Abstract
The (R)- and (S)-enantiomers of 2-amino-3-[1-(2-[18F]fluoroethyl)-1H-[1,2,3]triazol-4-yl]propanoic acid (4) were synthesized and evaluated in the rat 9L gliosarcoma brain tumor model using cell uptake assays, biodistribution studies, and micro-positron emission tomography (microPET). The (R)- and (S)-enantiomers of [18F]4 were radiolabeled separately using the click reaction in 57% and 51% decay-corrected yields, respectively. (S)-[18F]4 was a substrate for cationic amino acid transport and, to a lesser extent, system L transport in vitro. In vivo biodistribution studies demonstrated that (S)-[18F]4 provided higher tumor uptake and higher tumor to brain ratios (15:1 at the 30- and 60-minute time points) compared to the (R)-enantiomer (7:1 at the 30- and 60-minute time points). MicroPET studies with (S)-[18F]4 confirmed that this tracer provides good target to background ratios for both subcutaneous and intracranial 9L gliosarcoma tumors. Based on these results, the 1H-[1,2,3]triazole-substituted amino acid (S)-[18F]4 has promising PET properties for brain tumors and represents a novel class of radiolabeled amino acids for tumor imaging.
Highlights
The (R)- and (S)-enantiomers of 2-amino-3-[1-(2-[18F]fluoroethyl)-1H-[1,2,3]triazol-4-yl]propanoic acid (4) were synthesized and evaluated in the rat 9L gliosarcoma brain tumor model using cell uptake assays, biodistribution studies, and micro–positron emission tomography
No racemization was detected by chiral high-performance liquid chromatography (HPLC) analysis, and the enantiomeric excess was greater than 98% for each enantiomer
The initial step of the radiosynthesis of (R)- and (S)[18F]4 was performed using a method similar to that described by Glaser and Arstad
Summary
The (R)- and (S)-enantiomers of 2-amino-3-[1-(2-[18F]fluoroethyl)-1H-[1,2,3]triazol-4-yl]propanoic acid (4) were synthesized and evaluated in the rat 9L gliosarcoma brain tumor model using cell uptake assays, biodistribution studies, and micro–positron emission tomography (microPET). MicroPET studies with (S)-[18F]4 confirmed that this tracer provides good target to background ratios for both subcutaneous and intracranial 9L gliosarcoma tumors Based on these results, the 1H-[1,2,3]triazole-substituted amino acid (S)-[18F]4 has promising PET properties for brain tumors and represents a novel class of radiolabeled amino acids for tumor imaging. A number of radiolabeled amino acids, including L-[11C]methionine, (2[18F]fluoroethyl)-L-tyrosine (FET), 6-[18F]fluoro-3,4-dihydroxy-L-phenylalanine (FDOPA), 3-[123I]iodo-a-methylL-tyrosine (IMT), and 3-[18F]fluoro-a-methyl-L-tyrosine (FMT) have proven utility for imaging gliomas in human patients.. A number of radiolabeled amino acids, including L-[11C]methionine, (2[18F]fluoroethyl)-L-tyrosine (FET), 6-[18F]fluoro-3,4-dihydroxy-L-phenylalanine (FDOPA), 3-[123I]iodo-a-methylL-tyrosine (IMT), and 3-[18F]fluoro-a-methyl-L-tyrosine (FMT) have proven utility for imaging gliomas in human patients.1–6 These tracers have improved sensitivity and specificity relative to 2-[18F]fluoro-2-deoxy-D-glucose (FDG) for detecting brain gliomas, in the setting of recurrence after treatment. A number of amino acid transport subtypes, including the L-type amino acid transporter 1 (LAT1) and system ASC amino acid transporter 2 (ASCT2), have been shown to be upregulated in various human tumors, including breast cancers and gliomas, and their presence may have prognostic significance. System L
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