Tumor diagnosis with new 111In-radioligands based on truncated human gastrin releasing peptide sequences: Synthesis and preclinical comparison

Radiolabeled analogs of the frog tetradecapeptide bombesin (BBN) have been proposed for diagnosis and therapy of gastrin releasing peptide receptor (GRPR)-expressing tumors. Following a different and yet unexplored approach, we have developed four novel 111In-labeled truncated analogs of the human 27-mer GRP after conjugation of 1,4,7,10-tetraazacyclododecane-1,4,7,10- tetraacetic acid (DOTA) at the N-terminus of GRP(13/14/17/18-27) fragments. Analog affinities for the human GRPR determined against [125I- Tyr4]BBN were at the nanomolar level and dependent on truncation site. The respective 111In radioligands specifically internalized in GRPR-expressing PC-3 cells. The shorter chain [111In-DOTA]GRP(17/18- 27) analogs showed higher metabolic stability in mice. Radioligands specifically localized in human PC-3 xenografts in SCID mice, with [111In-DOTA] GRP(17-27) exhibiting the most favorable pharmacokinetic profile. This study has demonstrated the efficacy of human GRP-based radiopeptides to target GRPR-positive lesions in vivo and has revealed the impact of GRP chain length on key biological parameters of resulting radiotracers.

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