirectly, overexpression of the protein COX2 (cyclooxygenase-2) will lead to increased pathway stimulation through EGFR (11).

MYC protein

The MYC protein functions as a general transcription factor for a variety of genes associated with normal development; overexpression will therefore affect many, if not all, cellular pathways (some are illustrated in Figure 1). MYC sustained, or over-expression, can be found in virtually all tumor types, and is seen as a major driving force in oncogenesis (12, 13). In brain tumors, one of its main roles has been regulation and proliferation of a highly malignant tumor cell subtype (tumor stem-like cell) (14).

Fig 1

Figure 1. Simplified illustration of key metabolic and regulatory pathways that can be impaired, inhibited or upregulated in tumor cells, including the associated PET agents. The grey box represents the cytoplasm, while the yellow and blue boxes represent mitochondria and nucleus, respectively. Main results of the different pathways are highlighted by red boxes (e.g., increased protein synthesis). Red texts indicate oncogenic or tumoral changes influencing the illustrated pathways. Green texts indicate PET agents. Orange lines (both solid and dashed, different for clarity only) represent upregulated pathways, while normal interactions that are nonetheless relevant for the illustration are shown as black (solid or dashed) lines. The lipid raft (dashed box) was randomly placed, merely illustrating its function of clustering proteins and associated signaling pathways. Dark blue and light blue boxes crossing the plasma membrane represent resp. transporters and receptors.
Abbreviations: 2HG, 2-hydroxyglutarate; A1AR, A1 adenosine receptor; A2AAR, A2A adenosine receptor; ACSS, acyl coenzyme A synthetase; AKT, protein kinase B; AQP, aquaporin; ARF, ADP ribosylation factor; ATP, adenosine triphosphate; ATRX, alpha thalassemia / mental retardation syndrome X-linked; BRAF, B-Raf proto-oncogene; CHT1, high-affinity choline transporter; CKα, choline kinase alpha; CoA, acyl coenzyme A; COX, cyclooxygenase; CTL, choline transporter-like protein; Ctr1, copper transporter 1; CXCR4, C-X-C motif chemokine receptor 4 and its ligand CXCL12, C-X-C motif chemokine ligand; DAT, dopamine active transporter; DNA, deoxyribonucleic acid; EGF, epidermal growth factor and EGFR, its receptor; EMT, epithelial-mesenchymal transition; ENT, equilibrative nucleoside transporter; EP, prostaglandin E2 receptor; ERK, extracellular signal-regulated kinases; FAP, fibroblast activation protein; G6P, glucose-6-phosphate; GRP, gastrin releasing peptide and GRPR, its receptor; HIF, hypoxia-inducible factors; IDH, isocitrate dehydrogenase; IDO, indoleamine 2,3-dioxygenase; LDH, lactate dehydrogenase; MAPK, mitogen-activated protein kinase; MCT, monocarboxylate transporter; MDM, E3 ubiquitin-protein ligase; MGMT, O6-methylguanine-DNA-methyltransferase; MMP, matrix metalloproteinase; mTORC, mechanistic target of rapamycin complex 1; NFκB, nuclear factor kappa-B; NF, neurofibromatosis; PDGF, platelet-derived growth factor; PGE2, prostaglandin E2; PI3K, phosphatidylinositol 3-kinase; PKM2, pyruvate kinase M2; PS, phosphatidylserine; PSMA, prostate-specific membrane antigen; PTEN, phosphatase and tensin homolog; Rb, retinoblastoma protein; ROS, reactive oxygen species; SMCT, Na+ monocarboxylate cotransporter; SSTR, somatostatin receptor; TCA, tricarboxylic acid; TERT, telomerase reverse transcriptase; Tf, transferrin; TFRC, transferrin receptor; TGF-β, transforming growth factor beta; TNF-α, tumor necrosis factor alpha; TSPO, translocator protein; VEGF, vascular endothelial growth factor and VEGFR, its receptor.

p53 protein

Mutations of the TP53 tumor suppressor gene (most common) or inactivation of its protein p53 occur in virtually all tumor types (15). p53 normally regulates DNA damage repair (including oncogenic alterations), cell cycle progression and apoptosis (16). Causes of inactivation include deletions or mutations in the INK4/ARF (ADP ribosylation factor) tumor suppressor locus and increased MDM2/4 (E3 ubiquitin-protein ligase-2 and -4) gene expression. MDM2 and MDM4 are proteins that both directly inhibit activity of p53 as well as stimulate its degradation (17). The INK4/ARF locus harbors genes encoding ARF, a protein that normally inhibits MDM2 from impeding p53 function, thereby stabilizing and activating p53 (18).

Rb1 protein

This tumor suppressor protein (retinoblastoma-1) normally inhibits CDKs (cyclin-dependent kinases), stabilizes chromosome structure, and binds E2F transcription factors, thereby inhibiting gene transcription and subsequent cell cycle progression. Its functional impairment may be caused by direct mutation of its gene or (more commonly) increased expression of its regulators (cyclin D, CDK4, CDK6) that cause detachment of E2F from Rb (19). Additionally, Rb function can be influenced by deletions or mutations in the INK4/ARF tumor suppressor locus. Next to ARF, this locus also holds genes for proteins INK4a and INK4b that inhibit activity of CDK4/6 and (indirectly) cyclin D (18).

MGMT protein

Methylation of the MGMT (O6-methylguanine-DNA-methyltransferase) gene promoter renders gene transcription impossible and leads to decreased amounts of the DNA repair protein MGMT and, consequently, decreased DNA repair. A ‘positive’ methylation status will enable oncogenic genetic alterations to survive; on the other hand, DNA damage caused by chemotherapeutics will also evade repair, leading to chemotherapy-induced apoptosis. This is illustrated in patients with MGMT promotor methylated tumors who profit more from chemotherapy than those without ‘positive’ methylation status (20).

IDH protein

The discovery of the IDH (isocitrate dehydrogenase) mutation caused a radical rethinking of brain tumor development and classification (21). Mutations in the IDH1 and IDH2 gene are neomorph, resulting in an IDH protein with a new function: converting α-KG (alpha-ketoglutarate) to 2HG (2-hydroxyglutarate), which subsequently accumulates within the tumor cell and ultimately blocks cellular differentiation. The tumor cell will compensate for the altered flux of α-KG by increasing glutaminolysis. IDH-mutated tumors are often associated with younger age at diagnosis and better prognosis (22).


Mutations in telomere maintenance genes ATRX (alpha-thalassemia / mental retardation syndrome X-linked) and TERT (telomerase reverse transcriptase) are often seen together with IDH mutations. In general, the amount of cell divisions is limited by the length of telomeres, DNA-protein complexes capping chromosome ends, protecting them from end-to-end fusion and apoptosis. Successive cell divisions shorten telomeres, ultimately leading to cellular ‘ageing’ and death. TERT and ATRX are able to reverse telomere shortening by increasing telomerase activity and alternative lengthening of telomeres, respectively. Normally, these genes are downregulated; however, in tumor cells, (promotor) mutations will activate TERT and ATRX, resulting in telomere conservation and increased cellular survival (22, 23).

1p19q co-deletion

This genetic alteration has been classified as a key molecular feature of oligodendroglioma in the WHO classification of brain tumors (21). Although its exact role in tumorigenesis has not been elucidated yet, recent histopathological studies have shown an association with immune suppression in the tumor microenvironment (24).


While several of the above described genetic changes individually affect treatment options and can be used for prognostication, they have one main effect: the production of a variety of abnormal proteins and dysregulation of molecular pathways within cells (the tumor’s molecular phenotype) that ultimately promote cell cycle progression, proliferation and survival (2, 25). The most important dysregulated pathways for PET agent uptake are described below, while a more detailed overview can be found in Figure 1. Readers are also referred to two excellent reviews by DeBerardinis et al. (general cancer metabolism) and Park et al. (focus on gliomas) (26, 27).

Increased energy metabolism

A primary feature of tumor cells is upregulation of their energy metabolic pathways. Cells produce energy primarily by glucose degradation (glycolysis), with either subsequent incorporation of pyruvate in the TCA cycle and oxidative phosphorylation – yielding 36 molecules of adenosine triphosphate (ATP) – or degradation into lactate – yielding only 2 ATP but 10–100 times faster. When necessary, they may also use amino acids like glutamine as well as fatty acids and molecules like acetate as substrates. Multiple genetic changes can cause upregulation of these pathways in tumor cells and are summarized in Table 2 (10, 26, 28). To sustain these pathways, tumor cells will overexpress plasma membrane transporters, allowing increased inflow of energy substrates, or upregulate glutaminolysis and, to a lesser extent, fatty acid and acetate degradation (29). Upregulation of energy metabolic pathways enables tumor cells to proliferate as well as support all other energy-demanding metabolic processes. As a side-effect, their seemingly counterintuitive switch to less energy-efficient aerobic glycolysis (Warburg effect) stimulates angiogenesis and suppresses the innate immune response through production of lactate, which has emerged as a major factor in oncogenesis (3032). The subsequently increased reactive oxygen species (ROS) production, which is potentially toxic, can be neutralized by cystine influx through the often overexpressed system xCT transporter (33).

Increased fatty acid, protein, amino acid, and nucleotide synthesis

Increased cellular proliferation necessitates large amounts of cellular building blocks, like nucleotides for deoxyribonucleic acid (DNA) replication, fatty acids for plasma membrane construction and amino acids for protein synthesis. Apart from overexpressing transporters for increased inflow of these building blocks, tumor cells will also upregulate the associated metabolic pathways, i.e. protein, amino acid, fatty acid and nucleotide synthesis. The increased energy production discussed before facilitates these processes.

Increased angiogenesis

To sustain increased inflow of nutrients and building blocks, a high enough concentration of these molecules outside the cell will be required. Tumor cells facilitate this by initiating and upregulating several pathways of neovascularization, including vascular co-option, vasculogenesis, and (most commonly) angiogenesis, hereby significantly increasing the number of vessels supplying the tumor. Angiogenesis is a complex process in which tissue cells and their surrounding stroma interact and produce growth factors like vascular endothelial growth factor (VEGF) that attract and stimulate endothelial and mesenchymal cells to form new (micro)vessels (16, 34, 35). This will ensure sufficient supplies of nutrients and other molecules to reach the tumor (36). Of note, these tumor microvessels are often leaky and dilated because of continued pro-angiogenic signaling that results, amongst others, in mixing of tumor cells with endothelial cells and an absence of stabilizing pericytes. This not only decreases the supply of nutrients like glucose, but also the oxygen tension. Hence, this poses a clinical dilemma when interpreting uptake on PET images (34, 35).

The tumor microenvironment

Tumor cells establish the tumor microenvironment (TME), a complex network with various non-malignant cells like fibroblasts, endothelial and inflammatory cells, surrounded by extracellular matrix rich in proteins, cytokines and other signaling molecules. Interaction between the TME and tumor cells further facilitates tumor growth and angiogenesis, invasion and migration (metastasis), and plays an important role in suppressing the body’s natural immune reaction to tumor cells (37). Many of these interactions rely on increased expression of tumor cell receptors that subsequently cause upregulation of their associated signal transduction pathways. In more malignant brain tumors, they are also facilitated by hypoxia due to a lack of sufficient vasculature, dysfunctional (leaky) tumor microvessels, or both. Although tissue with very low pO2 will eventually die and become necrotic, mild to moderate hypoxia can be survived and is used to suppress the immune system and stimulate angiogenesis, tumor cell invasion and migration (38, 39). It also creates a relative resistance to radio- and chemotherapy, e.g. by inducing cell cycle arrest in the phase least sensitive to ionizing radiation, by limiting the detrimental effect of free radicals produced by interaction of radiation with water molecules, or by affecting delivery and uptake of chemotherapeutic drugs (39, 40). Consequently, a 2–3x higher radiation dose is necessary for hypoxic tissue to obtain effects equivalent to normoxic tissue (40). Other pathways of immune system inhibition include VEGF secretion and secretion of kynurenine, both of which attract immunosuppressive regulatory T cells (41) that inhibit the anti-tumor immune response and stimulate angiogenesis through suppression of helper T cells (35). The processes of immune suppression and invasion / migration involve many more mechanisms; however, only those with a role in PET agent uptake have been discussed here (42).

Targeting tumor molecular pathways for PET imaging

Most PET agents for brain tumor imaging have been designed to use the dysregulated pathways by targeting either upregulated transporters or -receptors on the tumor cell surface. They can be categorized based on the specific pathway they target: (i) increased energy metabolism and building block synthesis (glucose, amino acids and other nutrients); (ii) sustained cell cycle progression; (iii) increased angiogenesis; and (iv) the tumor microenvironment (hypoxia, growth factors). The following paragraphs discuss all PET agents used for this purpose in the last 2½ decades under nine broad categories. First, the monograph focuses on PET agents that target energy metabolism and building block synthesis under four sections: glucose-based agents, natural and non-natural amino acid-based agents, other nutrient-based agents, and agents not based on glucose or other nutrients. This is followed by five sections on various PET agents that target various aspects of tumor biology such as cell cycle progression, angiogenesis, tumor microenvironment, multiple pathways, with the last section on pet agents ‘incidentally’ found to accumulate in brain tumors. An overview of expression patterns of the targeted transporters and receptors can be found in Table 3.

TABLE 3 Tissue expression of transporters and receptors used by brain tumor PET agents in humans (alphabetically)

Transporter / Receptor Associated PET agent(s) Expression in healthy brain* Expression in brain tumors* Remarks
A1AR 18F-CPFPX Microglia/macrophages
Other immune cells
Unknown Plays crucial role in activation of expressed cells
A2AAR 18F-FLUDA Neurons (pre- and postsynaptic)
Immune cells (regT cells, macrophages, natural killer cells)
B-lymphocytes, primary CNS lymphoma May be able to differentiate primary CNS lymphoma from glioblastoma
AR 18F-FDHT Minimal to none Tumor cells, nuclei
Suppresses MYC expression, suggesting role in tumor cell maintenance and proliferation
AQP1/4 11C-TGN-020 Astrocytes (PM; localized to endfeet next to BBB)
Dural and vascular membranes (choroid plezus, ventricular ependymal layer, etc.)
Tumor cells (PM), gliomas & lymphomas
Endothelial cells (C + PM), lymphomas
AQP4 in tumors redistributed across complete PM; expression grade I & III gliomas and glioblastoma >> grade II gliomas; highest in peritumoral zone; in lymphomas associated with Ki-67
ASCT2 11C-MCYS, 18F-FGln, 11C-MET, 11C-ACBC, 18F-FACBC Unknown Upregulated and activated in gliomas Increased 18F-FACBC uptake in gliomas due to upregulation and activation of LAT and ASCT
B0 / B0+ 18F-FET Unknown Unknown Uptake through this transporter depends on specific cell type & differences in intra- and extracellular amino acid concentrations
CHT1 - CTL1/3 18F-FCHO, 11C-CHO Some neurons (PM; grey matter)
Endothelial cells (CTL)
N/A Increased choline (and 18F-FCHO / 11C-CHO) uptake in tumor cell possibly result of increased influx only, instead of overexpression transporter
Ctr1 64CuCl2 Unknown Unknown Increased copper (and 64CuCl2) uptake in tumor cell possibly result of increased influx only, instead of overexpression transporter
CXCR4 68Ga-Pentixafor All major CNS cell types, including neurons (but low expression) Tumor cells, cytoplasm
Tumor cells, nuclei
Endothelial cells
Large inter- and intra-tumoral variability in expression in glioblastomas
DAT 18F-FP-CIT Basal ganglia Unknown -
EGFR 11C-PD153035 Ependymal cells
Some neurons (e.g. hippocampus)
Expression in all glioma subtypes (approx. 50% or tumors per type) -
ENT-1 11C-TdR, 11C-4DST, 18F-FMAU, 18F-FLT Unknown Unknown Increased nucleoside (and nucleoside-based agent) uptake in tumor cell possibly result of increased influx only, instead of increased transporter
FAP 68Ga(-DOTA)-FAPI, 18F-FAPI No/little expression on either parenchymal or endothelial cells Tumor cells, gliomas (?)
Tumor microenvironment, near blood vessels, gliomas
While specific for fibroblasts in tumoral stroma of extracranial cancer, in the brain it will likely be present on other cells
GLUT 18F-FDG Throughout brain (mainly grey matter) including BBB Unknown FDG is transported across the intact BBB by GLUT, mainly GLUT1 and GLUT3, which are upregulated in many tumors, especially aggressive tumors
GRPR 68Ga-BBN Neurons Endothelial cells, gliomas
Tumor cells, gliomas
Integrin αvβ3 18F-RGD, 18F-galacto-RGD, 68Ga-PRGD2, 18F-FPPRGD2 No/little expression on either parenchymal or endothelial cells Endothelial cells (PM), gliomas
Tumor cells (C + PM, gliomas
Expression glioblastoma > grade II & III glioma & associated with IDH-mutation
Expression on activated macrophages, potentially within tumor microenvironment
LAT1 18F-FDOPA, 18F-FET, 18F-FAMT, 11C-MCYS, 18F-FGln, 11C-TYR, 11C-MET, 11C-AMT, 11C-ACBC, 18F-FACBC, 18F-OMFD, 18F-FBPA, 18F-FBY, 18F-FIMP Endothelial cells Endothelial cells (C + PM), gliomas
Tumor cells (C + PM), gliomas
Highest expression in peritumoral zone; positive correlation between expression & both tumor grade and Ki-67
Na/K-ATPase 82Rb-Chloride Ubiquitous in all human cells All tumor-associated cells Relatively nonspecific enzyme/ion pump, overexpressed in glioblastomas and other brain tumors
PKM2 18F-DASA-23 No/little expression on either parenchymal or healthy endothelial cells (BBB) Overexpressed but unknown which specific cells PKM2 expression is linked to increased glucose uptake, enhanced lactate production & decreased O2 consumption, and promotes macromolecule synthesis, cell proliferation & growth
PROT D-cys-18F-Fpro Unknown Unknown -
PSMA 18F-DCFPyL, 68Ga-PSMA, 89Zr-Df-IAB2M No/little expression on either parenchymal or endothelial cells Endothelial cells, glioblastoma > grade I astrocytomas
Tumor cells (minimal), grade II & III astrocytoma
Virtually no expression in lymphoma
SGLT2 19F-Me-4FDG No/little expression on either parenchymal or healthy endothelial cells (BBB) Endothelial cells, glioma
Tumor cells (PM), glioma
Microglial cells, glioma
Also expression in reactive astrocytes and neurons
SMCT1/2 - MCT1/4 11C-acetate Endothelial cells (MCT) Unknown Increased acetate (and 11C-acetate) uptake in tumor cell possibly result of increased influx only, instead of increased transporter
SSTR1-5 68Ga-DOTATATE, 68Ga-DOTATOC, 68Ga-DOTANOC Throughout brain Endothelial cells, meningiomas
Tumor cells (C), meningiomas
Tumor cells (C + PM), gliomas
Receptor activation has antineoplastic effect so tumor expression puzzling; oligodendrogliomas > IDH-wildtype & -mutant astrocytomas >> glioblastoma; less known about SSTR1 and SSTR3-5 except abundance on meningiomas
System xc- 18F-FSPG No/little expression on either parenchymal or endothelial cells Tumor cells (C + PM), gliomas Increased expression in high-grade tumors; inverse correlation between uptake and IDH-mutation
System A 11C-MeAIB Abluminal membrane of BBB Unknown Overexpression related to proliferation grade; associated with malignant transformation
TSPO 11C-PK11195, 18F-DPA-714 Mainly expressed on microglial and ependymal cells; no/little expression on either parenchymal or endothelial cells Normal endothelial cells in tumor, glioma
Tumor cells (C), glioma
Tumor-associated macrophages, glioma
Expression is positively correlated with WHO grade and Ki-67 index
Increased expression in macrophages, microglia and astrocytes in inflammation

Note: Transporter expression on healthy brain endothelial cells will facilitate BBB permeability of associated PET agent, which has both an advantage and a disadvantage: the PET agent will be able to reach tumor cells even in case of intact BBB, but will also easily reach the healthy brain parenchyma, causing a standard amount of background uptake.

*‘Unknown’ means no human immunohistochemical studies have been found for the specific transporter / receptor.

Not a transporter / receptor but an isoform of the enzyme pyruvate kinase

Abbreviations: A1AR, adenosine A1 receptor; A2AAR, adenosine A2A receptor; AQP1/4, aquaporin-1/4; AR, androgen receptor; ASCT, anti-neutral amino acid transporter; BBB, blood-brain barrier; C, cytoplasm; CHT1, high-affinity choline transporter-1; CTL1, choline transporter-like protein-1; Ctr1, copper transporter-1; CXCR4, C-X-C motif chemokine receptor 4; DAT, dopamine active transporter; EGFR, epidermal growth factor receptor; ENT-1, equilibrative nucleoside transporter-1; FAP, fibroblast activation protein; GLUT, glucose transporter; GRPR, gastrin releasing peptide receptor; IDH, isocitrate dehydrogenase; LAT1, large neutral amino acid transporter; MCT1/4, monocarboxylate transporter-1/4; PM, plasma membrane; PROT, proline transporter; PSMA, prostate-specific membrane antigen; SGLT2, sodium-glucose cotransporter-2; SMCT1/2, sodium monocarboxylate cotransporter-1/2; SSTR1-5, somatostatin receptor-1 to -5; TSPO, translocator protein; WHO, World Health Organization.


Glucose uses both the facilitated diffusion glucose transporter (GLUT) family and the sodium-glucose linked transporter (SGLT) family to enter brain cells. Due to increased glycolysis and the TCA cycle, these transporters are upregulated in brain tumor cells, resulting in high concentrations of glucose inside the cell that facilitate energy production (10, 43). 18F-FDG and 18F-Me-4DFG are two glucose analogues that use the increased number of glucose transporters to image brain tumor cells. 18F-FDG mainly uses GLUT-1 and to a lesser extent GLUT-3, both which are present on the BBB (Table 2); after entering the cell, it is phosphorylated and becomes trapped as 18FDG-6-phosphate (Figure 2). 18F-Me-4FDG uses SGLT2, which is not present on the healthy BBB, rather only on endothelial cells of tumor vasculature (Table 3); after entering the cell it becomes trapped without phosphorylation (Figure 2). In clinical practice, uptake of either agent will reflect overexpression of the transporters and therefore (indirectly) increased energy metabolism. The BBB does not hamper the uptake of 18F-FDG, and the uptake of 18F-Me-4FDG will additionally reflect increased tumor vasculature +/− BBB leakage. Since energy metabolism generally increases with increasing malignancy grade, 18F-FDG has often been used to differentiate between WHO grades, and recently even between IDH-mutated and IDH-wildtype tumors (44). It can also help differentiate tumor recurrence from treatment-related changes, and recent radiomics techniques with also show promise in predicting Ki-67 expression and patient prognosis non-invasively (45, 46). The main limitation of 18F-FDG lies in the generically high rate of glucose metabolism in the healthy cerebral cortex, leading to low tumor-to-normal-tissue (T/N) ratios for most tumors except those with very high cellular density and metabolic rate, like lymphoma (47). 18F-Me-4FDG does not have this problem since it does not cross the healthy BBB, causing a very low uptake in healthy brain tissue and consequently high T/N ratio, which is its main advantage over 18F-FDG (Figure 3) (48). For both agents, a major limitation is their intrinsic low tumor specificity: increased glucose consumption is also seen in other non-oncological processes such as (acute) inflammatory tissue, although 18F-Me-4FDG might prove more tumor-specific due to its inability to cross the BBB (49).

Fig 2

Figure 2. Illustration showing uptake mechanism and assimilation process of nutrient-based PET agents. See also main text. The grey box represents the cytoplasm, while the yellow box represents mitochondria. Green arrows represent metabolic route of specific PET agent, while black arrows represent metabolic route of associated nutrient / building block, and green-black arrows a similar route for PET agent and nutrient / building block. Red text / arrows show brain tumor cell-specific metabolic alterations. Of note, although 11C-MCYS is a derivative of the amino acid cysteine, it is analogous to 11C-MET and therefore grouped together with 11C-MET in this illustration.
Abbreviations: LAT, large neutral amino acid transporter; IDO, indoleamine 2,3-dioxygenase; ASCT, anti-neutral amino acid transporter; CKα, choline kinase alpha; CoA, acyl coenzyme A; G6P, glucose-6-phosphate; HIF, hypoxia-inducible factors; IDH, isocitrate dehydrogenase; PEP, phosphoenolpyruvate; PKM2, pyruvate kinase M2; PROT, proline transporter; SMCT, Na+ monocarboxylate cotransporter; MCT, monocarboxylate transporter; CHT1, high-affinity choline transporter; CTL, choline transporter-like protein; OCT / OCTN, organic cation transport proteins; GLUT, glucose transporter; SGLT, sodium-glucose linked transporter; TCA, tricarboxylic acid.

Fig 3

Figure 3. 18F-Me-4FDG PET (left), T1-weighted post-contrast (middle) and 18F-FDG PET (right) images of a patient with an anaplastic astrocytoma, WHO grade III. The 18F-FDG image shows mixed uptake within some portions of the mass, with highest uptake comparable to normal cortical uptake in the healthy contralateral cortex. The 18F-Me-4FDG image, however, shows uniform tumor uptake without any uptake in the surrounding healthy brain parenchyma, providing significantly higher T/N ratio than the 18F-FDG image. This figure is reproduced – with new figure legend appropriate for current book chapter – from Kepe et al. (2018), Figure 4, under the terms of the Creative Commons Attribution 4.0 International License ( (48).


Amino acids enter cells through a variety of transporters, the most important of which are system L (LAT) and system ASCT (alanine/serine/cysteine-preferring transporters) (50). LAT1 and ASCT2 in particular have been found overexpressed in brain tumor cells and are therefore the main targets for PET agents (Figure 2) (51). In the brain, LAT1 is mainly expressed by tumor cells and endothelial cells, facilitating easy BBB crossing of PET agents that use this transporter, while LAT2 is also expressed in non-tumor cells, and ASCT is minimally expressed in normal brain. On the other hand, ASCT1 and -2 are not expressed on endothelial cells and therefore do not facilitate transport across the BBB (50, 52). Both types of transporters can also be found in other pathological tissues like (chronic) inflammatory B- and T cells. After entering the cell, PET agent assimilation depends on whether the amino acid’s molecular structure has been significantly altered (Figure 2). Although all amino acid based agents, especially those using LAT1-2, have some background uptake because they can be used for energy production and protein synthesis in healthy brain parenchyma, or become part of healthy cellular amino acid pools, this is significantly less than 18F-FDG (50, 53).

LAT-dependent agents

Of the eight amino acid-based agents using LAT transporters, 11C-MET, 11C-TYR, 18F-FDOPA, 18F-FAMT and 18F-FIMP are currently believed to solely use LAT1, which is mainly expressed on tumor- and endothelial cells and will therefore easily cross the BBB. After entering the tumor cell, only 11C-MET and 11C-TYR become incorporated into proteins, and to a lesser extent into phospholipids and DNA, especially 11C-MET (Figure 2) (54, 55). In clinical practice, uptake of these two agents will reflect overexpression of LAT1 as well as (for 11C-MET partial) increased protein synthesis indicative of increased metabolism. One must keep in mind that uptake of PET agents such as 11C-MET may also potentially reflect a contribution from a more nonspecific process such as blood-brain barrier disruption that can occur with benign brain pathologies such as vascular lesions, posttreatment changes, tumefactive multiple sclerosis, and infection (56). 18F-FDOPA and 18F-FAMT do not become incorporated into proteins but instead stay inside the cytoplasmic amino acid pool (Figure 2); uptake in practice will therefore reflect LAT1 overexpression similar to 11C-MET and 11C-TYR but with only indirect evidence for increased protein synthesis (57–59). An additional disadvantage of 18F-FDOPA is its incorporation into dopaminergic neuron metabolism, causing high uptake in the basal ganglia that can significantly limit tumor assessment (60). However, 18F-FDOPA reportedly shows greater contrast for lesions outside the striatum when compared to 18F-FET (61). Of note, there is evidence suggesting that LAT1 expression alone does not entirely explain intensity variation in uptake of 18F-FDPOA in brain tumors (57).

Moreover, like 11C-MET discussed above, 18F-FDOPA is another example of a PET agent that has been shown to localize to pseudotumoral brain lesions possibly due to blood-brain barrier permeability, macrophage response, and/or adjacent reactive astrogliosis (61, 62). 18F-FIMP is a new agent that shows higher accumulation in higher-grade gliomas compared to lower grades and non-gliomas in a small first-in-human study, and might be better retained in the cytoplasm than e.g., 18F-FET below (63). The limited data so far, however, are unclear regarding its assimilation: it is not incorporated into proteins but whether it solely becomes trapped in the cytoplasm or is partially metabolized is as yet unknown (64). Uptake in clinical practice is therefore so far similarly interpreted as for 18F-FDOPA and 18F-FAMT. 11C-MCYS and 18F-FET use either LAT1 or LAT2 which is also expressed in non-tumor cells; after entering the tumor cell, they stay inside the cytoplasmic pool (Figure 2). It is assumed that 18F-FET transport is mediated predominantly by use of the LAT1 transporter, since LAT2 transporters are not expressed on the luminal side of the BBB (65). The use of LAT2 may account for the disappointing results of 11C-MCYS in a recent animal study, showing significantly higher healthy brain parenchymal uptake than 11C-MET, even though preliminary human results were promising (54, 66, 67). In clinical practice, uptake can be interpreted similar to 18F-FDOPA and 18F-FAMT with the addition of LAT2 overexpression. Interestingly, 18F-FET is one of the only amino acid-based agents for which time-activity curves, reflective of dynamic uptake, provide additional information on tumor grading and prognosis (68, 69). This suggests that the uptake mechanism may be slightly different from the other agents and although the main route of uptake uses the LAT1 transporter, studies also point to uptake using the Na+-dependent amino acid transporter B0,+ and b0,+This uptake mechanism is dependent on the specific cell type and the differences between intracellular and extracellular amino acid concentrations (70). 18F-OMFD is a metabolite of 18F-FDOPA with very limited and dated information on uptake and clinical value and will therefore not be discussed.

Even more advanced kinetic analysis will be necessary to interpret uptake of 11C-AMT. This agent, similar to its associated amino acid tryptophan, enters cells through LAT1 and is not only used for protein synthesis but can also be incorporated into the kynurenine pathway (71). In tumors, upregulation of this pathway by increased activity of one or both of its two main enzymes, indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO), plays a key role in escaping the body’s immune response to the tumor (Figure 1 and Figure 2). Although IDO overexpression is mainly a characteristic of low-grade astrocytic tumors, uptake of 11C-AMT can be seen in both low- and high-grade tumors. This suggests that the factors influencing uptake in low- and high-grade brain tumors might be different, with increased IDO activity dominating uptake in low-grade tumors, while increased transport of 11C-AMT into tumor cells might dominate in high-grade tumors. In clinical practice, uptake will reflect either an upregulated kynurenine pathway associated with immunosuppression, or increased transport due to LAT1 overexpression / increased vasculature, depending on the tumor type. High uptake in contrast-enhancing tumor regions is strongly prognostic for overall survival (72). A drawback is its extensive use for protein synthesis in healthy brain parenchymal cells, decreasing T/N ratios to levels quite similar to 18F-FDG (73, 74). The outlier 18F-FBPA is not an amino acid but selectively uses LAT1 to gain access to the tumor cell (Figure 2). It was primarily created to assess efficacy of boron neutron capture therapy with boronophenylalanine (BPA) in various tumor types, including gliomas (75, 76). It may be more tumor-specific than agents that also rely on LAT2 for access to cells (77). Nevertheless, subsequent studies have questioned whether FBPA can accurately estimate BPA distribution considering its distinct molecular structure, and it is relatively unstable with fast deboronation. 18F-FBY (fluoroboronotyrosine) has recently been introduced as a more stable alternative; it is a boron-derived tyrosine using the same LAT1 transporter, and while it is amino acid-based (tyrosine) it will not be recognized as such by the cell due to its aberrant structure and will therefore be quickly excreted instead of becoming either trapped in the cytoplasm or incorporated (Figure 2), which leads to a lower background activity than other amino acid-based agents. In addition, like other agents using the LAT1 transporter, uptake will not depend on BBB permeability; indeed, 18F-FBY uptake has been seen in non-enhancing brain tumor areas and shows a pattern distinct from the pattern of enhancement. Uptake will therefore primarily reflect overexpression of the LAT1 transporter. An additional advantage is that FBY can be used for treatment by substituting 18F for 19F for boron neutron capture therapy; however, treatment results with this agent have not yet been published (78, 79).

ASCT-dependent agents

Only three agents – 18F-FGln, 11C-ACBC and 18F-FACBC – use ASCT(2) transporters. Although ASCTs are absent on endothelial cells, all three agents have shown to readily cross the BBB, probably through LAT transporters. Their main advantage over LAT-associated agents stems from the fact that ASCTs are minimally expressed in normal brain, leading to very low uptake in healthy tissues (Figure 4) (80). After entering the tumor cell, only 18F-FGln becomes incorporated into proteins; 11C-ACBC and 18F-FACBC (also called 18F-Flucoclovine), two non-natural amino acid-based agents, cannot be used in metabolic pathways and will instead be trapped in the cell (Figure 2) (29). In clinical practice, uptake of all three agents will reflect overexpression of ASCT2 (and LAT for crossing the BBB); direct evidence for increased protein synthesis however is only seen for 18F-FGln uptake (49, 52, 81, 82).

Fig 4

Figure 4. T1-weighted post-contrast (A), FLAIR (fluid-attenuated inversion recovery; B), 11C-MET PET (C) and 18F-FACBC PET (D) images of a patient with diffuse astrocytoma, WHO grade II, IDH mutated. The conventional MR images show a poorly enhancing lesion with some high signal surrounding the lesion. Although increased PET agent uptake can be seen in a small part of the tumor on both the 11C-MET and 18F-FACBC PET images, this case also illustrates the relatively high uptake of the natural amino acid-based 11C-MET in the healthy brain parenchyma compared to the unnatural amino-acid based 18F-FACBC which can result in decreased T/N ratios. This figure is reproduced – with new figure legend appropriate for current book chapter – from Tsuyuguchi et al. (2017), Figure 1 Case 1, under the terms of the Creative Commons Attribution License ( (80).

Non-LAT, non-ASCT PET agents

Three amino acid-based agents use transporters other than LATs or ASCTs. 18F-FSPG crosses the plasma membrane through system xCT- (Figure 2), a glutamate/cystine exchanger which is absent from the BBB and becomes overexpressed in response to increased levels of ROS, a byproduct of tumor-upregulated metabolic pathways (Figure 1). Although background uptake is very low, in clinical practice uptake will reflect at least increased BBB permeability, with or without increased oxidative stress / ROS production and indirectly increased metabolic activity (83). Tumor cell specificity however may be higher than other amino acid-based agents because system xCT is not expressed on inflammatory cells (49). There are also significant differences in the uptake curves of primary brain tumors, though not metastases, of lesions with good versus poor outcomes (84). D-cis-18F-FPro is transported across the plasma membrane via the proline transporter PROT. Uptake is thought to represent pathological cell death / necrosis (Figure 2), as opposed to the apoptosis-targeting PET agent 18F-ML-10 (see paragraph ‘PET agents targeting multiple pathways’). However, conflicting results regarding its transport through the BBB currently restrict any certain statements regarding its uptake in clinical practice (85). 11C-MeAIB uses the system A neutral amino acid transporter to gain access to the tumor cell, after which it becomes trapped (Figure 2) (86). In addition to the natural amino acids alanine, serine and cysteine, the system A transporter accepts MeAIB (an artificial amino acid) as a unique substrate, and it becomes overexpressed with increasing proliferation rate and malignant transformation in several carcinoma cell lines (87, 88). While considered ubiquitously present on mammalian cells, not much is known about the location of system A transporters in the brain except that it is present on the abluminal membrane of the bovine BBB, which explains the poor penetration of 11C-MeAIB through the BBB. In a sole clinical study, 11C-MeAIB could differentiate between low-grade and high-grade astrocytoma with higher T/N ratios than 11C-MET; however, no other studies have been performed since, perhaps because uptake will likely be highly dependent on BBB permeability (86).


Like choline, 11C-choline and 18F-FCho enter brain cells mainly through high-affinity choline transporter 1 (CHT1) and choline transporter-like proteins 1 and 3 (CTL1/3), are subsequently phosphorylated to phosphocholine by choline kinase alpha (CKα) and become incorporated into fatty acids, facilitating cell membrane synthesis (Figure 1 and Figure 2). Increased cellular uptake in brain tumors is caused by both increased expression of CTL1 and increased activity of CKα, facilitating the growing demand for membrane building blocks and energy (89, 90). CTL1 is present on the BBB (Table 3) so uptake will not depend on BBB permeability. In addition, healthy brain cells are generally in a non-dividing state, requiring little choline and thereby causing a very low background uptake (91). Nonetheless, vascularity does seem to play a role in uptake since BBB-lacking tissues as well as benign highly vascularized tumors (e.g., meningiomas) show highest uptake even though their cellular proliferation rates are generally low (92, 93). This might also explain the increased uptake seen in abscesses and other inflammatory processes, further lowering tumor specificity (94). However, there is potential clinical benefit in metabolic post-operative assessment for residual tumor and treatment response assessment in diffuse non-enhancing gliomas where quantitative MRI is limited (95, 96). In clinical practice, uptake will reflect overexpression of CTL1 and/or increased CKα activity and fatty acid synthesis, while vascularity needs to be taken into account.

11C-acetate crosses the plasma membrane through either sodium monocarboxylate cotransporter (SMCT) or monocarboxylate transporter (MCT), the latter of which is present on the BBB (Figure 2 and Table 3). After entering the cell, it becomes primarily incorporated into fatty acid synthesis and the TCA cycle. Increased lactate can further increase uptake of 11C-acetate by hetero-exchange through the MCT transporters; consequently, uptake in patients has been most pronounced in fast-growing, high-grade tumors, although reports vary whether the agent can differentiate between tumor grades (97, 98). In clinical practice, uptake will reflect upregulation of both transporters, fatty acid synthesis and (especially) energy metabolism (99, 100). Drawbacks are the use of (11C-)acetate by healthy brain cells, causing significant background uptake, and uptake in non-tumor tissue like necrotic/fibrotic and granulomatous tissue due to unknown mechanisms (98).

13N-ammonia freely diffuses across the plasma membrane, and once inside the cell becomes converted with glutamate into glutamine by the enzyme glutamine synthetase (GS; Figure 1 and Figure 2) which can subsequently be used for amino acid synthesis. Although GS has been shown to be overexpressed in glioblastomas, it is also abundantly present in normal and reactive astrocytes, causing high uptake in healthy brain tissue, especially cerebral cortex. In addition, the agent does not easily cross the BBB. In clinical practice, uptake will reflect at least increased BBB permeability, with or without increased expression of GS and amino acid synthesis (101).


One relatively new agent is not based on glucose, amino acids, or other nutrients, but does target an associated pathway. 18F-DASA-23 binds to pyruvate kinase M2 (PKM2), an isoform of the enzyme pyruvate kinase which catalyzes the last step in glycolysis by converting phosphoenolpyruvate to pyruvate (Figure 1). Contrary to the M1 isoform, PKM2 can be dynamically controlled in its activity, a feature that tumor cells use – via oncogenes c-Myc and HIF-1 – to regulate their need for either anabolic or catabolic metabolism. PKM2 is found ubiquitously in human cells except in muscle, liver and brain, and is preferentially expressed in all types of cancers; in brain tumors, PKM2 expression is mildly increased in grade I to II gliomas but highly expressed in glioblastomas (102). The agent can readily cross the BBB and binding to PKM2 is slowly reversible; however, it is unclear how it is taken up inside the cell, either through a transporter or via passive diffusion (Figure 2). In clinical practice, uptake will therefore reflect PKM2 expression and therefore glycolytic status within tumor tissue alone, with a potential but as yet unknown role of the transport mechanism across the cell membrane. This agent could be of lar interest considering the therapeutic efforts of targeting PKM2 for various diseases including cancer over the last couple of years (103). A first clinical study showed significant binding of 18F-DASA-23 in brain tumors with a high T/N ratio, and a follow-up clinical study is underway (Table 1) (104).


All four nucleoside-based agents – 18F-FLT, 11C-4DST, 18F-FMAU and 11C-TdR – are based on thymidine, which pairs with adenine in the DNA double helix and is therefore directly involved in cellular proliferation. These agents use equilibrative nucleoside transporter 1 (ENT1) to enter cells (Figure 5). Although ENT1 is present throughout the brain including endothelial cells (Table 3), none of these agents can readily cross the BBB leading to a high T/N ratio. In clinical practice, uptake of either agent will therefore reflect at least increased BBB permeability next to ENT1 overexpression (105). After entering the cell, most become phosphorylated by thymidine kinase 1 (TK1), which is cell-cycle dependent and therefore upregulated in tumor cells, or TK2, which is restricted to mitochondria and is cell-cycle independent. Only 18F-FLT and 11C-4DST interact with TK1: 18F-FLT subsequently becomes trapped in the cytoplasm because it lacks an essential hydroxyl group, causing uptake to indirectly reflect increased cellular proliferation, while 11C-4DST becomes incorporated into DNA, thereby directly reflecting increased DNA synthesis and proliferation (Figure 5) (105). Kinetic analyses will be necessary to distinguish uptake due to disrupted BBB from that due to increased cellular proliferation(106), decreasing their sensitivity for brain tumor cells compared to amino acid agents like 11C-MET and 18F-FET (Figure 6), and they should not be used for e.g., recurrent non-enhancing brain tumors (107, 108). However, uptake of 18F-FLT has been shown to differentiate between grade III and IV gliomas, and is sometimes seen in non-enhancing areas on MRI, suggesting not all uptake is BBB-related; it has also been suggested that even a small number of glioma cells can cause BBB disruption without additional contrast agent leakage (108, 109). Tumor uptake of 18F-FLT can also be used to predict tumor progression in meningiomas (110). Background uptake of 11C-4DST is paradoxically high compared with 18F-FLT, and it has not been studied much (111). 18F-FMAU becomes phosphorylated by TK2, raising the question whether uptake really reflects cellular progression, while 11C-TdR is not used anymore because of its high catabolism into 11C-CO2 which causes significant background uptake.

Fig 5

Figure 5. Illustration showing uptake mechanism and assimilation process of the nucleoside-based PET agents. See also main text. The grey box represents the cytoplasm, while the blue box represents the nucleus. Green arrows represent metabolic route of specific PET agent, while black arrows represent metabolic route of associated nutrient / building block, and green-black arrows a similar route for PET agent and nutrient / building block. Red text / arrows show brain tumor cell-specific metabolic alterations.
Abbreviations: ARF, ADP ribosylation factor; ATRX, alpha thalassemia / mental retardation syndrome X-linked; DNA, deoxyribonucleic acid; ENT, equilibrative nucleoside transporter; MGMT, O6-methylguanine-DNA-methyltransferase; MDM, E3 ubiquitin-protein ligase; Rb, retinoblastoma protein; TERT, telomerase reverse transcriptase; TK, tyrosine kinase.

Fig 6

Figure 6. T1-weighted post-contrast (cT1), T2-weighted (T2), 18F-FLT PET ([18]F-FLT) and 18F-FET ([18]F-FET) images of a patient with a non-enhancing glioblastoma, WHO grade IV. The lesion is hyperintense on the T2-weighted image but does not show contrast enhancement. Increased uptake in the T2-hyperintense region can clearly be seen on the 18F-FET PET image, but there is no uptake visible on the 18F-FLT PET image, illustrating the drawback of PET agents that cannot easily cross the BBB. This figure is reproduced – with new figure legend appropriate for current article – from Nowosielski et al. (2014), Figure 1, under the terms of the Creative Commons Attribution 4.0 International (CC BY) License ( (107).


68Ga-PSMA, 18F-DCFPyL and 89Zr-Df-IAB2M specifically bind to the prostate-specific membrane antigen (PSMA), a receptor thought to induce VEGF-independent angiogenesis in pathological conditions like tumors (Figure 7). PSMA is variably expressed on tumoral blood vessels and tumor cells depending on the tumor type, while no expression is seen on healthy brain parenchymal cells or normal vessels (Table 3); BBB transport will therefore depend on the tumor type (112). Preliminary studies showed high T/N ratios due to the virtually non-existent uptake in the healthy brain. Since all tested tumors showed contrast enhancement, this also raises the question whether uptake on PET images is not simply representative of increased BBB permeability without any role of PSMA. This hypothesis is strengthened by early reports on high uptake in enhancing radiation necrosis and ischemia (113, 114), although more recent studies have demonstrated the ability to distinguish recurrent high-grade gliomas from radiation necrosis (115). In clinical practice, with the limited data so far, uptake will likely reflect BBB permeability, overexpression of PSMA on endothelium or tumor cell (depending on tumor grade), or a combination of both. 68Ga-PSMA is used most often because of its extensive use in prostate cancer, while 18F-DCFPyL is similar but uses 18F as radionuclide. 89Zr-Df-IAB2M is a small part of the PSMA antibody and shows faster clearance, thereby achieving higher T/N ratios than the other two agents (116).

Fig 7

Figure 7. Illustration showing binding mechanism and associated signaling pathways of PET agents that become bound to receptors / transporters. See also main text. The grey box represents the cytoplasm, while the yellow and blue boxes represent mitochondria and nucleus, respectively. Green arrows represent binding of specific PET agent, while black arrows represent signaling pathway of receptor. Red text / arrows show brain tumor cell-specific alterations. Not shown for the sake of clarity: positive effect of adenosine / adenosine receptor pathway on tumor invasion and migration, as well as on suppressing immune reaction to the tumor.
Abbreviations: A1AR, adenosine A1 receptor; A2AAR, adenosine A2A receptor; AKT, protein kinase B; AQP, aquaporin; ARF, ADP ribosylation factor; ATRX, alpha-thalassemia / mental retardation syndrome X; CXCR4, C-X-C motif chemokine receptor 4; CXCL12, C-X-C motif chemokine ligand 12; EGF, epidermal growth factor and EGFR, its receptor; EMT, epithelial-mesenchymal transition; FAP, fibroblast activation protein; GLUT, glucose transporter; GRP, gastrin releasing peptide and GRPR, its receptor; MAPK, mitogen-activated protein kinase; MDM, E3 ubiquitin-protein ligase; MGMT, O6-methylguanine-DNA-methyltransferase; MMP, matrix metalloproteinase; mTORC, mechanistic target of rapamycin complex 1; NFκB, nuclear factor kappa-B; PI3K, phosphatidylinositol 3-kinase; PSMA, prostate-specific membrane antigen; PTEN, phosphatase and tensin homolog; Rb, retinoblastoma protein; ROS, reactive oxygen species; SSTR, somatostatin receptor; TERT, telomerase reverse transcriptase; TNF-α, tumor necrosis factor alpha; TSPO, translocator protein; VEGF, vascular endothelial growth factor and VEGFR, its receptor.

The arginine-glycine-aspartic acid (RGD)-based PET agents 18F-galacto-RGD, 18F-FPPRGD2, 18F-RGD and 68Ga-PRGD2 bind to the receptor integrin αvβ3, which is not expressed on healthy brain parenchymal cells but specifically on tumor endothelial cells and, to a slightly lesser extent, on tumor cells themselves (Table 3). In glioblastomas, it promotes tumor cell migration and invasion, angiogenesis, and multiple signaling pathways like the PI3K-AKT pathway leading to cell proliferation (Figure 7). It has also been observed on activated macrophages, suggesting a role within the tumor microenvironment (117, 118). Given the limited clinical data thus far, uptake in clinical practice can reflect overexpression of αvβ3 on endothelial cells related to angiogenesis, and/or BBB permeability with overexpression of αvβ3 on tumor cells related to a pathway such as angiogenesis, and/or presence of activated macrophages within the tumor microenvironment (119). Future studies, if feasible, will be necessary to elucidate their clinical implications.


Hypoxia is one of the hallmarks of more malignant, treatment-resistant tumor tissue. Five PET agents (18F-EF5, 62Cu2+-ATSM, 18F-FAZA, 18F-FRP170 and 18F-FMISO) use this feature to become trapped inside the tumor cell. These agents passively diffuse across the plasma membrane and become reduced to radical anions, a process which is reversible in normoxia and permanent in hypoxia. This leads to macromolecular binding and cellular trapping (Figure 8) (120, 121). 18F-FMISO, 18F-EF5 and 62Cu2+-ATSM are relatively lipophilic and consequently have no difficulty crossing the BBB and plasma membranes, but do so relatively slowly. In the case of 18F-EF5, this leads to prolonged high background uptake which significantly restricts its use, while for 18F-FMISO several hours between injection and PET imaging are necessary for optimal T/N ratios. 62Cu2+-ATSM is similarly lipophilic, but instead of binding to macromolecules it undergoes further dissociation into H2-ATSM and free Cu+, the latter of which can be used by the tumor cell in angiogenesis and protein synthesis (Figure 8) (120). Conflicting results from preclinical and clinical studies regarding the relation between uptake and cellular hypoxia markers, however, have so far limited its use (122). 18F-FAZA and 18F-FRP170 are more hydrophilic and therefore have more difficulty crossing plasma membranes; however, when successful they do so relatively fast. Their advantage is the faster clearance rates resulting in little to no uptake in healthy tissue. In the case of 18F-FAZA, this comes at the cost of an unclear role of BBB permeability; nevertheless, retention of this agent will solely depend on the hypoxic condition in the tumor tissue (121).

Fig 8

Figure 8. Illustration showing uptake mechanism and assimilation process of nucleoside-based, hypoxia- and miscellaneous (transporter-targeting) PET agents. See also main text. The grey box represents the cytoplasm. Green arrows represent metabolic route of specific PET agent, while black arrows represent metabolic route of associated nutrient / building block, and green-black arrows a similar route for PET agent and nutrient / building block. Red text / arrows show brain tumor cell-specific metabolic alterations.
Abbreviations: Ctr, copper transporter; NFκB, nuclear factor kappa-B; PS, phosphatidylserine; TME, tumor microenvironment; VEGF, vascular endothelial growth factor.

18F-FMISO and 18F-FAZA have been most successful; uptake of these agents (either dynamic or static ratios) has been correlated with immunohistochemical hypoxia markers (123). However, due to their different uptake mechanisms, clinical use and image interpretation differ substantially. For 18F-FMISO, uptake in clinical practice is thought to solely reflect decreased pO2 or hypoxia, and is therefore almost exclusively seen in more malignant tumors (124). Considering its slow clearance from the blood, timing of acquisition after injection is still an area of much debate – varying between 90 minutes and 4 hours in literature – as is the choice between static and dynamic imaging, the latter providing more quantitative measurements (40, 125, 126). Interestingly, while 18F-FMISO is considered to only accumulate in severely hypoxic tissue, uptake partially overlaps with areas of increased metabolism, suggesting that at least parts of these hypoxic areas are still viable (38, 127, 128). For 18F-FAZA, uptake in clinical practice will likely reflect hypoxia, with an additional role of BBB permeability, the extent of which is still not clear. It has a superior blood clearance compared with 18F-FMISO and therefore a higher image contrast. Several preclinical studies have suggested that redox-disbalancing metabolic changes other than hypoxia might play a role in FAZA retention, such as fatty acid metabolism and oncogene expression (129).


Unlike transporters, receptors are often connected to a variety of different intracellular pathways. Hence, most PET agents targeting receptors will therefore indirectly target multiple pathways, like the ones discussed below.

Somatostatin-based (receptor-targeting) agents

Somatostatin binds to one of 5 different somatostatin receptors (SSTRs), of which SSTR1 and -2 are most abundant in the brain (Table 3) (130). In tumors, SSTR activation exerts an anti-tumor effect, interfering with PI3K- and MAPK pathways and VEGF (Figure 1), and inhibiting cell cycle progression; therefore, overexpression can be seen in low-grade tumors like meningiomas and oligodendrogliomas (130, 131). 68Ga-DOTATATE, 68Ga-DOTATOC and 68Ga-DOTANOC are based on the somatostatin analog octreotide and mainly target SSTR2, especially 68Ga-DOTATATE (Figure 7). None of these agents can cross the intact BBB; uptake in clinical practice will therefore reflect at BBB permeability +/- overexpression of SSTR2, and increased uptake in meningiomas has been associated with faster growth although no correlation was found with tumor grade (132134). Among brain tumors, 68Ga-DOTA-SSTR is by far the most commonly used PET agent in the evaluation of meningiomas, and pituitary adenomas are the second most common indication (135). Tumor specificity is somewhat limited due to the abundance of SSTRs in the pituitary gland and (variably) on inflammatory (T and B) cells and macrophages (136).

Growth factor-based (receptor-targeting) agents

68Ga-BBN and 11C-PD153035 target growth factor receptors. 68Ga-BBN binds to the gastrin releasing peptide receptor (GRPR), which is involved in PI3K- and MAPK pathways (amongst others) that ultimately lead to glycolysis, fatty acid synthesis and cell progression (Figure 1 and Figure 7). Both low- and high-grade gliomas overexpress GRPR (Table 3) and have shown high uptake of 68Ga-BBN irrespective of grade; however, healthy brain parenchyma shows very low uptake even though neurons express GRPR (Table 3). This suggests that the agent does not cross the BBB even though non-enhancing low-grade tumors do show uptake (137). In clinical practice, uptake might therefore reflect increased cellular metabolism and progression, however with an unclear role of the BBB. Interestingly, Li et al. modified 68Ga-BBN to include a near-infrared fluorescent dye creating a dual-modality imaging probe known as 68Ga-IRDye800CW-BBN that allowed for both preoperative imaging with PET and fluorescent-guided surgery resulting in improved intraoperative glioblastoma visualization and optimal resection (138). 11C-PD153035 binds to the epidermal growth factor receptor (EGFR), which is involved in pathways similar to GRPR, contributes to tumor cell progression and invasiveness (Figure 7), and is overexpressed in a majority of primary glioblastomas. 11C-PD153035 was able to cross the BBB and showed high uptake in EGFR-overexpressing tumors, but its popularity was short-lived, perhaps because therapeutic targeting of EGFR has been disappointing (139).

Adenosine-based (receptor-targeting) agents

18F-CPFPX and 18F-FLUDA both target adenosine receptors. Adenosine and its receptors have multiple roles in the brain, including activation of microglia/macrophages and neurons, regulation of the immune response, and modulation of neurotransmitter release and neuronal plasticity. In brain tumors, increased levels of adenosine – created by the tumor microenvironment, e.g., hypoxia – are thought to inhibit T cells leading to immune response evasion; the effect of adenosine on tumor cell proliferation (through the MAPK signaling pathway) has been more controversial, with equal reports on anti-tumor effects (140). 18F-CPFPX is a specific ligand for the adenosine receptor A1AR (Figure 7) and in one preliminary study showed uptake restricted to the peritumoral tissue, suggesting a possible cellular reaction of this tissue to infiltrating tumor cells; however, T/N ratios were low and the at that time ambivalent role of adenosine receptors likely precluded further investigations (141). 18F-FLUDA was introduced more recently and is a specific ligand for the adenosine receptor A2AAR which has the highest expression in the striatum where it interacts with dopamine signaling (142). More than A1AR this receptor plays a crucial role in inflammatory processes involving microglia. 18F-FLUDA also specifically links with B-lymphocytes and a recent first-in-human study demonstrated the potential to distinguish primary central nervous system lymphomas from glioblastoma (143). Nevertheless, whether these agents readily cross the BBB is as yet unknown, precluding clear statements on uptake interpretation.

Translocator protein (TSPO) agents

11C-PK11195 and 18F-DPA-714 selectively bind to the mitochondrial translocator protein (TSPO) located on the outer mitochondrial membrane (Figure 7). In the brain, TSPO helps maintaining homeostasis and is thought to be involved in steroidogenesis through intramitochondrial cholesterol metabolism (producing ROS as a byproduct). Although its role in oncogenesis has yet to be elucidated, it has been found overexpressed in neurological diseases associated with neuroinflammation – being upregulated in pro-inflammatory microglia/macrophages and astrocytes in preclinical studies – and its presence is increased in glioblastomas tumor microenvironment (144146). In gliomas, overexpression is associated with a higher malignancy grade, increased invasiveness and a poor survival. Interestingly, due to the high expression of TSPO on inflammatory cells including those recruited by the tumor (like glioma-associated microglia/macrophages), TSPO-targeting agents might be able to directly visualize the tumor microenvironment (Table 3) (147). Both agents can passively diffuse across the BBB so uptake will not depend on BBB permeability, but how they subsequently reach the cell nucleus is less clear, limiting clear statements on uptake interpretation (147149).

While not targeting the mitochondrial membrane, 18F-FDHT does target a receptor inside the tumor cell, namely androgen receptor (AR), a nuclear membrane receptor that is translocated into the nucleus after binding with 5α-dihydrotestosterone (derivative from testosterone in males and dehydroepiandrosterone in females). Within the nucleus, it functions as nuclear transcription factor, facilitating transcription of genes promoting cellular growth and survival. AR has been found overexpressed in glioblastoma nuclei and surrounding tumor-associated arteries. Although the exact role of AR in brain tumorigenesis has not been elucidated yet, AR antagonists have been shown to suppress MYC expression, suggesting a role in tumor cell maintenance and proliferation (Figure 7) (150, 151). A preliminary study showed uptake in glioma and a very low target-to-background ratio; however, whether the agent crosses the BBB and how it enters tumor cells is unknown, limiting clear statements on uptake mechanisms and its clinical interpretation (Table 1) (152).

Transporter-targeting agents

Three targeted transporters also indirectly target multiple pathways. For entering tumor cells 124I-CLR1404 uses lipid rafts, dynamic domains within the plasma membrane that are overexpressed on tumor cells and support a variety of signaling pathways. 124I-CLR1404 is thought to cross the BBB through passive diffusion – although there have been some contradictory results – and becomes trapped once inside the tumor cell. In clinical practice, uptake will reflect lipid raft overexpression and indirectly upregulation of their associated pathways, with a yet uncertain role for the BBB (Figure 8). Although CLR1404 can also be labeled with 131I for therapeutic options, mild uptake in benign treatment-related brain parenchymal changes may lower specificity of this agent and limit its (theragnostic) use (153155). 18F-ML-10 enters apoptotic cells that are characterized by externalized phosphatidylserine (PS) and an intact plasma membrane (Figure 8), features not present in necrotic, dying cells. The agent does not seem to cross the intact BBB. In clinical practice, uptake will therefore likely reflect BBB permeability +/- increased apoptotic rates. High apoptotic rates, however, are common in both tumor tissue and tissue treated with radiotherapy or e.g., ischemia, decreasing tumor specificity of this agent as well (156). 64CuCl2 enters cells through the Ctr1 copper transporter after which it becomes directly incorporated into cellular pathways in the same way as Cu+ released from 62Cu2+-ATSM (Figure 8). The agent has the added advantage of being both a diagnostic agent (β+ decay) and a therapeutic agent (Auger electrons). Nonetheless, how 64CuCl2 crosses the BBB, if it does at all, is not known yet, and its use has remained limited to two somewhat older clinical studies (157).

Miscellaneous agents

For some additional agents, uptake mechanisms are less clear. 11C-TGN-020 is a ligand for aquaporins (AQP) 1 and 4, water channel proteins that play a role in cerebrospinal fluid absorption and regulation of BBB permeability; in brain tumors they stimulate angiogenesis, BBB permeability, tumor cell migration and invasion (Figure 1 and Figure 7) (158). AQPs are only present on dural and vascular membranes and neurons (Table 3), causing low healthy brain uptake of 11C-TGN-020 (Figure 9). The role of AQPs in tumor invasion and microvascular proliferation suggests 11C-TGN-020 could improve differentiation between tumor grades (Figure 9); however, so far only WHO grade III and IV astrocytomas have been studied (159). If and how this agent crosses the BBB is not known yet, although AQPs have been described next to the BBB (Table 3). 68Ga-citrate binds to transferrin in blood, and this complex subsequently binds to the transferrin receptor TFRC after which it most likely becomes endocytosed (Figure 7) (160). TFRC plays an essential part in iron homeostasis, is often overexpressed on brain tumor cells (at least partly because of MYC overexpression) and thought to stimulate multiple tumor cellular pathways by supplying the necessary increased amounts of iron as building block (Figure 1) (161). Tumor specificity, whether the agent crosses the BBB, and what happens after the 68Ga-citrate-transferrin complex is endocytosed inside the cell however remain to be seen (160).

Fig 9

Figure 9. T2-weighted MR (left) and 11C-TGN-020 PET (right) images of two patients with an astrocytoma WHO grade III (top row) and glioblastoma WHO grade IV (bottom row), respectively. Both tumors show a high T/N ratio; in addition, uptake in the glioblastoma is more intense than in the WHO grade III tumor. This figure is reproduced – with new figure legend (with permission) appropriate for current article – from Suzuki et al. (2018), Figure 1, under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs license ( (159).

Fibroblast activation protein (FAP) inhibitor (FAPI) PET imaging using 68Ga-(DOTA)-FAPI or 18F-FAPI is only recently being explored. FAP is a cell membrane-bound glycoprotein with serine protease activity that can cleave proteins in the surrounding tissue allowing for protein degradation and matrix remodeling. In tumors, it promotes cellular proliferation, migration and invasion, angiogenesis, and immune suppression through several pathways, not all of which have been completely elucidated (Figure 1 and Figure 7). It is generally absent or shows very low expression in normal cells, but is a universal marker of tumor-associated fibroblasts (162). In extracranial tumors, 68Ga-(DOTA)-FAPI and 18F-FAPI can target these fibroblast within the tumor microenvironment (163). Fibroblasts are not present in brain (tumors); however, it does appear that there are FAP-positive cells such as FAP-positive foci of neoplastic cells in gliomas and FAP-positive vessels in glial tumors, and FAP seems to be overexpressed in most glioblastomas. Neither agent crosses the BBB, so uptake in clinical practice will reflect at least BBB permeability, possibly combined with FAP overexpression (164). One advantage is that FAPI agents have low background activity in the brain parenchyma (165). There is some initial evidence suggesting that FAPI agents may be helpful in distinguishing between low-grade IDH-mutant and high-grade gliomas (166).

68Ga-Pentixafor targets C-X-C motif chemokine receptor 4 (CXCR4). CXCR4 is a transmembrane receptor that is involved in multiple physiological processes such as embryogenesis, neoangiogenesis, hematopoiesis and inflammation. In tumors, the interaction of CXCR4 and its ligand CXCL12 (C-X-C motif chemokine ligand) plays a critical role in tumor cell growth and survival, angiogenesis, and regulation of interactions between tumor cells and the TME (Figure 7) (167). The receptor is overexpressed in numerous human tumor types, including glioblastoma and lymphoma, and is associated with poorer progression-free survival and overall survival (168). Recent studies have demonstrated 68Ga-Pentixafor uptake in glioblastoma and primary central nervous system lymphoma on PET and the agent may have therapeutic potential if labelled with 177Lu or 90Y (169, 170). A recent histopathologic study on glioblastoma tissue samples, however, showed a large inter- and even intra-tumoral variation in CXCR4 expression, and an inconsistent correlation between ex vivo CXCR4 expression and in vivo uptake of 68Ga-Pentixafor (171). In addition, the agent cannot cross the intact BBB. These factors bear the question to what extent uptake reflects BBB permeability versus CXCR4 overexpression.

82Rb-chloride is an analog of potassium and enters cells through the sodium-potassium pump or Na/K-ATPase found ubiquitously in human cells as well as tumor cells. Next to maintaining cellular ionic homeostasis, the Na/K-ATPase is also involved in many intracellular pathways affecting cellular proliferation, motility and apoptosis; in glioblastomas its overexpression sustains growth and invasion (Figure 8) (172). Although the agent can penetrate the BBB from extracellular fluid, uptake does depend on BBB integrity since no uptake is seen in healthy brain parenchyma. After entering cells, retention depends at least partly on ATP-driven transport of the Na/K-ATPase. In clinical practice, uptake will therefore likely reflect a combination of vascularization rate, BBB permeability, and efficiency of Na/K-ATPase (173). All three of these factors are often higher in malignant tumors as compared to benign tumors, which may allow for differentiation between malignant and benign gliomas. However, due to its non-specificity, 82Rb-chloride uptake can be seen in both tumors and other lesions such as AVMs (174).


Three agents were initially developed for imaging of other pathologic processes such as inflammation (18F-FDS), Parkinson’s disease (18F-FP-CIT) and Alzheimer’s disease (11C-PiB). Their mechanisms of interaction and assimilation within brain tumor cells are unclear, and data on brain tumor uptake is limited to case reports. 18F-FDS showed uptake in spindle cell carcinoma of the pituitary gland, although the confounding effect of BBB leakage in this case was unclear (175).18F-FP-CIT has shown uptake in meningiomas, although the cause of its uptake and role of the dopamine active transporter (DAT) in meningioma oncogenesis is still unknown(176).11C-PiB binds β-amyloid in PET-imaging of Alzheimer’s disease but has also shown uptake in meningiomas. A lack of uptake in other tumors suggests 11C-PiB may be able to differentiate between meningiomas and other brain tumor types; however, the general absence or minimal presence of β-amyloid within meningioma suggests uptake might primarily be due to high vascularity (177).


Interpretation of PET agent uptake in brain tumors remains complex. This is due in part to the various factors influencing uptake, such as transporter / receptor expression in non-tumorous tissues, BBB permeability, and metabolic incorporation versus ‘inactive’ trapping. For many agents, these factors have not been completely elucidated. In addition, knowledge on oncogenesis improves rapidly, shedding new light on brain tumor development and emphasizing molecular pathways that are not targeted by existing PET agents. Finally, although the Response Assessment in Neuro-Oncology working group (RANO) published guidelines for the use of a few common PET agents for glioma imaging, many countries allow PET agents that have been used in clinical studies to be synthesized and used in the associated institution’s clinical practice, as long as the institution can substantiate it may improve patient care, increasing exposure of clinical radiologists to these often less well-known PET agents.(178) We hope that this monograph of PET agents used for human brain tumors has contributed to a better understanding of uptake mechanisms and their clinical implications. None of the PET agents described have been shown to be the ‘ideal’, tumor-specific agent. Perhaps in the future, simultaneous PET/MRI, combining the advantages of conventional and molecular MR imaging with targeted PET imaging, could prove the optimal combination for brain tumor diagnosis, treatment monitoring and follow-up.

Conflict of Interest: The authors declare no potential conflict of interest with respect to research, authorship and/or publication of this article.

Copyright and Permission Statement: The authors confirm that the materials included in this chapter do not violate copyright laws. Where relevant, appropriate permissions have been obtained from the original copyright holder(s), and all original sources have been appropriately acknowledged or referenced. Where relevant, informed consent has been obtained from patients or their caregivers according to applicable national or institutional policies.


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