Development of a Ga-68 labeled PET tracer with short linker for prostate-specific membrane antigen (PSMA) targeting

Glu-Urea-Lys (GUL) derivatives have been reported as prostate-specific membrane antigen (PSMA) agent. We developed derivatives of GUL conjugated with NOTA or DOTA via a thiourea linker and tested their feasibility as PSMA imaging agents after labeling with Ga-68. NOTA-GUL and DOTA-GUL were synthesized and labeled with Ga-68 using generator-eluted (GaCl3)-Ga-68 in 0.1 M HCl in the presence of 1 M NaOAc at pH 5.5. The stabilities of Ga-68-labeled compounds in human serum were tested at 37.5 degrees C. A competitive binding assay was performed using the PSMA-positive prostate cancer cell line 22Rv1 and [I-125] MIP-1072 (PSMA-specific binding agent) as a tracer. Biodistribution and micro-PET studies were performed using 22Rv1-xenograft BALB/c nude mice. The radiolabeling efficiency of NOTA-GUL (>99%) was higher than that of DOTA-GUL (92%). The IC50 of Ga-NOTA-GUL was 18.3 nM. In the biodistribution study, tumor uptake of Ga-68-NOTA-GUL (5.40% ID/g) was higher than that of Ga-68-DOTA-GUL (4.66% ID/g) at 1 h. Tumor/muscle and tumor/blood uptake ratios of Ga-68-NOTA-GUL (31.8 and 135, respectively) were significantly higher than those of Ga-68-DOTA-GUL (16.1 and 31.1, respectively). The tumor/kidney uptake ratio of Ga-68-NOTA-GUL was 3.4-fold higher than that of Ga-68-DOTA-GUL. Ga-68-NOTA-GUL showed specific uptake to PSMA positive tumor xenograft and was blocked by co-injection of the cold ligand. In conclusion, we successfully synthesized Ga-68-NOTA-GUL and Ga-68-DOTA-GUL for prostate cancer imaging. Ga-68-NOTA-GUL showed better radiochemical and biodistribution results. Ga-68-NOTA-GUL may be a promising PSMA targeting radiopharmaceutical. (C) 2018 Elsevier Ltd. All rights reserved.