Radiolabeled high affinity peptidomimetic antagonist selectively targets αvβ3 receptor-positive tumor in mice

Objectives: The aim of this research was to synthesize radiolabeled peptidomimetic integrin alpha(v)beta(3) antagonists that selectively target integrin alpha(v)beta(3) receptor and clear rapidly from the whole body. Methods: Integrin alpha(v)beta(3) antagonists, 4-[2-(3,4,5,6-tetrahydropyrimidine-2-ylamino)etbyloxy]benzoyl-2-(S)-aminoethylsulfonyl-amino-alanine (IA) and 4-[2-(3,4,5,6-tetrahydro-pyrimidin-2-ylamino)-ethyloxy]benzoyl-2-(S)-[N-(3-amino-neopenta-1-carbamyl)]-aminoethylsulfonylamino-beta-alanine hydrochloride (IAC), a hydrophobic carbamate derivative of IA, were conjugated with 2-p-isothiocyanatobenzyl-DOTA at the amino terminus and labeled with In-111. The In-111 labeled IA and JAC were subjected to in vitro receptor binding, biodistribution and imaging studies using nude mice bearing the receptor-positive M21 human melanoma xenografts. Results: The In-111-labeled IA (40%) and -IAC (72%) specifically bound in vitro to 003 (0.8 mu M) at a molar excess. This receptor binding was completely blocked by a molar excess of cold IA to alpha(v)beta(3). The higher receptor-binding affinity of the In-111-labeled IAC was reflected in higher tumor uptake and retention: 5.6 +/- 1.4 and 4.5 +/- 0.7 %ID/g vs. 3.8 +/- 0.9 and 2.0 +/- 0.3 %ID/g for the In-111-labeled IA at 0.33 and 2 h. The tumor uptakes were inhibited by the co-injection of 200 mu g of IA, indicating that the uptake was receptor mediated. These antagonists were excreted primarily via the renal system. The In-111 activity retained in the whole body was quite comparable between the In-111-labeled IA (24% ID) and the In-111-labeled IAC (33% ID) at 2 h. The higher peak tumor uptake and longer retention resulted in higher tumor-to-background ratios for the In-111-labeled IAC at 2 h with 9.7, 2.3, 0.8, 1.9, 7.1, 2.2, 0.9, 3.7 and 9.9 for blood, liver, kidney, lung, heart, stomach, intestine, bone and muscle, respectively. The imaging studies with the In-111-labeled IAC also clearly visualized the receptor-positive tumor at 4 h. Conclusions: The In-111-labeled IAC showed an improve tumor targeting kinetics with rapid accumulation and prolonged retention in the alpha(v)beta(3) receptor-positive tumor. This together with the rapid whole-body clearance pharmacokinetics warrants further studies on this IAC analog for molecular imaging of tumor-induced angiogenic vessels and various malignant human tumors expressing the receptor. (c) 2007 Elsevier Inc. All rights reserved.