Current Topics in Medicinal Chemistry - Volume 13, Issue 8, 2013

18F-labeled amino acids are an important class of imaging agents for positron emission tomography (PET) that target the increased rates of amino acid transport by many tumor cells. This class of tracers is structurally diverse, and the biological and imaging properties of a given 18F-labeled amino acid depends largely upon its mechanism of transport. The system L amino acid transport system has been a major focus of tracer development in this field, but more recently 18Flabeled amino acids have been developed for other transporters including system A, glutamine, glutamate and cationic amino acid transport systems. Radiolabeled amino acids are best established for brain tumor imaging, but there are emerging applications in other types of cancer such as neuroendocrine tumors and prostate cancer. This review provides an overview of 18F-labeled amino acids for oncologic imaging in terms of design considerations, radiosynthetic methods, and key clinical applications.

In recent years, two different methods have been developed to image cell proliferation with the functional imaging technique, Positron emission Tomography (PET), proliferation rate and proliferative status. Proliferation rate is a measure of the tumor doubling time and uses radiolabeled analogs of the DNA precursor thymidine. This approach measures the activity of the enzyme thymidine kinase 1 (TK1) and provides a pulse label of the S phase fraction of a tumor. Proliferative status provides a measure of the ratio of proliferating (P) and quiescent (Q) cells in a tumor. This imaging approach for measuring proliferative status involves measuring the sigma-2 (σ2) receptor status of a tumor, the only protein which has been validated for making this measurement in vivo with PET. This article provides an overview of the biological information obtained from these different imaging strategies, and the development of radiotracers for imaging proliferation rate and proliferative status.

Alzheimer's disease (AD), the most common form of dementia, is a progressive and fatal neurodegenerative disorder. The neuropathological hallmarks of AD generally revealed on postmortem brain tissue are the extracellular neuritic plaque deposits and intracellular neurofibrillary tangles. Significant evidence supports the pivotal role of β-amyloid peptides in the pathogenesis of AD. Therefore, The ability to image β-amyloid plaques in brain with noninvasive techniques such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) may not only aid in presymptomatic identification of AD patients and differential diagnosis of patients with dementia, but also monitoring the effectiveness of anti-amyloid therapeutic strategies. For these reasons, development of β-amyloid plaquespecific imaging agents has been extensively pursued and reported. This review summarizes the current status of 18Flabeled radioligand development for PET imaging of β-amyloid plaques. [18F]FDDNP is the first PET radioligand that demonstrated differential uptake and retention in the brain of AD patients, while a low signal-to-noise ratio in PET studies was indicated. At this time, [18F]3'-F-PIB (flutemetamol), [18F]AV-1 (florbetaben), [18F]AZD4694, and [18F]MK-3328 are undergoing phase II and III clinical trial. [18F]AV-45 (florbetapir) has recently been approved by FDA for use in patients being evaluated for Alzheimer's disease and other causes of cognitive decline. Several other 18F-labeled radioligands based upon imidazo[1,2-a]pyridine, benzothiazole, stilbene, benzofuran, and benzoxazole core structures have also been synthesized and evaluated.

The development of tropane-derivatives as cocaine-addiction therapeutics identified numerous compounds with affinities for the dopamine, serotonin, and norepinephrine transporters. Many of these compounds were then adapted for use as imaging radiotracers. Incorporation of fluorine into the molecule often improved the physiochemical properties of the compound and also provided a position for radiolabeling with fluorine-18. This review provides an overview of the efforts devoted to developing fluorine-18 radiolabeled tropanes for imaging use with positron emission tomography.

Diaryl sulfides also known as diphenyl sulfides, phenylthiobenzylamines, and biphenylthiols are a class of compounds with phenylthiophenyl scaffold that have been validated as biomarkers to label the brain serotonin transporter (SERT), in vivo. The development of those synthetic and non-natural compounds started more than a decade ago when the observation that 5-chloro-((2-((dimethylamino)methyl)phenyl)thio)benzene-methanol hydrochloride also called 403U76 inhibited the serotonin and norepinephrine uptake into rat brain synaptosomes, led to the preparation of few derivatives based on 403U76 chemical structure. The new class of compounds, called the diaryl sulfide family, was investigated as biomarkers for the brain SERT. The promising data demonstrated by the carbon-11 labeled diaryl sulfides led to the translation of few of them into humans and the further evaluation of the phenylthiophenyl core structure by developing some fluorinated derivatives. This review will mainly focus on the fluorinated diaryl sulfides as fluorine-containing tracers validated to image the human brain SERT using positron emission tomography.

2-Deoxy-2-[18F]fluoro-D-glucose (2-18FDG) has represented radiofluorinated carbohydrates as the most successful tracer for positron emission tomography (PET). 2-18FDG uptake depends on glucose metabolism, which is related to a disease progression. 2-18FDG has been widely used in oncology, neurology, cardiology, infectious diseases, and inflammation, to complement anatomical modalities such as CT and MRI. Followed by the success of 2-18FDG, various radiofluorinated carbohydrates have been evaluated as PET tracers, which include analogs of D-ribose, D-mannose, Dgalactose, D-talose, D-fructose, D-allose, lactose, L-fucose, N-acetylneuraminic acid, and L-ascorbic acid. Among those radiofluorinated carbohydrates, several have implied potential for further development. 2-Deoxy-2-[18F]fluoro-Dgalactose has been developed to assess liver function and diagnose hepatic carcinoma. 6-Deoxy-6-[18F]fluoro-D-fructose showed promising characteristics for diagnosis of breast cancer. Three radiofluorinated analogs of lactose have been designed as the substrates of the overexpressed hepatocarcinoma-intestine-pancreas/pancreatitis-associated protein in peritumoral pancreatic tissue for early diagnosis of pancreatic cancer. The metabolism of 6-[18F]fluoro-L-fucose suggested that it is a bioactive analog of L-fucose in the synthesis of glycoconjugate macromolecules. 6-Deoxy-6-[18F]fluoro-Lascorbic acid was evaluated to assess antioxidant function of L-ascorbic acid in rodent models of transient global ischemia and glutathione deficiency.

Prostate cancer (PCa) is the second leading cause of cancer-related death in American men. Positron emission tomography/computed tomography (PET/CT) with emerging radiopharmaceuticals promises accurate staging of primary disease, restaging of recurrent disease, detection of metastatic lesions and, ultimately, for predicting the aggressiveness of disease. Prostate-specific membrane antigen (PSMA) is a well-characterized imaging biomarker of PCa. Because PSMA levels are directly related to androgen independence, metastasis and progression, PSMA could prove an important target for the development of new radiopharmaceuticals for PET. Preclinical data for new PSMA-based radiotracers are discussed and include new 89Zr- and 64Cu-labeled anti-PSMA antibodies and antibody fragments, 64Cu-labeled aptamers, and 11C-, 18F-, 68Ga-, 64Cu-, and 86Y-labeled low molecular weight inhibitors of PSMA. Several of these agents, namely 68Ga- HBED-CC conjugate 15, 18F-DCFBC 8, and BAY1075553 are particularly promising, each having detected sites of PCa in initial clinical studies. These early clinical results suggest that PET/CT using PSMA-targeted agents, especially with compounds of low molecular weight, will make valuable contributions to the management of PCa.