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Novel Bombesin Analogues Conjugated with DOTA-Ala(SO3H)-4 aminobenzoic acid and DOTA-Lys(glucose)-4 aminobenzoic acid: Synthesis, Radiolabeling, and Gastrin Releasing Peptide Receptor Binding Affinity

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초록

In this study, a novel bombesin (BBN) analogues, DOTA-Ala(SO3H)-4 aminobenzoyl-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2 (DOTA-sBBN) and DOTA-Lys(glucose)-4 aminobenzoyl-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2 (DOTA-gluBBN), were synthesized and radiolabeled,and their binding affinities were evaluated. Peptides were prepared by a solid phase synthesismethod and their purities were over 98%. DOTA is the chelating agent for 177Lu-labeling, and theDOTA-conjugated peptides were radiolabeled with 177Lu by a high radiolabeling yield (¤98%). The Log P values of DOTA-sBBN and DOTA-gluBBN were -2.20 and -2.79, respectively. 50.41%of 177Lu-DOTA-sBBN and 72.97% of 177Lu-DOTA-gluBBN were left undegraded by the serumincubation at 37􀆆􀆆C for 48 hr. A competitive displacement of 125I-[Tyr4]-BBN on the PC-3 humanprostate carcinoma cells revealed that 50% inhibitory concentration (IC50) were 1.46 nM ofDOTA-sBBN and 4.67 nM of DOTA-gluBBN indicating a highly nanomolar binding affinity forGRPR. Therefore, it is concluded that 177Lu-DOTA-sBBN and 177Lu-DOTA-gluBBN can bepotential candidates as a targeting modality for the Gastrin-releasing peptide receptor (GRPR)-over-expressing tumors, and further studies to evaluate their biological and pharmacological characteristicsare needed.

Abstract

In this study, a novel bombesin (BBN) analogues, DOTA-Ala(SO3H)-4 aminobenzoyl-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2 (DOTA-sBBN) and DOTA-Lys(glucose)-4 aminobenzoyl-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2 (DOTA-gluBBN), were synthesized and radiolabeled,and their binding affinities were evaluated. Peptides were prepared by a solid phase synthesismethod and their purities were over 98%. DOTA is the chelating agent for 177Lu-labeling, and theDOTA-conjugated peptides were radiolabeled with 177Lu by a high radiolabeling yield (¤98%). The Log P values of DOTA-sBBN and DOTA-gluBBN were -2.20 and -2.79, respectively. 50.41%of 177Lu-DOTA-sBBN and 72.97% of 177Lu-DOTA-gluBBN were left undegraded by the serumincubation at 37􀆆􀆆C for 48 hr. A competitive displacement of 125I-[Tyr4]-BBN on the PC-3 humanprostate carcinoma cells revealed that 50% inhibitory concentration (IC50) were 1.46 nM ofDOTA-sBBN and 4.67 nM of DOTA-gluBBN indicating a highly nanomolar binding affinity forGRPR. Therefore, it is concluded that 177Lu-DOTA-sBBN and 177Lu-DOTA-gluBBN can bepotential candidates as a targeting modality for the Gastrin-releasing peptide receptor (GRPR)-over-expressing tumors, and further studies to evaluate their biological and pharmacological characteristicsare needed.

참고문헌 (34)

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