Synthesis and evaluation of a novel urea-based 68 Ga-complex for imaging PSMA binding in tumor.

INTRODUCTION: Prostate specific membrane antigen (PSMA) is a well-established target for diagnostic and therapeutic applications for prostate cancer. It is know that [68 Ga]PSMA 11 ([68 Ga]Glu-NH-CO-NH-Lys(Ahx)-HBED-CC) is the most well studied PET imaging agent for detecting over expressed PSMA binding sites of tumors in humans. In an effort to provide new agents with improved characteristics for PET imaging, we report a novel [68 Ga]-Glu-NH-CO-NH-Lys(Ahx)-linker-HBED-CC conjugate with a novel O-(carboxymethyl)-L-tyrosine, as the linker group.

METHODS: Radiosynthesis was performed by a direct method. In vitro binding and cell internalization of [68 Ga]10 was investigated in PSMA positive LNCaP cell lines. Biodistribution and MicroPET imaging studies were performed in LNCaP tumor bearing mice.

RESULTS: In vitro binding to LNCaP cells showed that nat Ga labeled O-(carboxymethyl)-L-tyrosine conjugate, [nat Ga]10, displayed excellent affinity and specificity (IC50  = 16.5 nM) a value comparable to that of PSMA 11. In vitro cell binding and internalization showed excellent uptake and retention; [68 Ga]10 displayed significantly higher cellular internalization than [68 Ga]PSMA 11 (12.5 vs 7.4% ID/106 cells at 1 h). Biodistribution studies in LNCaP tumor-bearing mice exhibited a high specific uptake in PSMA expressing tumors and fast clearance in normal organs (19.7 tumor/blood; 20.7 tumor/muscle at 1 h after iv injection). MicroPET imaging studies in mice confirmed that [68 Ga]10 displayed excellent uptake and distinctive tumor localization, which was blocked by iv injection of a competing drug, 2-PMPA.

CONCLUSIONS: The preliminary results strongly suggest that [68 Ga]10 may be promising candidates as a PET imaging radiotracer for detecting PSMA expression in prostate cancer.