68Ga-Labeled homoalanine derivatives of 1,4,7,10-tetraazacyclododecane-1,7-diacetic acid and 1,4,7,10-tetraazacyclododecane-1,4,7,-triacetic acid

The 68Ga-labeled alanine derivatives of 1,4,7,10-tetraazacyclododecane-1,7-diacetic acid (DO2A) and 1,4,7,10-tetraazacyclododecane-1,4,7,-triacetic acid (DO3A), abbreviated as 68Ga-21 and 68Ga-22, respectively, were synthesized by Shetty et al. for positron emission tomography (PET) of cancer cells (1).Radiolabeled amino acids represent a diverse class of tracers that target the increased amino acid transport in cancer cells (2, 3). To date, >20 distinct amino acid transporters have been identified in mammalian cells, and these transporters differ in terms of substrate specificity, tissue expression patterns, sodium and other ion dependence, pH sensitivity, and transport mechanism (4, 5). Because of increased demand for amino acids in malignant cells, some transporters have been shown to be overexpressed in different types of tumors, and the process of amino acid transport is relatively fast (2, 6, 7). These features make tumor imaging with amino acid tracers possible within 20 min. Indeed, there is growing evidence that radiolabeled amino acids have the potential to overcome some of the limitations of 2-deoxy-2-[18F]fluoro- d -glucose ([18F]FDG) in tumor imaging, especially in the imaging of primary and recurrent brain tumors, neuroendocrine tumors, and prostate cancers (2, 3, 8). Different studies also showed that radiotracers that target different amino acid transporters exhibit different imaging properties that may provide unique biological information of tumors (1, 2, 7).The first group of widely investigated amino acids is the analogs of phenylalanine and tyrosine (2, 3). Because of their bulky neutral side chains, these natural amino acids are the substrates of system L transporters and have been proven to be useful for tumor imaging, particularly for brain tumors. The limitation common to most of the natural amino acids is the susceptibility to in vivo metabolism, which decreases tumor specificity and complicates kinetic analysis. Because none of the natural amino acids contain fluorine or iodine, labeling with fluorine-18 or iodine-123 can change the biochemical properties compared to the parent amino acids. These shortcomings associated with natural amino acids can be partially overcome by using non-natural amino acids. Typically, non-natural amino acids are neither metabolized nor readily incorporated into protein in vivo (2, 3, 7). One group of non-natural amino acids is a,a-dialkyl amino acids, which are generated by substituting the a-carbon hydrogen of natural amino acids with a methyl group or other alkyl chains. These amino acids are primarily the substrates of system A transporters. The second group is alicyclic amino acids, which are a,a-dialkyl amino acids with side chains bonded covalently to each other to form a cyclic ring. These amino acids are the substrates of system L transporters. The third group is non-natural proline derivatives, which exhibit different transport selectivity. One challenge in developing amino acid radiotracers is to overcome the low selectivity and the decreased recognition after radiolabeling to specific transporters (1-3). Another challenge is the low uptake of amino acid agents in tumors, which leads to less sensitivity for tumor detection than with [18F]FDG (8).Shetty et al. synthesized a group of 68Ga-labeled alanine and lysine derivatives of 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), DO2A, and DO3A (1, 7). The four bifunctional chelating agents have similar sizes, but they differ in the net charges because of the different numbers of pendent carboxylate arms. The amino acids have been conjugated to one of the carboxylate arms, and the nitrogen atoms in the heterocyclic ring are presumed to coordinate with metals to form chelates. Biodistribution studies and PET imaging indicate the structure–activity relationship of the amino acid derivatives, and the selective uptakes of these compounds by different cancer tissues might provide an insight on the different modes of amino acid uptake by cancer cells (1, 7).This chapter summarizes the data obtained with 68Ga-labeled alanine derivatives: 68Ga-21 (68Ga-DO2A-alanine) and 68Ga-22 (68Ga-DO3A-alanine). These alanine derivatives were comparatively analyzed with the corresponding homoalanine derivatives (68Ga-23 and 68Ga-24, respectively) (1).