Radiohalogenated nonnatural amino acids as PET and SPECT tumor imaging agents

Abstract

Radiohalogenated α-amino acids are a diverse and useful class tumor imaging agents suitable for positron emission tomography and single photon emission computed tomography. These tracers target the increased rates of amino acid transport exhibited by many tumor cells. The most established clinical use for radiolabeled amino acids is imaging primary and recurrent gliomas, and there is growing evidence that they may also be useful for other oncologic applications, including neuroendocrine tumors and prostate cancer. This review focuses on the synthesis, radiolabeling, and preclinical evaluation of three series of nonnatural radiohalogenated amino acids: alicyclic, α,α-dialkyl, and 1H-[1,2,3]triazole amino acids which target system L, system A, and cationic amino acid transport systems, respectively.

Relationship between [ 14 C]MeAIB uptake and amino acid transporter family gene expression levels or proliferative activity in a pilot study in human carcinoma cells: Comparison with [ 3 H]methionine uptake

“…In contrast, system A, which also transports amino acids into cells, has no counter transport activity. Amino acid transporter function can therefore be evaluated directly using MeAIB (system A substrate), allowing differentiation from system L [42,43]. The correlation between the uptake of radiotracers and the gene expression of amino acid transporter in tumor cells has been evaluated in a number of recent nuclear medicine studies.…”

Evaluation of Prostate Cancer with Radiolabeled Amino Acid Analogs

“…(The standard international nomenclature for this radiotracer is 18 F-fluciclovine; therefore, 18 F-fluciclovine is used in this review.) 18 F-labeled 1-amino-cycloalkane-1-carboxylic acids such as 18 F-fluciclovine are a class of a,a-dialkyl amino acids that have a fluorine atom on the side chain, that are covalently bonded to each other to form a cyclic ring, and that are neither metabolized nor incorporated into proteins (3,12,(34)(35)(36).…”

“…The development of fluorinated methionine and tryptophan derivatives has been reported (62)(63)(64). In addition, 11 C and 18 F system A transport radiotracers have been tested in preclinical prostate cancer animal models and are in the early stages of human translation (3,65,66). A homolog of 18 F-fluciclovine, anti-1-amino-2-18 F-fluorocyclopentane-1-carboxylic acid ( 18 F-FACPC), had been evaluated as a prostate cancer imaging agent in humans.…”

“…Amino acid transport is upregulated in carcinomas because of increased amino acid use for energy requirements and protein synthesis (2)(3)(4). Therefore, the molecular imaging of amino acid activity is an attractive target, especially in situations in which 18 F-FDG PET has limitations, such as in the detection of prostate cancer (5-7).…”

“…Specific amino acid transporters that are overexpressed in prostate cancer include system L amino acid transporters (LAT1, LAT3, and LAT4), system alanine-serine-cysteine transporters (ASCT1 and ASCT2), the system A sodium-coupled neutral amino acid transporter, system X 2 c, system B 0,1 , and proton-assisted transporters (PAT1 and PAT4) (9)(10)(11)(12)(13)(14)(15)(16)(17)(18). Of these amino acid transporters, ASCT2 and LAT1 appear to be the most important in cancer metabolism and have been described as "partners in crime" (3,10). LAT1 expression in prostate cancer specimens has been correlated with poor survival and an elevated Gleason score (13,14).…”