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Cover of PET Agents for Primary Brain Tumor Imaging

PET Agents for Primary Brain Tumor Imaging

, MD, PhD, , MD, PhD, , MD, PhD, and , MD.

Author Information and Affiliations
Brisbane (AU): Exon Publications; .
ISBN-13: 978-0-6458663-0-8

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.

INTRODUCTION

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.

UNDERSTANDING UPTAKE OF PET AGENTS

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

Table 1

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

GENETIC CHANGES IN BRAIN TUMORS

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

Table 2

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

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).

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.

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 (more...)

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).

ATRX & TERT

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).

ENERGY METABOLISM IN BRAIN TUMORS

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

Table 3

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

GLUCOSE-BASED AGENTS

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).

Figure 2. Illustration showing uptake mechanism and assimilation process of nutrient-based PET agents.

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 (more...)

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.

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 (more...)

NATURAL AND NON-NATURAL AMINO ACID-BASED AGENTS

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 (5759). 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).

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.

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 (more...)

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).

OTHER NUTRIENT-BASED AGENTS

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).

AGENTS NOT BASED ON GLUCOSE OR OTHER NUTRIENTS

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).

PET AGENTS TARGETING CELL CYCLE PROGRESSION

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.

Figure 5. Illustration showing uptake mechanism and assimilation process of the nucleoside-based PET agents.

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 (more...)

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.

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. (more...)

PET AGENTS TARGETING ANGIOGENESIS

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).

Figure 7. Illustration showing binding mechanism and associated signaling pathways of PET agents that become bound to receptors / transporters.

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 (more...)

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.

PET AGENTS TARGETING THE TUMOR MICROENVIRONMENT

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).

Figure 8. Illustration showing uptake mechanism and assimilation process of nucleoside-based, hypoxia- and miscellaneous (transporter-targeting) PET agents.

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 (more...)

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).

PET AGENTS TARGETING MULTIPLE PATHWAYS

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).

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.

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...)

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).

PET AGENTS ‘INCIDENTALLY’ FOUND TO ACCUMULATE IN BRAIN TUMORS

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).

CONCLUSION

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.

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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.

Doi: https://doi​.org/10.36255​/pet-agents-for-primary-brain-tumor-imaging

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

Dr. Lance T. Hall is a Nuclear Medicine and Molecular Imaging physician. He has extensive clinical and research experience in molecular imaging of central nervous system disease processes and is the principle investigator of first-in-human and first-in-child clinical trials evaluating novel molecular imaging agents in brain tumors.

Dr. Anja van der Kolk is a radiologist and clinician-scientist, and an expert in MR and PET imaging of neurological diseases, in particular brain tumors. Her current research includes metabolic imaging of primary brain tumors and epilepsy, and non-invasive imaging of neuroinflammation, both at ultrahigh field (7 tesla) MRI.

Dr. Dylan Henssen is a resident in radiology and nuclear medicine, as well as a clinician-scientist with a primary focus on experimental neuro-imaging. Utilizing both MRI and PET, Dr. Henssen investigates neuro-oncological and neurodegenerative disorders. His current research also encompasses the early health technology assessment of Artificial Intelligence applications in clinical imaging for neuro-oncological diseases.

Dr. Harry W. Schroeder III is a diagnostic radiologist and nuclear medicine physician. He was trained as a physician-scientist in biochemistry and biophysics, currently enjoys his clinical work and teaching residents at an academic medical center, and provides PET/CT image analysis for oncology clinical trials.

PET Agents for Primary Brain Tumor Imaging

ISBN: 978-0-6458663-0-8

DOI: https://doi.org/10.36255/pet-agents-for-primary-brain-tumor-imaging

Authors and affiliation

Anja G van der Kolk, MD, PhD

Department of Medical Imaging, Radboudumc, Nijmegen, the Netherlands

Donders Center for Cognitive Neuroscience, Nijmegen University, Nijmegen, the Netherlands

Dylan Henssen, MD, PhD

Department of Medical Imaging, Radboudumc, Nijmegen, the Netherlands

Harry W Schroeder III, MD, PhD

Department of Radiology and Imaging Sciences, Emory University, Atlanta, GA, USA

Lance T Hall, MD

Department of Radiology and Imaging Sciences, Emory University, Atlanta, GA, USA

Published by

Exon Publications, Brisbane, Australia

Copyright© 2023 Exon Publications

Copyright of the monograph belongs to the authors. The authors grant unrestricted publishing and distribution rights to the publisher. The electronic versions of the monograph is published under Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). https://creativecommons.org/licenses/by-nc/4.0/. Users are allowed to share and adapt the monograph for any non-commercial purposes as long as the authors and the publisher are explicitly identified and properly acknowledged as the original source. The monograph in its entirety is subject to copyright by the publisher. The reproduction, modification, replication and display of the monograph in its entirety, in any form, by anyone, for commercial purposes are strictly prohibited without the written consent of the publisher.

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The views and opinions expressed in this monograph are believed to be accurate at the time of publication. The publisher, editors or authors cannot be held responsible or liable for any errors, omissions or consequences arising from the use of the information contained in this monograph. The publisher makes no warranty, implicit or explicit, with respect to the contents of this monograph, or its use.

First Published in December 2023

Copyright© 2023 Exon Publications.

Copyright of individual chapters belongs to the respective authors. The authors grant unrestricted publishing and distribution rights to the publisher. The electronic versions of the chapters are published under Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). https://creativecommons.org/licenses/by-nc/4.0/. Users are allowed to share and adapt the chapters for any non-commercial purposes as long as the authors and the publisher are explicitly identified and properly acknowledged as the original source. The book in its entirety is subject to copyright by the publisher. The reproduction, modification, replication and display of the book in its entirety, in any form, by anyone, for commercial purposes are strictly prohibited without the written consent of the publisher.

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