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

Publication date: 15 May 2018
Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 9
Author(s): Sung-Hyun Moon, Mee Kyung Hong, Young Ju Kim, Yun-Sang Lee, Dong Soo Lee, June-Key Chung, Jae Min Jeong
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 ⁶⁸Ga. NOTA-GUL and DOTA-GUL were synthesized and labeled with ⁶⁸Ga using generator-eluted ⁶⁸GaCl3 in 0.1 M HCl in the presence of 1 M NaOAc at pH 5.5. The stabilities of ⁶⁸Ga-labeled compounds in human serum were tested at 37.5 °C. A competitive binding assay was performed using the PSMA-positive prostate cancer cell line 22Rv1 and [¹²⁵I]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 ⁶⁸Ga-NOTA-GUL (5.40% ID/g) was higher than that of ⁶⁸Ga-DOTA-GUL (4.66% ID/g) at 1 h. Tumor/muscle and tumor/blood uptake ratios of ⁶⁸Ga-NOTA-GUL (31.8 and 135, respectively) were significantly higher than those of ⁶⁸Ga-DOTA-GUL (16.1 and 31.1, respectively). The tumor/kidney uptake ratio of ⁶⁸Ga-NOTA-GUL was 3.4-fold higher than that of ⁶⁸Ga-DOTA-GUL. ⁶⁸Ga-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 ⁶⁸Ga-NOTA-GUL and ⁶⁸Ga-DOTA-GUL for prostate cancer imaging. ⁶⁸Ga-NOTA-GUL showed better radiochemical and biodistribution results. ⁶⁸Ga-NOTA-GUL may be a promising PSMA targeting radiopharmaceutical.

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