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Novel Positron Emitting Radiopharmaceuticals

  • Mirkka SarparantaEmail author
  • Dustin W. DemoinEmail author
  • Brendon E. CookEmail author
  • Jason S. LewisEmail author
  • Brian M. ZeglisEmail author
Living reference work entry

Latest version View entry history

Abstract

Over the past two decades, nuclear imaging has transformed cancer care. Positron emission tomography (PET) and single photon emission computed tomography (SPECT) can provide clinicians with functional and biochemical information about tumor tissue that complement the anatomical data acquired through magnetic resonance imaging (MRI) and computed tomography (CT). In this chapter, we highlight a number of emerging radiotracers in oncology that are currently employed in clinical trials in the USA and worldwide yet are awaiting regulatory approval in the USA. The radiotracers discussed range from small molecule probes that target cellular transport mechanisms and metabolic pathways to antibody-based agents that target cell-surface receptors. In order to help the reader appreciate the diversity and potential of each of these imaging agents, we present the underlying mechanisms of each agent’s targeting and trapping in tumor tissue and provide examples of clinical studies in diverse cancer types as well as descriptions of the utility of each tracer for staging and treatment monitoring.

Keywords

Nuclear imaging Oncology Positron emission tomography, PET Single photon emission tomography, SPECT Radiotracer Imaging agent Fluorine-18 Carbon-11 Gallium-68 Zirconium-89 Technetium-99m Indium-111 Amino acid transport Lipid biosynthesis Cellular proliferation Somatostatin receptor Integrin Bombesin receptor Prostate-specific membrane antigen, PSMA Steroid hormone receptor Hypoxia 

Glossary

[123I]MIBG

[123I]-meta-iodobenzylguanidine

[18F]DCFBC

N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-4-[18F]fluorobenzyl-L-cysteine

[18F]FACBC

anti-1-amino-3-18F-fluorocyclobutane-1-carboxylic acid

[18F]FDG

[18F]2-fluoro-2-deoxyglucose

[18F]FDHT

16ß-[18F]fluoro-5-dihydrotestosterone

[18F]FDOPA

L-3,4-dihydroxy-6-[18F]fluorophenylalanine

[18F]FES

16a-[18F]fluoro-17ß-estradiol

[18F]FET

O-(2-18F-fluoroethyl)-L-tyrosine

[18F]FGln

4-[18F]-(2S,4R)fluoroglutamine

[18F]FLT

3’-deoxy-3’-[18F]fluorothymidine

[18F]FMISO

[18F]-fluoromisonidazole, 1-fluoro-3-(2-nitroimidazol-1-yl)-propan-2-ol

[18F]RGD-K5

[18F]flotegatide-RGD

18F-AH111585

[18F]fluciclatide

18F-alfatide II

[18F]AlF-NOTA-E[PEG4-c(RGDfk)]2

64Cu-ATSM

64Cu-diacetyl-bis(N4-methylsemicarbazone)

68Ga-PSMA

Glu-urea-Lys-(Ahx)-[68Ga(HBED-CC)]

AACD

Aromatic amino acid decarboxylase

AR

Androgen receptor

ASCT

Alanine-serine-cysteine transporter

BB2

Bombesin receptor subtype-2

BB2r

Bombesin receptor subtype-2

ChoK

Choline kinase

CNS

Central nervous system

COMT

Catechol-o-methyl transferase

CT

Computed tomography

DOTA

1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid

DTPA

Diethylenetriaminepentaacetic acid

ER

Estrogen receptor

FAS

Fatty acid synthase

GRPr

Gastrin-releasing peptide receptor

IMRT

Intensity-modulated radiation therapy

LAT1

L-type amino acid transporter 1

MRI

Magnetic resonance imaging

MTC

Medullary thyroid cancer

mTOR

Mammalian target of rapamycin

NET

Neuroendocrine tumor

NSCLC

Non–small cell lung cancer

OC

Octreotide

PEG

Polyethylene glycol

PET

Positron emission tomography

PET/MRI

Positron emission tomography/magnetic resonance imaging

PSA

Prostate-specific antigen

PSMA

Prostate-specific membrane antigen

RGD

Arginine-glycine-aspartic acid

SHBG

Steroid hormone-binding globulin

SPECT

Single photon emission computed tomography

SSR

Somatostatin receptor

SST

Somatostatin

SSTr

Somatostatin receptor

SUV

Standardized uptake value

TATE

Octreotate

TCA

Tricarboxylic acid

TK

Thymidine kinase

TOC

Tyr3-octreotide

TTPmin

Minimum time to peak

Introduction

Over the past two decades, nuclear imaging has transformed cancer care. Both positron emission tomography (PET) and single photon emission computed tomography (SPECT) have empowered clinicians with imaging tools capable of providing functional and biochemical information about tissues that complement the anatomical maps created by magnetic resonance imaging (MRI) and computed tomography (CT). A remarkable array of radiotracers has been created that enables the visualization of targets ranging from the expression of biomarkers by individual cancer cells to the pH of the tumor microenvironment.

The most widely used radiotracer in oncology – [18F]2-fluoro-2-deoxyglucose, [18F]FDG – is only one of a few PET radiopharmaceuticals that has been approved by the US Food and Drug Administration. Yet despite its utility, [18F]FDG is limited in many cases and cannot possibly be expected to fulfill all of the imaging needs of clinicians as we enter the era of personalized medicine. As a result, recent years have played witness to ever-increasing efforts toward the development and translation of novel, molecularly targeted imaging agents. In this chapter, we will focus on radiopharmaceuticals that have reached a particularly critical point in their journey from bench to bedside: imaging agents that have been the subject of multiple clinical trials but have yet to be approved by regulatory agencies for routine clinical use. While a multitude of radiopharmaceuticals have reached the clinic in some capacity, we have chosen to discuss a handful of particularly promising agents as case studies. We truly believe that these radiotracers represent the next generation of clinical nuclear imaging agents. We have organized these imaging agents into three groups according to their target: (I) the machinery of cellular metabolism and biosynthesis, (II) cell surface receptors, and (III) the tumor microenvironment, with a focus on imaging hypoxia. Importantly, the intrinsic technological advantages of PET over SPECT – principally the former’s quantitative output and higher resolution – mean that over the past half decade (the time span covered by this chapter), the vast majority of newly translated radiopharmaceuticals have been PET tracers. As a result, this chapter will focus on these agents.

Before we begin, we believe that a brief tutorial on the anatomy of a radiotracer is in order (Fig. 1). Broadly speaking, the vast majority of radiopharmaceuticals are composed of two parts: a targeting vector and a radioisotope. A wide range of molecules has been employed as vectors, including small molecules, peptides, proteins, antibodies, and nanoparticles (and even whole cells!). A similarly varied array of radioisotopes has been used. In this arena, two physical considerations are particularly important: the type of radioactive emission and the half-life of decay. While SPECT radiotracers employ gamma-emitting isotopes such as 111In and 99mTc, PET agents use positron-emitting nuclides such as 18F, 64Cu, and 68Ga. Radioisotopes with half-lives ranging from 9.97 min (13N) to 4.18 days (124I) have been employed in radiotracers. A key consideration is matching the physical half-life of the radioisotope to the pharmacokinetic half-life of the targeting vector. As a result, short-lived isotopes such as 11C (t1/2 = 20.4 min) and 18F (t1/2 = 110 min) are typically used for radiolabeling small molecules, while long-lived nuclides such as 89Zr (t1/2 = 78.4 h) and 111In (t1/2 = 67.3 h) are more commonly employed for radiolabeling proteins and antibodies. Finally, the chemistry of radionuclides plays an important role in the design of radiotracers. While nonmetallic radioisotopes such as 11C, 15O, 18F, and 124I can often be incorporated directly into the structure of the radiotracer (e.g., [15O]H2O or [11C]CO2), radiometals such as 111In, 68Ga, and 89Zr require that a metal chelator (e.g., DOTA or desferrioxamine) be attached to the vector in order to stably coordinate the radiometal in vivo.
Fig. 1

The basic anatomy of a radiotracer (a) as well as three different strategies for the design of radiotracers: the direct replacement of an atom in the parent molecule with a radioactive isotopologue (b), the use of a small structural modification to create a “handle” for the incorporation of a radioisotope (c), and the use of a chelator along with a radiometal (d)

Targeting Cellular Transport, Metabolism, and Proliferation

Overview

The aberrant growth of cancer cells results in numerous metabolic changes that can be targeted for diagnostic imaging. A classic example of a metabolism-targeting radiotracer is [18F]2-fluoro-2-deoxyglucose ([18F]FDG), a radiolabeled glucose analog that is avidly taken into cancer cells trying to meet their augmented energy requirements by increasing the expression of glucose transporters. Unfortunately, however, because of the ubiquitous role of glucose as an energy source, the increased uptake of [18F]FDG is not a phenomenon specific to cancer cells. Needless to say, this deficiency has spurred significant interest in the development of new, more tumor-selective radiotracers. Over the last decade, several small-molecule radiotracers specific for various metabolic pathways have been developed and clinically evaluated with promising results. Broadly speaking, these tracers can be divided into two groups: (i) radiolabeled amino acids and amino acid analogs that target amino acid transport and metabolism and (ii) acetate, choline, and analogs thereof that target lipid biosynthetic pathways. It is important to note that many of these radiotracers were originally developed for other purposes and only recently have been reevaluated for oncologic imaging. For example, [11C]acetate was initially created for imaging cardiac oxidative metabolism, while L-3,4-dihydroxy-6-[18F]fluorophenylalanine ([18F]FDOPA) was developed for imaging dopaminergic neurons in the central nervous system. Lastly, we will highlight the potential for imaging proliferating tumor cells using 3′-deoxy-3′-[18F]fluorothymidine ([18F]FLT), a nucleoside analog that is taken up and retained in proliferating cells without incorporation into DNA.

Imaging Amino Acid Transport and Metabolism

Amino acids are vital sources of carbon and nitrogen and are precursors for the biosynthesis of proteins. Thus, they are an extremely valuable commodity to rapidly proliferating tumor cells. In order to accommodate the increased need for these molecular building blocks, cancer cells often overexpress cell membrane-bound amino acid transporters [1]. Radiolabeled amino acids and their analogs are therefore enticing options for the development of cancer-specific radiotracers. Although radiolabeled amino acids can participate in a variety of metabolic processes, the currently available amino acid radiotracers exclusively visualize the upregulation of transporter expression and the rate of amino acid uptake [2]. More specifically, the amino acid transporter systems known to be upregulated in various cancers are the ASC transporter 2 (ASCT2) and L-type amino acid transporter 1 (LAT1) systems [3, 4]. ASCT2 is responsible for the Na+-dependent transport of small neutral amino acids – such as alanine, serine, and cysteine (which give the abbreviated name of the transporter) – and is the principal route for the uptake of glutamine. LAT1, in contrast, transports bulky, hydrophobic payloads including leucine, phenylalanine, and tyrosine. The overexpression of amino acid transporters in cancer cells induces nutrient-sensitive mTOR (mammalian target of rapamycin) signaling pathways, resulting in the upregulation of cell growth and proliferation [4]. In addition, unlike in normal cells, the metabolism of cancer cells relies on ASCT2-transported glutamine, which is used as a carbon source for the synthesis of tricarboxylic acid (TCA) cycle intermediates and to maintain pools of nonessential amino acids [5]. The transporter-mediated uptake of amino acid radiotracers and their postulated participation in cellular processes are presented in Fig. 2.
Fig. 2

The transport mechanisms of amino acid radiotracers and the postulated routes of their downstream participation in cellular processes

The radiolabeled amino acids currently in clinical use include 11C-labeled L-[11C-methyl]methionine ([11C]methionine), anti-1-amino-3-18F-fluorocyclobutane-1-carboxylic acid ([18F]FACBC), 3,4-dihydroxy-6-[18F]fluorophenylalanine ([18F]FDOPA), and O-(2-18F-fluoroethyl)-l-tyrosine (18F[FET]). Moreover, out of the many radiofluorinated analogs of glutamine evaluated to date, 4-[18F]-(2S,4R)fluoroglutamine ([18F]FGln) looks to be the most promising candidate for clinical translation. The structures of these amino acid radiotracers are shown in Fig. 3. As the reader will note, all of these tracers are radiolabeled with the short-lived positron-emitting radioisotopes 11C and 18F. It is important to note that despite their common mode of decay, there are fundamental differences between 11C- and 18F-labeled tracers, and care should be taken to select the appropriately labeled radiotracer for the purpose. Since fluorine is not a common constituent in natural compounds, the introduction of the 18F radiolabel generally yields nonidentical structural analogs in which the label is attached via substitution for another halogen, substitution for a hydroxyl group, or incorporation of an 18F-labeled prosthetic group. In contrast, most radiotracers labeled with 11C are typically chemically identical to their non-labeled counterparts, with the only difference being the replacement of a 12C atom with a 11C atom (making the two compounds isotopologues). Consequently, the pharmacokinetic and biochemical behavior of the 11C-labeled isotopologue is identical to the non-labeled parent compound, and the radiotracer undergoes transport, metabolism, and elimination in the exact same manner as the compound it “traces.” There are, however, advantages to using 18F-labeled tracers. For example, the longer physical half-life of the isotope allows for multistep syntheses and the transportation of tracers to remote imaging facilities. In addition, in some cases, the chemical differences between the natural molecule and its 18F-labeled counterparts can be useful. For example, the 18F label can block the downstream metabolism of a tracer after it has entered a cell, resulting in intracellular accumulation and higher tumor signal. By far the best example of this phenomenon is the trapping mechanism of [18F]FDG.
Fig. 3

The structures of selected amino acid radiotracers

One metabolism-targeting radiotracer provides a particularly good example of a case in which a drastic structural modification to the tracer facilitates metabolic trapping. The alicyclic amino acid [18F]FACBC – a compound in which the amino and carboxylic acid termini are joined by a nonnatural 18F-substituted cyclobutane – is still recognized and transported into cells by ASCT2, but the cyclobutane moiety renders the compound immune to subsequent metabolism [6]. To date, [18F]FACBC has been evaluated in clinical studies primarily for the imaging of prostate cancer. Prostate cancer imaging is a particularly promising application of [18F]FACBC, as it takes advantage of the low background accumulation of the tracer in the urinary bladder [7]. In recent clinical trials in patients with primary prostate cancer from Emory University, the National Cancer Institute, and Uppsala University in Sweden, [18F]FACBC uptake was found to correlate well with intraprostatic lesions, while metastases remained largely undetected (Fig. 4) [8, 9, 10]. Furthermore, Schuster et al. originally reported a good correlation between [18F]FACBC uptake and histopathology and the Gleason score. However, later reports have challenged this by showing nonspecific uptake of the radiotracer by B and T lymphocytes [11] and, consequently, in inflammatory lesions including prostatitis and benign prostatic hyperplasia as well as benign growths such as osteomata [12]. The sensitivity of [18F]FACBC PET toward malignant lesions was, however, drastically improved when combined with positron-emission tomography/magnetic resonance imaging (PET/MRI). The current consensus on the potential utility of [18F]FACBC PET for clinical applications is that it has potential for the diagnosis of the most aggressive prostate cancer lesions to support radiotherapy planning.
Fig. 4

Sagittal, coronal, and maximum intensity projection (MIP) [18F]FACBC PET images acquired over three time intervals in a patient with recurrent prostate cancer. Uptake can be seen in the right iliac lymph node (arrows) at a site of metastatic recurrence. Bladder activity initially is absent but moderately increases with time upon tracer excretion. Also noted is mild to moderate diffuse activity in the esophagus (arrowheads) (This research was originally published in JNM. Schuster et al. [12]. © by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Standing in stark contrast to the unnatural [18F]FACBC, 11C-labeled methionine (L-[11C-methyl]methionine) is a radiotracer in which the radiopharmaceutical is chemically identical to the natural amino acid. Developed in the 1970s as part of a series of 11C-labeled amino acid tracers for the assessment of the rate of protein synthesis, [11C]methionine is the only radiotracer from this lot in active clinical use today and can be efficiently radiolabeled in a single-step reaction using [11C]methyl iodide [13]. [11C]methionine is a substrate of the LAT1 transporter and is readily incorporated into proteins during translation. Consequently, [11C]methionine uptake in subjects with glioma and non-small cell lung cancer (NSCLC) has been shown to correlate with both tumor microvessel density (i.e., the upregulation of LAT1) and proliferative capacity (i.e., the rate of tracer incorporation into cells) [14, 15]. Due to their high expression levels of LAT1 and prominent exocrine activity, both healthy liver and pancreas display high uptake of [11C]methionine, limiting the utility of the tracer to visualize neoplasms in those organs [16, 17]. In contrast, the background accumulation of [11C]methionine in the brain is low. As a result, the tracer’s greatest potential lies in the imaging of tumors of the CNS (Fig. 5). Current clinical use of [11C]methionine for the diagnosis and post-treatment follow-up of brain tumors is widespread in both Europe and Japan, where several clinical studies have established the potential of 11C-methionine PET for the sensitive and specific diagnosis of primary gliomas. This allows for the identification of the proliferating tumor margin, which is important for radiotherapy planning [18]. The uptake of [11C]methionine in gliomas may also be used as a survival factor, as initially low tracer uptake correlates with a more favorable prognosis [19]. However, reliable correlation between tracer uptake and the grade of the disease has not been achieved. Additionally, [11C]methionine has been shown to aid in differentiating between tumors and radiation necrosis in conjunction with anatomical imaging modalities MRI and CT (Fig. 6).
Fig. 5

Dynamic changes in [11C]methionine accumulation in various brain malignancies. (a) Oligodendroglioma, (b) anaplastic oligodendroglioma, (c) meningioma, (d) diffuse astrocytoma, (e) anaplastic astrocytoma, (f) glioblastoma, and (g) malignant lymphoma (Reproduced with permission from Springer from Aki et al. [146])

Fig. 6

The MRI, PET, and fused images depicting differences in [11C]methionine uptake in a brain tumor (a) and an area of radiation necrosis (b) (Reproduced with permission from Springer from Glaudemans et al. [18])

18F-labeled o-(2-[18F]-fluoroethyl)-l-tyrosine ([18F]FET) is another nonnatural amino acid that localizes into tissues via LAT1-mediated transport [20]. Unlike [11C]methionine, however, [18F]FET cannot be incorporated into proteins and is thus considered non-metabolic. [18F]FET is commonly prepared either using a two-step synthesis based on 18F-labeled fluoroethyltosylate and a protected tyrosine or a single-step reaction using an ethyltosylate-substituted tyrosine precursor [21, 22]. As with [11C]methionine, clinical studies with [18F]FET have focused on tumors of the CNS, for which radiolabeled amino acids seem to offer the advantage of low background uptake compared to [18F]FDG [23]. Dynamic [18F]FET imaging has proven to be especially useful in patients with glioma, as differences in the kinetic parameters of [18F]FET uptake allow for the differentiation between low-grade and high-grade gliomas. The time-activity curves for [18F]FET uptake in low-grade and high-grade gliomas from the study of Pöpperl et al. [24] are presented in Fig. 7. More recently, select kinetic parameters – including the minimum time to peak (TTPmin) – have been proposed to derive quantitative data from dynamic [18F]FET imaging for the grading and functional characterization of primary brain tumors [25].
Fig. 7

Differences in the uptake kinetics of [18F]FET in subjects with low-grade (WHO II) and high-grade (WHO III) gliomas. In the latter, a sharp peak in the SUV at early time points after administration can be seen (Reproduced with permission from Springer from Pöpperl et al. [24])

A fluorinated analog of the brain-permeable dopamine precursor L-dihydroxyphenylalanine (L-DOPA) – L-3,4-dihydroxy-6-[18F]-fluorophenylalanine ([18F]FDOPA) – was first developed for the study of changes in dopaminergic signaling in the brains of patients with Parkinson’s disease [26]. Unlike other fluorinated amino acid analogs, [18F]FDOPA is readily metabolized in vivo in the same manner as natural L-DOPA by catechol-o-methyl transferase (COMT) and aromatic amino acid decarboxylase (AACD) to yield 3-O-methyl-6-[18F]-fluoro-l-dopa ([18F]3-OMFDOPA) and [18F]6-fluorodopamine ([18F]FDA), respectively (Fig. 8) [27]. Recently, [18F]FDOPA PET has been explored in oncology for the diagnosis of neuroendocrine tumors (NET). NETs are often challenging imaging targets, as the tumors are small and dispersed and constitute a metabolically and biologically diverse group. The current clinical standards for the diagnostic imaging of NETs are somatostatin receptor (SSR)-targeted PET/CT, [18F]FDG, and SPECT with [123I]-meta-iodobenzylguanidine ([123I]MIBG) or 111In-pentetreotide. The preferential uptake of [18F]FDOPA in NETs is a result of the ability of the tumors to synthesize and store biogenic amines and polypeptide hormones [28]. The NET lesions most efficiently delineated with [18F]FDOPA PET are those that originate from the chromaffin cells of the adrenal medulla (pheochromocytomas), paragangliomas of the sympathetic nervous system, and medullary thyroid cancer (MTC) [29]. Figure 9 shows a pancreatic NET lesion that remains completely undetected by [18F]FDG but is clearly visualized with [18F]FDOPA. Comprehensive comparisons between SSR PET/CT and [18F]FDOPA are scarce, but in general, a higher tumor burden is detected with SSR PET/CT [30]. Despite these alternative techniques, the utility of [18F]FDOPA PET/CT imaging in NET is highlighted in cases with variable or low SSR expression like medullary thyroid carcinoma or in which a closer metabolic dissection of the tumor is warranted [31]. In CNS tumors, including high-grade glioma, [18F]FDOPA has been shown to yield comparable results to [18F]FET in tumor delineation [32]. However, widespread clinical use of [18F]FDOPA is currently limited by its complex radiosynthesis and the low specific activity of the compound when synthesized via electrophilic radiofluorination. As a result, only a handful of institutes worldwide have access to high specific activity [18F]FDOPA [33]. Thankfully, this is expected to change in the future due to recent developments in the automated enantioselective synthesis of [18F]FDOPA from 2-[18F]fluoro-4,5-dimethoxybenzyl iodide using a phase transfer catalyst [34].
Fig. 8

The metabolic fates of [18F]FDOPA. 3-O-Methyl-6-fluoro-l-dopa (3-OMFDOPA), 6-fluorodopamine (FDA), L-3,4-dihydroxy-6-fluorophenylacetic acid (FDOPAC), and 6-fluorohomovanillic acid (FHVA) (Figure redrawn from Vallabhajosula [27], with permission from Elsevier)

Fig. 9

[18F]FDG and [18F]FDOPA PET images of a patient with a low-grade metastatic pancreatic neuroendocrine tumor showing the lack of [18F]FDG tumor detection and the positive [18F]FDOPA uptake in the lesion (Reprinted from Minn et al. [29], with permission from Elsevier)

As a source of both carbon and nitrogen, glutamine is a vital feedstock for a number of biosynthetic pathways in cancer cells. This efficient use of glutamine by cancer cells is achieved by the upregulation of glutamine transporters on the cell membrane as well as the increased expression of mitochondrial glutaminase that drives the synthesis of glutamate from glutamine to feed the TCA cycle [35]. The creation of a PET tracer for glutamine-based imaging has required the careful consideration of radiolabeling strategies. The seemingly obvious choices for a radiolabel are 11C and 13N (t1/2 = 9.97 min) both of which could yield chemically identical isotopologues of glutamine. However, in addition to the synthetic challenges posed by the short physical half-lives of the two radioisotopes, 11C- and 13N-labeled glutamine radiotracers undergo rapid degradation and elimination of the radiolabel from the tracer in tumor cells as a result of glutaminolysis.

This has left 18F-radiofluorinated glutamine analogs as the only feasible alternative. The most promising 18F-labeled glutamine analog – 4-[18F]-(2S,4R)fluoroglutamine ([18F]FGln) – was recently evaluated for the imaging of gliomas in a pilot, open-label human microdosing study [36]. The uptake of [18F]FGln in gliomas was comparable to [18F]FDG, though the uptake of [18F]FGln in healthy brain was markedly lower (Fig. 10). As a result, the use of [18F]FGln was proposed over [18F]FDG due to its improved contrast. However, later studies revealed that [18F]FGln is prone to defluorination in vivo in humans, a problem which could result in the deposition of high concentrations of 18F-fluoride in the bone. Studies investigating new [18F]fluoropropyl-substituted derivatives as alternatives to [18F]FGln with more selective radiosyntheses and improved in vivo stability are underway [37]. The final utility of glutamine-based radiotracers in oncology will remain unknown until these tracers become widely available for clinical studies. Nevertheless, glutamine PET holds great promise as a novel tool for metabolic imaging in oncology.
Fig. 10

[18F]FGln PET shows uptake in glioma under progression of the disease in a patient with a IDH1m oligodendroglioma (ak) and a patient with a glioblastoma (gk). T1-weighted MRI with contrast enhancement (a or g), fusion image of [18F]FGln PET/CT (b or h) of CT (d or j) and [18F]FGln PET (e or k), and [18F]FDG PET image (c or i) showing the utility of [18F]FGln PET in delineating tumor (indicated by red arrows) from the background brain activity and tumor surgical cavity (white dotted line). The standard uptake values (SUV) of [18F]FGln corresponding to tumor uptake (black squares) and blood clearance (clear circles) plotted over time (f). Comparison of [18F]FGln (blue bars) and [18F]FDG (red bars) illustrates differences in background uptake with both radiotracers in normal brain (top panel) and tumor-to-brain ratios from three clinically stable glioma patients and three glioma patients with clinically progressive disease (l) (From Venneti et al. [36]. Reprinted with permission from AAAS)

Imaging Lipid Biosynthesis

In addition to glucose and amino acids, tumor cells also crave nutrients to drive the biosynthesis of the cell membrane lipids needed to sustain rapid cell division. The PET radiotracers suitable for imaging lipid biosynthesis include 11C-labeled acetate, 11C-labeled choline and its 18F-labeled analogs, 18F-fluoromethylcholine, and 18F-fluoroethylcholine (structures are given in Fig. 11).
Fig. 11

The structures of [11C]acetate, [11C]choline, [18F]fluoromethylcholine, and [18F]fluoroethylcholine

[11C]Acetate participates in the synthesis of fatty acids and is readily incorporated in phosphatidylcholine in tumor cells [38, 39]. In contrast to normal cells (in which the preferred fate for acetate is oxidative metabolism), cancer cells seem to utilize [11C]acetate almost exclusively as a building block [39, 40]. Fatty acid synthase (FAS, EC 2.3.1.85) catalyzes de novo lipogenesis: the synthesis of saturated fatty acids like myristate, palmitate, and stearate from acetyl-CoA, malonyl-CoA, and NADPH [41, 42]. FAS has been found to be upregulated in many cancers and is considered a potential target for chemotherapy, prompting the use of [11C]acetate in oncologic imaging [43]. To date, the most promising application of [11C]acetate PET lies in prostate cancer, a malignancy in which FAS upregulation is an important part of pathogenesis. Furthermore, the enzyme has been established as a measure of aggressiveness of the disease via correlation with high Gleason scores [44, 45]. Figure 12a shows a typical finding in [11C]acetate PET, in which anatomical (MRI) and histopathological findings correlate well with the uptake of the radiotracer in the primary tumor. In Fig. 12b, a representative whole-body scan of a patient with recurrent prostate carcinoma is shown to illustrate both the avid uptake of the tracer in the pancreas and liver as well as the lack of urinary excretion. These two characteristics combine to make [11C]acetate ideal for the imaging of prostate cancer but of limited value in tumors proximal to the gastrointestinal tract. In addition to the detection of primary tumors, [11C]acetate PET has been shown to be especially effective for the delineation of bone and lymph node metastases and in the diagnosis of recurrent disease with predictive value for treatment response [46, 47]. Recently, Leisser et al. showed that the predictive value of [11C]acetate PET has a positive correlation with serum PSA levels [44].
Fig. 12

(a) Imaging of a patient with prostate carcinoma – T2-weighed MRI (a), [11C]acetate PET image (b), and fused [11C]acetate PET/MRI – demonstrates low-intensity focus in right mid-gland peripheral zone (arrows). Corresponding pathology (d) confirmed tumor with a Gleason score of 3 + 4 (inked in black) (This research was originally published in JNM, Mena et al. [147]. © by the Society of Nuclear Medicine and Molecular Imaging, Inc.). b Whole-body [11C]acetate PET (a) and transaxial slices through the tumor (green line in a) of the [11C]acetate PET (b), CT (c), and fusion PET/CT (d) indicating local prostate cancer recurrence in a 74-year-old patient with serum PSA level of 2.5 ng/ml (Reprinted from Sandblom et al. [46], with permission from Elsevier)

In addition to FAS, cancer cells upregulate choline kinase (ChoK, EC 2.7.1.32), the first enzyme in the synthetic pathway for another constituent of the cell membrane: phosphatidyl choline. Consequently, 11C-radiolabeled [11C]choline and 18F-labeled choline analogs have been proposed as diagnostic agents in oncology. As with [11C]acetate, the most promising applications of both choline tracers have been found in prostate cancer, in which energy metabolism favors fatty acid oxidation. Like [11C]acetate, [11C]choline behaves in exactly the same way as natural choline: it is metabolized into 11C-labeled phosphatidyl choline and incorporated into cells. Curiously, while two of the methyl groups in choline are necessary for ChoK specificity, longer alkyl chains in the third position are well tolerated [48], allowing for the creation of 18F-labeled fluoromethyl and fluoroethyl analogs with favorable imaging properties. The vast majority of recent clinical studies has been carried out using [18F]fluoromethylcholine, which has shown potential for the detection of lymph node and bone metastasis in patients with castration-resistant prostate cancer (Fig. 13). However, contrasting observations have also been reported, warranting further studies before firmly establishing the clinical utility of 18F-fluoromethylcholine PET in the diagnosis and prognosis of prostate cancer [49]. Regardless of the tracer used, the uptake of choline in prostate cancer seems to be dependent on serum PSA levels, allowing for the detection of disease recurrence at a sensitivity exceeding 40% at serum PSA levels of 1 ng/mL [50, 51]. Moving beyond prostate cancer, the upregulation of ChoK and increased intracellular concentrations of phosphocholine have also been observed in breast and epithelial ovarian carcinomas, prompting clinical imaging studies with radiolabeled choline tracers in patients with these malignancies [52, 53]. Figure 14 shows the uptake of [11C]choline in HER2-positive breast cancer at baseline and 3 days after the initiation of trastuzumab chemotherapy, illustrating the potential value of [11C]choline PET for monitoring treatment response. That said, more studies are warranted to establish the utility of [11C]choline PET in malignancies other than prostate cancer.
Fig. 13

[18F]fluorocholine PET/CT of a patient with castration-resistant prostate cancer. A patient with relatively low tumor burden and a PSA level of 4.9 ng/mL shows areas of increased [18F]fluorocholine uptake corresponding to lesions in the thoracic spine, ribs, and iliac bone (a). In contrast, [18F]fluorocholine PET/CT from a patient with a PSA level of 28.1 ng/mL shows numerous areas of increased [18F]fluorocholine uptake in the skeleton along with the lymph nodes (arrows) in the left supraclavicular fossa, retroperitoneum, and pelvis (b). Arrows denote metastatic sites (This research was originally published in JNM. Kwee et al. [148]. © by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Fig. 14

Representative [11C]choline PET images from a patient with HER+ breast tumor showing response to trastuzumab chemotherapy (Reprinted from Kenny et al. [149]. © by the American Association for Cancer Research)

Imaging Cellular Proliferation with [18F]FLT

Elevated rates of cellular proliferation are one of the hallmarks of cancer [54]. Given that these increased rates of proliferation are often accompanied by the upregulation of free nucleotide scavenging, the latter has attracted a great deal of attention as a target for the imaging of proliferation. Radiolabeled analogs of thymidine have emerged as particularly promising imaging agents for the evaluation of cell proliferation and viability. Chosen for their exclusive incorporation into DNA rather than RNA, thymidine-based radiotracers have yielded varying degrees of success. Easily the most promising variant is 3′-deoxy-3′-[18F]fluorothymidine (FLT), modified from the original nucleoside structure via the substitution of the 3′ hydroxyl group with 18F (Fig. 15). 11C-labeled tracers such as [11C]methionine and [11C]thymidine have been proposed, but the 20-min half-life of 11C has proven to be too short for effective PET imaging [55].
Fig. 15

The structure of [18F]FLT

The structure of FLT allows it to interact with enzymes specific to nucleoside uptake, processing, and metabolism. However, the absence of a 3′ hydroxyl group prevents its incorporation into cellular DNA (3H-FLT inclusion <1%) [56]. FLT enters cells either through passive diffusion or facilitated transport via Na+-dependent channels. In a mechanism reminiscent of [18F]FDG, intracellular FLT is phosphorylated by thymidine kinase 1 (TK1) to form [18F]FLT-monophosphate. This traps the radiotracer within the cell where it can undergo further phosphorylation to form FLT-diphosphate and FLT-triphosphate [56]. TK1 activity has been found to be higher in some malignant cell lines, leading to increased retention of FLT and higher uptake within the proliferating tissue [57]. The mechanism of uptake and retention of [18F]FLT is illustrated in Fig. 16.
Fig. 16

[18F]FLT enters the cell through identical pathways to thymidine (δT), becoming phosphorylated and trapped in the cell by thymidine kinase 1 (TK1). However, FLT is not incorporated into the DNA due to the absence of a 3′ hydroxyl group

[18F]FLT PET has been utilized in dozens of clinical trials with a variety of cancers [56, 58]. One of the most common uses of [18F]FLT has been as a noninvasive tool for assessing the viability of tumors. Such scans can be administered following a cycle of chemotherapy or radiation therapy and have been repeatedly confirmed as an effective predictive measure of whether a patient will benefit from further treatment. For example, Contractor et al. found that a reduction in [18F]FLT uptake in the weeks following the treatment of breast cancer with docetaxel correlated significantly to lesion size evaluated via ultrasound and CT (P = 0.004) [59]. Such results are mirrored in nearly every case: the overall uptake of [18F]FLT decreases significantly in response to therapy, providing an effective method to monitor the progression of treatment [58].

The current clinical standard for monitoring tumor response to treatment is through the use of [18F]FDG. Not surprisingly, there are many studies comparing [18F]FLT and [18F]FDG uptake [60, 61, 62]. One potential advantage of FLT over [18F]FDG is that the former does not show increased uptake in inflammatory lesions, a common source of false-positive indications with [18F]FDG [56, 63]. Additionally, due to the low rates of proliferation in healthy brain tissue, excellent tumor-to-background ratios have been achieved in clinical trials with [18F]FLT in gliomas (Fig. 17). Furthermore, [18F]FLT is also able to significantly distinguish high- vs. low-grade tumors, while [18F]FDG was not [64].
Fig. 17

A germ cell tumor located in the right basal ganglia is obscured by background signal in the [18F]FDG PET scan (middle) and shows very slightly decreased uptake. In contrast, the [18F]FLT PET image (right) demonstrates significant uptake, revealing a malignant tumor with greater certainty than either MRI (left) or [18F]FDG (Reproduced with permission from Springer from Choi et al. [64])

Interestingly, in some instances, it has been noted that a “flare effect” can occur immediately following the administration of therapeutic agents, during which there is a marked increase in [18F]FLT uptake at the tumor. This may be due to the inhibition of de novo thymidine synthesis pathways [65]. A greater flare response was found to be associated with poorer patient prognosis and survival rate [66]. Such flares may be useful indicators to evaluate the efficacy of chemotherapy on a patient-by-patient basis.

A significant mechanistic obstacle to the widespread use of [18F]FLT is the ability of some cancers to convert deoxyuridine monophosphate to thymidine monophosphate [67]. Therefore, [18F]FLT uptake does not necessarily correlate to overall cellular proliferation but rather reflects the activity of the thymidine salvage pathway. Going forward, clarifying the relationship between cellular viability, cellular proliferation, and [18F]FLT uptake is crucial to the further clinical implementation of this imaging agent.

Targeting Cell Surface Receptors

Overview

Targeting cancer cells can also be achieved through the use of molecules that interact with cell surface receptors (Fig. 18). In this way, imaging can guide clinicians during the planning and monitoring of receptor-targeted therapies. The caveat to this approach, however, is that many of the cell surface receptors found on cancer cells are also expressed on noncancerous cells. Thus, the specific targeting of cancer cells requires that the cell surface receptor be expressed in much higher quantities on malignant cells than on healthy cells. Broadly speaking, ligands that target cell surface receptors can be subdivided into two classes: agonists, which potentiate the receptor activity, and antagonists, which bind to the receptor and render it inactive.
Fig. 18

A schematic illustrating cell surface receptor targeting with molecules designed for molecular imaging

Imaging the Expression of Somatostatin Receptors

Somatostatin receptors (SSTr) are a group of transmembrane G protein-coupled receptors that have been subdivided into five subtypes, numbered 1–5 [68]. Specifically, somatostatin subtype-2 (SST2) receptors are prevalent throughout the body (brain, pituitary gland, pancreatic islets, stomach, and kidney) [69] but are expressed in higher amounts on certain tumor types, including neuroendocrine, pituitary, breast, brain, and small cell lung cancers [70]. Naturally occurring somatostatin (SST) is a cyclic polypeptide that has been used to inspire synthetic analogs that have greater receptor affinity while retaining selectivity toward SST2 (Table 1). These compounds consist of a cyclic portion that targets the receptor along with a radiometal chelator moiety coupled to the N-terminus of the peptide sequence. In the search for optimal pharmacokinetic properties, a number of different somatostatin analogs have been created; perhaps most notably, altering the C-terminal amino acid from Thr(ol) to Thr changes octreotide (OC) to octreotate (TATE) (see Fig. 19). In addition, altering the amino acid sequence has led to some compounds that are agonists [e.g., octreotide (OC), Tyr3-octreotide (TOC), lanreotide (NOC), and vapreotide] and others that are antagonists [e.g., JR10, JR11(OPS202), and LM3]. Currently, the FDA has approved the use of 111In-DTPATOC – variously known as 111In-DTPA-Tyr3-octreotide, 111In-DTPA-pentetreotide, Octreoscan™ – for the SPECT imaging of somatostatin receptor-expressing tumors. Additionally, the United States FDA has designated an orphan drug status for 68Ga-DOTATOC in an effort to allow continued investigation of the radiopharmaceutical for the imaging of neuroendocrine tumors and carcinoids.
Table 1

Naturally occurring SST and a subset of SST2-targeting peptides used to deliver PET radioisotopes to tumor sites. Also shown are two common chelators conjugated to these peptides

Name(s)

Peptide sequence a

SST-28b

SANSNPAMAPRERKAGCKNFFWKTFTSC

SST-14b

AGCKNFFWKTFTSC

Cortistatin

DRMPCRNFFWKTFSSCK

Octreotide (OC)

fCFwKTC-Thr(ol)

Octreotate (TATE)

fCYwKTCT

Tyr3-Octreotide (TOC)

fCYwKTC-Thr(ol)

Lanreotide (NOC)

DβNal-CYwKVC-Thr(ol)

Vapreotide (VAP)

fCFwKVCW

JR10

p-NO2-Phe-cY-DAph(Cbm)-KTCy-NH2

JR11 (OPS202)

Cpa-c-Aph(Hor)-DAph(Cbm)-KTCy-NH2

LM3

p-Cl-Phe-cY-DAph(Cbm)-KTCy-NH2

Abbreviation

Chelator

DTPA

Diethylene triamine pentaacetic acid

DOTA

1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid

aStandard amino acids are represented by their single-letter abbreviation; nonstandard amino acids are given via common abbreviations [Thr(ol) is threoninol, βNal is 3(2-naphthyl)alanine, p-NO 2 -Phe is p-nitrophenylalanine, Aph(Cbm) is 4-(aminocarbonyl)amino phenylalanine, Cpa is cyano-propionic amino acid, Aph(Hor) is 4-(4S)-hexahydro-2,6-dioxo-4pyrimidinylcarbonylamino phenylalanine, p-Cl-Phe is p-chlorophenylalanine]. D amino acids are signified by lowercase letters or superscripted D. Bolded and italicized letters indicate cyclized peptide sequence portions

bNaturally occurring peptides that target SSTr

Fig. 19

A schematic depiction of octreotide-like pharmacophores that can be radiolabeled for the PET imaging of SSTr positive tumors. The two most commonly conjugated chelators for octreotide-like radiopharmaceuticals are provided to clarify how they are each attached to the peptide. The amino acid labels indicate variations from octreotide (structure drawn) at each position for the peptides listed in Table 1

In the clinic, 68Ga-DOTATOC has been shown to quickly target cranial meningiomas with very good image quality (Fig. 20) [71]. In these studies, there was striking contrast between the meningioma and the pituitary gland, which was further delineated using PET/MRI. Because of the utility of imaging SST-positive tumors with 68Ga-DOTATATE, patients receiving peptide receptor radionuclide therapy (e.g., 177Lu-DOTATATE) have been imaged using PET throughout treatment to assess the efficacy of therapy [72, 73]. In studies in which treatment was monitored by 68Ga-DOTATATE, patients receiving two or more doses of 177Lu-DOTATATE showed no significant progression of disease for longer than those with only one round of therapy [73]. A DOTANOC variant has also been used in the clinic. Lococo et al. showed that pulmonary carcinoids that showed an absence of [18F]FDG uptake were clearly visible in 68Ga-DOTANOC PET scans, while other tumors displayed decreased or similar uptake relative to [18F]FDG [74]. As a result, the authors of this study suggest using both radiopharmaceuticals in concert to identify tumors. Additionally, this multicentered trial showed that including nonstandard amino acids in the octreotide sequence (i.e., DOTANOC) might not strongly impact the overall targeting ability of the imaging agent. However, other studies have indicated that varying the metal-chelator complex or the peptide sequence does impact the radiopharmaceutical’s binding affinity for SSTr [75, 76, 77]. Specifically, Fani et al. showed that the tumor uptake of antagonist-based radiotracers was greater than that of agonist-based imaging agents [77].
Fig. 20

PET/MRI imaging of a patient injected with 68Ga-DOTATOC at 30 min p.i. (ac) and 1 h p.i. (df) indicating tumors (arrows) using T1-weighted MRI (a, d), PET (b, e), and PET/MRI fusion (c, f) (Afshar-Oromieh et al. [71], reproduced by permission of the Society for Neuro-Oncology)

Imaging the Expression of Integrins

Integrin receptors are comprised of two binding regions – α and β – that can be made up of a variety of amino acid sequences, ultimately yielding 24 unique combinations [78]. One of these combinations, the αvβ3 integrin receptor, has been associated with cells responsible for angiogenesis in melanoma, neuroblastoma, and glioblastoma as well as ovarian, breast, and lung cancers [70]. Also, it has been shown that the αvβ3 integrin receptors are not expressed in most noncancerous tissues [78]. Peptides containing an arginine-glycine-aspartic acid (RGD) sequence mediate cell adhesion and have been shown to target αvβ3 integrin receptors [79, 80]. Due to the unique function of RGD peptides, attempts to utilize these peptides to treat or target disease (by tracking angiogenesis or metastatic tumor formation) have been carried out [81, 82]. Notably, three PET imaging agents based on RGD peptides have entered clinical trials: [18F]FPPRGD2, alfatide, and [18F]galacto-RGD. The structures of each of these compounds (as well as a few related structures) are presented in Fig. 21.
Fig. 21

A schematic of PET tracers used to target αvβ3 integrin receptors in clinical studies

Several review articles covering clinical imaging with radiolabeled RGD peptides have cataloged the achievements of these radiopharmaceuticals [83, 84, 85, 86]. A variety of modifications to the core RGD structure have been tested to improve the in vivo behavior of the radiotracers. For example, the introduction of a sugar onto a single RGD peptide sequence resulted in improved in vivo stability while maintaining favorable tumor-to-background ratios [87, 88]. Studies with [18F]galacto-RGD showed variation in uptake between patients, indicating differences in tumor vascularization and cancer stage [89]. In a different investigation, in order to decrease the labeling time, a click reaction was used to conjugate an 18F-labeled prosthetic group to galacto-RGD to form [18F]flotegatide-RDG (or [18F]RGD-K5) [90]. In initial human studies, [18F]RGD-K5 uptake did not correlate with that of [18F]FDG, a result similar to that observed with [18F]galacto-RGD. However, [18F]RGD-K5 PET was determined to be an effective tool for the delineation of integrin expression in breast cancers [91]. Thus, the principal utility of [18F]RGD-K5 may be in monitoring response to therapy rather than tumor identification [92]. Yet another RGD-based radiotracer features a polyethylene glycol (PEG) spacer that is radiolabeled with 18F. This compound, [18F]fluciclatide (18F-AH111585), was injected into a small number of patients with metastatic breast cancer and displayed uptake in lesions that were also visible via CT. Unfortunately, in these patients, the liver uptake of the tracer was too high to identify liver metastases. Further [18F]fluciclatide imaging studies in patients with brain tumors, lung cancer, squamous cell carcinoma of the head and neck, differentiated thyroid carcinoma, sarcoma, and melanoma will focus on the ability of the tracer to delineate angiogenesis [92]. In a study utilizing [15O]H2O as a comparison to [18F]fluciclatide in patients with non-small cell lung cancer and melanoma, Kenny et al. showed that the uptake of [18F]fluciclatide was not merely a function of perfusion and suggested using later imaging time points to determine sites of neovasculature [93].

Due to their relatively low uptake in tumor lesions (<5%ID/g), suboptimal background contrast, and synthetic complexity, the aforementioned 18F-labeled RGD peptides have shown limited utility in the clinic. This has led to investigations using 68Ga-labeled peptides in hopes of increasing the uptake of the tracer in the tumor or decreasing its uptake in nontarget tissues [94]. For example, 68Ga-NOTA-RGD has been used in patients to identify colorectal cancer metastases prior to therapy [92]. These studies suggest that PET scans using RGD-based peptides could aid in the selection of patients for anti-angiogenic therapy [92].

In another effort to improve the tumor retention of RGD-based peptides, multimeric radiopharmaceuticals have also been investigated. In light of this topic, it is important to diverge – if only briefly – to discuss a concept known as “bivalent targeting.” Bivalent targeting strategies are predicated on the use of two biological targeting moieties that are tethered together (1) to increase the probability of interactions with a single cell surface receptor or (2) to facilitate the binding of two cell surface receptors simultaneously. Homodimers (or homomultimers) utilize the same biological targeting vector to achieve greater cell surface receptor occupancy, whereas heterodimers target different receptors often in an effort to increase the types of cancer targeted by the radiopharmaceutical [95, 96]. The use of two targeting moieties may also increase the chance that the peptide will interact with the cell surface in the correct orientation for receptor binding. Because the distance between any two cell surface receptors is unknown, researchers have attempted to investigate various linking molecules that can accommodate cell surface variations [97]. Additionally, increased linker size may decrease the metabolism rate of the radiopharmaceutical and alter its pharmacokinetic properties, ensuring a longer biological half-life and possibly resulting in greater tumor uptake.

One class of homodimers containing two RGD cyclic peptide sequences (RGD2) has shown utility across multiple tumor types in a complementary role to [18F]FDG PET imaging. First, Gao et al. noted positive results in identifying lung cancers from hamartomas with the bivalent RGD-based radiotracer 18F-alfatide (Fig. 21) but noted difficulties distinguishing disease from inflammation [98]. Second, Yu et al. used another bivalent agent – [18F]AlF-NOTA-E[PEG4-c(RGDfk))]2 (18F-alfatide II, Fig. 21) – to visualize 20 brain metastases in nine patients and illustrated that in the same patients, [18F]FDG and CT only identified 10 and 13 metastases, respectively [99]. Third, the analysis of several clinical patient scans with both [18F]FDG and [18F]FPPRGD2 (Fig. 21) has demonstrated differences in maximal uptake in lesions and biodistributions, which may indicate that the information gained from an [18F]FPPRGD2 PET scan may compliment those results from an [18F]FDG scan [100]. Similarly, a preliminary study of [18F]FPPRGD2 uptake in patients with breast cancer demonstrated primary and metastatic imaging utility (Fig. 22) [101]. 68Ga labeling of these agents can also be achieved through the use of NOTA chelators attached to the homodimers; not surprisingly, comparative studies using 68Ga-NOTA-labeled compounds are currently underway.
Fig. 22

Comparison of [18F]FPPRGD2 and [18F]FDG in a woman diagnosed with multicentric lobular carcinoma of the right breast. [18F]FDG uptake was not observed at the lesions indicated by the red arrows (areas proven to be tumors through biopsy) (From Iagaru et al. [101]. Reprinted with permission from the Radiological Society of North America)

Imaging the Expression of Bombesin Receptors

Bombesin – a linear, 14-amino acid homolog to the gastrin-releasing peptide – is found in the skin of the European fire-bellied toad (Bombina bombina, Fig. 23). Bombesin-based peptides target bombesin receptor subtype-2 (seen in the literature as BB2 and BB2r and originally referred to gastrin-releasing peptide receptor or GRPr), which has been shown to be highly expressed by prostate, breast, pancreatic, small cell lung, and colorectal cancers [70]. BB2 is also highly expressed in the murine pancreas; consequently, preclinical studies with radiolabeled bombesin peptides show increased uptake in the pancreas in non-tumor-bearing mice if the biological targeting portion of the peptide is functioning properly. Importantly, Coy et al. have shown that only the 7th-14th amino acids were necessary for binding to the BB2 [this is commonly abbreviated in the literature as BBN(7-14)] [102]. Further variation in the amino acid sequence has led to a number of bombesin analogs, including RM2, BAY86-7548, and Demobesin 4 (Table 2). Various linkers and chelators have been conjugated to the end of the peptide sequence to alter the pharmacokinetics of the radiopharmaceutical and allow for the use of radiometals with different physical properties and half-lives.
Fig. 23

European fire-bellied toad (Bombina bombina)

Table 2

Naturally occurring BBN and a subset of the BB2-targeting peptides used to deliver PET radioisotopes to tumor sites

Name(s)

Peptide sequence a

Gastrin

VPLPAGGGTVLTKMYPRGNHWAVGHLM-NH2

Bombesin (BBN)

pGlu-QRLGNQWAVGHLM-NH2

Bombesin7-14 [BBN(7-14)]

QWAVGHLM-NH2

BAY86-7548 [DOTA-RM2]

DOTA-4-amino-1-carboxymethyl-piperidine-fQWAVGHSta-L-NH2

Demobesin 4 [DB4]

N4-pGlu-QRYGNQWAVGHL-Nle-NH2

aAmino acids are given by the one-letter abbreviation, lowercase indicates D amino acids. Sta is statine and Nle is norleucine, nonstandard amino acids. N4 refers to a tetraamine ligand used to chelate the dioxotechnetium(V) core

68Ga-labeled BBN analogs have been quickly translated to the clinic. BBN(7-14) conjugated to a radiometallated NOTA chelator via an aminocaproic acid – 68Ga-NOTA-Aca-BBN(7-14) – has been investigated to image primary gliomas. Normal, healthy subjects showed rapid clearance of the 68Ga-NOTA-Aca-BBN(7-14) through the kidneys and had higher accumulation of the radioactivity in the bladder [103]. Twelve patients with high- to low-grade gliomas also showed rapid accumulation of 68Ga-NOTA-Aca-BBN(7-14) in lesions within 30 min with very high tumor-to-background ratios (24 ± 9), and all 14 lesions in the 12 patients were identified [103]. Zhang et al. suggested the possible utility of 68Ga-NOTA-Aca-BBN(7-14) PET not only to identify tumors but also to delineate tumor margins that are difficult to determine clinically using five-aminolevulinic acid (ALA) [103].

Another BB2-targeting radiotracer, 68Ga-BAY86-7548 (68Ga-DOTA-RM2), has been extensively investigated for imaging prostate cancers. Roivainen et al. reported the clearance and metabolism of 68Ga-BAY86-7548 in normal, healthy patients [104] and indicated that 68Ga-BAY86-7548 was rapidly cleared through the renal-urinary pathway and rapidly metabolized in vivo. Kähkönen et al. demonstrated that 68Ga-BAY86-7548 can be used to visualize primary lesions in the pancreas but is less successful at identifying metastases (Fig. 24) [105]. Borkowski et al. similarly remarked that no off-target binding was observed in prostate cancer patients and that there was high and prolonged uptake in PC-3 tumor xenografts in mice [106].
Fig. 24

PET/CT of a patient with prostate cancer metastasis to multiple lymph nodes using 68Ga-BAY86-7548 – coronal (a) and axial views (b, c) – showing increased uptake in metastases (red arrows), confirmed through histology. The ureters are indicated with the green arrows (Reprinted from Kähkönen et al. [105]. © the American Association for Cancer Research)

Utilizing a SPECT radiometal, 99mTc-Demobesin-4 (Fig. 25) has been investigated for the possible identification of primary and metastatic prostate cancer. Initial studies with 99mTc-Demobesin-4 indicate that SPECT/CT images of bone metastases in patients with prostate cancer can be visualized as early as 1 h postinjection [107]. However, Mather et al. have also indicated that imaging metastases with 99mTc-Demobesin-4 in patients who had undergone extensive therapy was not feasible [107]. Thus, 99mTc-Demobesin-4 may be useful in identifying new patients, but its suitability to visualize response to therapy is limited.
Fig. 25

The structure of 99mTc-Demobesin 4 (99mTc-DB4)

Imaging the Expression of Prostate-Specific Membrane Antigen

Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein with a large extracellular portion and small intracellular segment. PSMA expression has been shown in normal prostate tissue, but the level of expression increases in prostate cancer, making it an enticing target for the imaging and therapy of prostate cancers. Despite the number of studies implicating PSMA expression in the diagnosis of prostate cancer, the normal function of PSMA is still unknown [108]. The elevated levels of shed PSMA in the serum of patients require that PSMA-targeting agents must localize in cancerous tissues in high enough abundance to compensate for high background activity concentrations.

The only commercially available PSMA-targeted imaging agent is 111In-capromab pendetide (ProstaScint®), a murine monoclonal antibody that targets the intracellular portion of the antigen [108]. Unfortunately, 111In-capromab pendetide has two major drawbacks. First, the radiotracer only targets PSMA in apoptotic or necrotic tissues, in which the intracellular portion of PSMA is available due to membrane damage. And second, because of the limited sensitivity and selectivity of the radiolabeled antibody, the clinical use of 111In-capromab requires a relatively long delay between injection and imaging in order to increase target-to-background contrast [108, 109].

Due to the higher image resolution and improved quantification in PET and PET/CT, most recent efforts have focused on the creation of tracers for PET rather than SPECT. Specifically, [18F]DCFBC (N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-4-fluorobenzyl-l-cysteine, Fig. 26) – a low-molecular-weight urea-based inhibitor of PSMA – shows rapid uptake in PSMA-positive metastases with predominantly renal excretion but with some prolonged liver uptake and blood-pool activity [110]. These limitations in clearance could limit the efficacy of [18F]DCFBC in delineating disease from healthy tissue near major blood vessels [110], but clinical studies have shown the usefulness of [18F]DCFBC in detecting high-grade prostate cancer lesions and differentiating these from nonmalignant tissue (Fig. 27) [111]. The use of [18F]DCFBC in conjunction with MR may also aid in directing clinicians toward which tissues to biopsy [111].
Fig. 26

The chemical structures of [18F]DCFBC and Glu-urea-Lys-6-Ahx-HBED-CC

Fig. 27

Anterior MIP at 2 h p.i. of [18F]DCFBC in a patient with bone metastases indicated with an arrow (a) and a patient with lymph node metastases indicated with an arrow (b) using PET (This research was published in JNM. Cho et al. [110]. © by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

In order to produce a 68Ga-labeled PSMA-targeting small molecule, 68Ga-PSMA – (Glu-urea-Lys-(Ahx)-[68Ga(HBED-CC)]) – was synthesized by conjugating HBED-CC (a chelator for gallium) to a lysine attached via a urea linker to glumatic acid and subsequently radiolabeled with 68Ga (Fig. 26) [112]. In healthy volunteers, high levels of uptake of 68Ga-PSMA were observed in the salivary glands and the kidneys, while moderate uptake was seen in the lacrimal glands, liver, and gallbladder (Fig. 28) [113]. Afshar-Oromieh et al. noted that 60% of lesions in patients with <2.2 ng/mL PSMA expression in blood and 100% of lesions in patients with >2.2 ng/mL PSMA expression in blood were identified with 68Ga-PSMA within 1 h of injection, but image contrast may improve with scanning 3 h post-injection (Fig. 28) [113].
Fig. 28

Maximum intensity projections (MIP) of 68Ga-PSMA showing in vivo distribution in a healthy patient (a), a patient with minimal lymph node metastatic prostate cancer (indicated by red arrow, b), and a patient with extensive lymph node and bone metastatic prostate cancer (c) (Reproduced with permission from Springer from Afshar-Oromieh et al. [113])

Due to the longer residence times of antibodies in the blood, longer-lived isotopes are necessary for the radiolabeling of antibody-based tracers. Zirconium-89 is a positron-emitting radiometal with a half-life of 3.3 days, which complements the multiday circulation time of antibodies. J591, a humanized monoclonal antibody that targets the extracellular portion of PSMA, has been conjugated to the siderophore-derived chelator desferrioxamine (DFO) to prepare the PET tracer 89Zr-J591 (89Zr-huJ591, 89Zr-DFO-J591). Clinical studies by Pandit-Taskar et al. have indicated that the optimal time to image patients is 7 ± 1 days after the administration of the radiolabeled antibody. Critically, these data reveal significant uptake in tumor tissue with 11 of 12 lesions imaged with 89Zr-J591 and 10 of 12 lesions imaged with [18F]FDG PET/CT [114]. Figure 29 provides an illustration of the potential of 89Zr-J591 compared to [18F]FDG, 99mTc-MDP, and CT for the imaging of patients with metastatic prostate cancer [114]. Similarly, 111In-labeled J591 has also shown clinical utility for identifying metastases in patients with a variety of PSMA-positive tumor types [115].
Fig. 29

Comparison of Tc-MDP, FDG, and Zr-J591 uptake in a patient with metastatic prostate cancer using SPECT anterior and posterior images (a), PET MIPs (b), and planar images of fused PET/CT (c) (Reproduced with permission from Springer from Pandit-Taskar et al. [115])

Imaging the Expression of Steroid Hormone Receptors

Steroid hormone receptor (SHR) status has been established as an important biomarker in breast and prostate cancer. While the assessment of SHR status in primary tumors is often easily achieved with histological methods, noninvasive molecular imaging could be used to address temporal changes in SHR levels, delineate metastases, and monitor response to treatment [116]. The molecular imaging of steroid hormone receptors relies primarily on the use of 18F-radiolabeled analogs of the endogenous SHR ligands estrogen (17β-estradiol) and testosterone, which target the estrogen (ER) and androgen receptors (AR), respectively. The structures of 16α-[18F]fluoro-17β-estradiol ([18F]FES) and 16β-[18F]fluoro-5-dihydrotestosterone ([18F]FDHT) are presented in Fig. 30. The estrogen and androgen receptors share a common mechanism of action in which the ligand is bound by the intracellular receptor, and the ligand-receptor complex is transported to the nucleus, where it then binds to the respective steroid response elements in DNA and initiates the transcription of hormone-induced genes (Fig. 31) [117, 118]. Additionally, steroid hormones exert nonnuclear actions via a subpopulation of cell surface SHR, but the mechanisms of these nonnuclear effects remain poorly understood. Another notable feature of the biochemistry of sex steroids is their transport in the circulation by the steroid hormone-binding globulin (SHBG). Because of the 18F substitution in the radiotracers, the affinity of [18F]FES and [18F]FDHT for SHBG is lower than that of estradiol and testosterone; consequently, the radiotracers are primarily distributed in the bloodstream nonspecifically bound to serum albumin, which is more abundant than SHBG [119]. Furthermore, both [18F]FES and [18F]FDHT are rapidly metabolized in humans, with only about 20% of the tracer remaining intact 20 min after injection [120, 121].
Fig. 30

The structures of [18F]FES and [18F]FDHT

Fig. 31

The uptake mechanisms and interactions of SHR radioligands in cells

Estrogen receptor status is an important prognostic indicator of disease-free and overall survival in breast cancer. Figure 32 shows typical PET imaging results in a patient with ER-positive primary breast tumor. In the same study, the authors demonstrated that [18F]FES PET could be used to delineate metastatic sites in the bone and axillary lymph nodes, with the degree of lymph node uptake correlating with disease burden [122]. However, the degree of ER expression in distant sites is variable, and [18F]FES imaging can provide insight on the heterogeneity of metastatic disease, especially when combined with [18F]FDG PET [123]. In a retrospective study of patients undergoing chemotherapy with ER blockade or ligand-depleting agents, Linden et al. have been able to demonstrate that the standard uptake values (SUV) of [18F]FES in tumors is sensitive to changes in circulating estrogen levels as well as ER blockade. In addition, [18F]FES PET imaging was used to distinguish between the pharmacological effects of tamoxifen and fulvestrant, two ER modulators with different mechanisms of action (as illustrated in Fig. 33) [124]. Recently, [18F]FES has been evaluated in small patient populations with various gynecologic cancers including endometrial adenocarcinoma and uterine sarcoma and compared to histopathological findings. These data suggest that [18F]FES PET shows some promise for the evaluation of disease severity and the differentiation of malignant lesions from benign growths like leiomyoma [125].
Fig. 32

Axial [18F]FES image in ER-positive breast cancer showing intense uptake (arrow) in the left breast lesion (a), corresponding to a 2.3-cm lesion seen on CT (c) and confirmed by [18F]FES PET/CT overlay (b) (This research was published in JNM. Gemignani et al. [122]. © by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Fig. 33

Pre- and posttreatment [18F]FES PET images in representative patients treated with ER-blocking and estrogen-lowering therapies. Top coronal (i) and sagittal (ii) views pretreatment and bottom panels show the same patient following treatment with coronal (iii) and sagittal (iv) views. Tumor in the upper spine shows baseline uptake and complete ER blockade in the tumor and uterus following 21 days of tamoxifen (a). Tumor in mediastinal nodes shows baseline uptake and incomplete ER blockade in tumor and uterus following 68 days of fulvestrant (b). Sternal tumor shows ER uptake and no blockade in the tumor and uterus following 29 days of letrozole (c) (Reprinted from Linden et al. [124]. © the American Association for Cancer Research)

The use of [18F]FDHT in prostate cancer is, in principle, analogous to that of [18F]FES in breast cancer. Indeed, an estimated 80–90% of newly diagnosed prostate cancers are androgen dependent and thus are likely to benefit from endocrine therapy through AR blockade or androgen depletion [126]. However, [18F]FDHT PET does not exhibit similar predictive value for the success of endocrine therapy because of the relatively high prevalence of “androgen withdrawal syndrome,” whereby clinical improvement is seen after the discontinuation of endocrine therapy as a result of ligand-independent activation of AR [127]. Understandably, the downstream effects of ligand-independent activation and genomic silencing of AR go undetected in molecular imaging studies with [18F]FDHT. Nevertheless, [18F]FDHT has proven to be a powerful tool for imaging AR status in metastatic, progressive, and advanced prostate cancers. The initial patient studies by the groups at Memorial Sloan Kettering Cancer Center [128] and Washington University in St. Louis [129] focused on lesion-by-lesion comparisons of [18F]FDHT and [18F]FDG uptake, as shown in representative images in Fig. 34. In both studies, [18F]FDHT PET allowed for the detection of 79–89% of [18F]FDG-positive lesions, and the tumor uptake of the tracer was established to be AR-mediated. The studies of Vargas et al. [130] established a significant association between the number of bone lesions detected by different imaging modalities including [18F]FDHT PET with overall survival in patients with castration-resistant prostate cancer. Furthermore, the negative correlation of the intensity of [18F]FDHT accumulation in bone metastases with patient survival supports the prognostic value of the tracer in prostate cancer patients undergoing AR blocking therapies.
Fig. 34

Maximum intensity projections of [18F]FDHT (a) and [18F]FDG (b) PET images of a patient with prostate cancer. A greater number of extraprostatic lesions are detected by [18F]FDHT compared to [18F]FDG (This research was published in JNM. Larson et al. [128]. © by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Targeting the Hypoxic Tumor Microenvironment

Overview

Cancer cells release growth factors such as vascular endothelial growth factor to stimulate angiogenesis from neighboring vasculature. However, these new blood vessels are often poorly formed and inefficient at facilitating the transport of nutrients and oxygen. Within the tumor microenvironment, high rates of cellular proliferation and metabolism combine with this poorly defined vasculature to create local regions of hypoxia [131]. Tumor hypoxia is often indicative of aggressive and metastatic malignant phenotypes and frequent portend complications during disease management. As a result, it follows that the ability to noninvasively delineate hypoxic from normoxic tumors could benefit clinicians during staging, prognosis, treatment planning, and treatment monitoring. The presence of tumor hypoxia is often associated with increased resistance to radiation therapy as well, as much of the damage done by radiation is mediated by reactive oxygen species. Therefore, the identification and mapping of hypoxia are also important for planning optimal radiation therapy treatment regimes.

Imaging Tumor Hypoxia with [18F]FMISO

Any imaging agent that is intended to target poorly vascularized tissue must be transported through cellular membranes, thereby allowing it to diffuse through tissue independently of the circulatory system. One of the most widely utilized hypoxia-targeting imaging agents is [18F]FMISO – ([18F]-fluoromisonidazole, 1-fluoro-3-(2-nitroimidazol-1-yl)-propan-2-ol) (Fig. 35) – which was designed to have a partition coefficient of 0.4. This allows the radiotracer to strike a delicate balance: lipophilic enough to reach hypoxic tissue but hydrophilic enough to be cleared quickly from the blood [132]. The key to [18F]FMISO’s selectivity for hypoxic tissue is the redox chemistry of its nitro group. The mechanisms of [18F]FMISO escaping in normoxic and trapping in hypoxic tissues are shown in Fig. 36.
Fig. 35

The structure of [18F]FMISO

Fig. 36

The mechanism of the uptake and retention of [18F]FMISO. In both hypoxic and normoxic cellular environments, the nitro group of [18F]FMISO picks up electrons released from the electron transport chain, generating a radical anion. Under normoxic conditions, oxygen is able to reduce the nitro group, allowing for the subsequent egress of [18F]FMISO from the cell. Under hypoxic conditions, there is far less O2 to serve as an oxidizing agent. This permits the radicalized [18F]FMISO to undergo covalent cross-linking with nearby macromolecules, effectively trapping it within the cell

[18F]FMISO accumulation has been shown to be indicative of hypoxia in gliomas, breast, head and neck, lung, and renal tumors [133]. Figure 37 shows a representative [18F]FMISO scan in a patient with a glioma. [18F]FMISO PET has been used to differentiate levels of uptake between grades of glioblastomas, in which low-grade gliomas (grades I and II) were found to have no increased uptake of [18F]FMISO, while all high-grade gliomas studied (grades III and IV) demonstrated increased [18F]FMISO uptake [134] (Fig. 38). Another study showed that images generated through [18F]FMISO PET can help guide the precision targeting of hypoxic regions by intensity-modulated radiation therapy (IMRT), which resulted in an estimated 17% increase in tumor control probability (TCP) [135]. In addition, high uptake of [18F]FMISO in non-small cell lung carcinomas was predictive of increased rates of tumor recurrence following radiation therapy in 90% of patients [136]. Thus, [18F]FMISO has been shown to be useful in determining glioma lesion grades, directing radiation therapy, and predicting subsequent tumor response. Unfortunately, however, [18F]FMISO displays comparatively low contrast between hypoxic tissue and background tissues, which likely results from slow clearance from normoxic tissue. Alternative nitroimidazole-based agents are under investigation to mitigate the limitations of [18F]FMISO.
Fig. 37

A glioblastoma in the right superior frontal lobe as imaged by MRI (left), [18F]FMISO PET (middle), and a PET/MRI overlay (right). The fused image shows the areas of highest [18F]FMISO uptake, correlating to localized regions of hypoxia within the tumor mass (Reprinted from Rajendran and Krohn [150], with permission from Elsevier)

Fig. 38

There is a significant difference (P < 0.01) between the T/Bamax of [18F]FMISO (a) and the hypoxic volume (HV) of Grade III and Grade IV gliomas (Reproduced with permission from Springer from Kawai et al. [151])

Imaging Tumor Hypoxia with 64Cu-ATSM

Discussions centered upon the imaging of tumor hypoxia must invariably include 64Cu-ATSM [64Cu-diacetyl-bis(N4-methylsemicarbazone)] as well (Fig. 39). This tracer – initially developed for the diagnosis of cardiac ischemia – was applied to the imaging of cancer as an alternative to [18F]FMISO. Cu-ATSM is a planar tetradentate metal complex in which a central copper atom is coordinated by two nitrogen and two sulfur atoms. The ATSM ligand has been used to chelate a number of the positron-emitting isotopes of copper, including 60Cu (t1/2 = 23.7 min), 61Cu (t1/2 = 3.3 h), 62Cu (t1/2 = 9.7 min), and 64Cu (t1/2 = 12.7 h). Of these, the physical half-life of 64Cu has been shown to best match the biological half-life of the compound and, interestingly, may even produce images with higher tumor-to-background activity concentration ratios than other isotopes of copper [137]. There is some controversy regarding the exact mechanism by which Cu-ATSM is retained in hypoxic cells. Currently, the accepted mechanism of Cu-ATSM retention involves the reduction of Cu(II)-ATSM to Cu(I)-ATSM by reductases present in both hypoxic and normoxic cells (Fig. 40). This reduction causes a conformational shift from Cu(II)-ATSM’s initial planar conformation to a less-stable geometry. Under normoxic cellular conditions, molecular oxygen can reoxidize the copper center, thereby restoring the complex to its more stable planar geometry and allowing the compound to diffuse freely out of the cell. Importantly, however, this reoxidation step does not occur in hypoxic cells. Instead, in these cells, the Cu(I)-ATSM complex is subjected to an acid-catalyzed dissociation reaction, leading to the formation of H2ATSM and free Cu(I). The Cu(I) can then become irreversibly trapped within the cell by thiol-bearing proteins. This mechanism has been supported by a range of experimental evidence [138, 139, 140, 141, 142, 143].
Fig. 39

The structure of 64Cu-ATSM

Fig. 40

A schematic depicting the uptake and retention mechanisms of Cu-ATSM. Under anoxic conditions, oxidation by molecular O2 (k4) cannot occur, therefore promoting the irreversible trapping of Cu(I) within the cell

Cu-ATSM has seen clinical applications as a prognostic indicator in head and neck cancer, non-small cell lung cancer, rectal carcinoma, and cervical cancer. As with [18F]FMISO, Cu-ATSM can be utilized to visualize and evaluate the extent of tumor hypoxia (Fig. 41), to direct the application and intensity of IMRT [144], and to determine patient prognosis. 64Cu-ATSM has also shown limited promise as a therapeutic agent in a hamster model of colon cancer, in which 64Cu-ATSM treatment increased survival by six times over control animals [145].
Fig. 41

60Cu-ATSM uptake can be an indicator of patient response to radiation therapy, as demonstrated here in two lung cancer patients. The responding patient (a) exhibited only a minimal increase in uptake of 60Cu-ATSM (T/M = 1.3) and exhibited negligible growth after treatment. In contrast, the non-responding patient (b) had a significantly increased uptake (T/M = 3.0), and the tumor size increased over the 3 months following treatment (Reproduced with permission from Springer from Dehdashti et al. [144])

Despite the utility of Cu-ATSM in some cancer models, there is variability in its hypoxia-dependent uptake between different cell lines, which could be due in part to the complexity – and particularly the pH dependence – of its intracellular trapping mechanism. As with [18F]FMISO, a series of Cu-ATSM derivatives have been developed in hopes of improving the hypoxia-selective uptake and tumor retention [143].

Concluding Remarks

In the preceding pages, we have covered a number of extremely promising imaging agents that stand on the cusp of regulatory approval and routine clinical use. The diversity of these radiopharmaceuticals reflects the wide array of information that clinicians seek as they make patient care and treatment decisions. The case studies we have discussed have included small molecules and antibodies, short-lived radiohalogens and long-lived radiometals, and targets ranging from cell surface antigens to tumor hypoxia. Yet despite the potential of these radiopharmaceuticals, the final obstacle (regulatory approval) is often the biggest hurdle of all. In the United States, this has been particularly true – and frustrating – in the case of 68Ga-DOTATOC. In light of this, we are eager to take this opportunity to underscore the paramount importance of the standardization of procedures across clinical trials and institutions, as this is absolutely essential to developing the substantial body of evidence required for regulatory approval. Hopefully, such measures will streamline the path of these imaging agents from the laboratory to the clinic and thus expedite the positive impact that they will undoubtedly have on patient care.

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Copyright information

© Springer International Publishing AG 2016

Authors and Affiliations

  1. 1.Radiochemistry and Imaging Sciences Service, Department of RadiologyMemorial Sloan Kettering Cancer CenterNew YorkUSA
  2. 2.Laboratory of Radiochemistry, Department of ChemistryUniversity of HelsinkiHelsinkiFinland
  3. 3.Department of ChemistryHunter College of the City University of New YorkNew YorkUSA
  4. 4.Ph.D. Program in ChemistryGraduate Center of the City University of New YorkNew YorkUSA
  5. 5.Program in Molecular PharmacologyMemorial Sloan Kettering Cancer CenterNew YorkUSA
  6. 6.Department of RadiologyWeill Cornell Medical CollegeNew YorkUSA
  7. 7.Department of PharmacologyWeill Cornell Medical CollegeNew YorkUSA

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