Introduction: Gastrin-releasing peptide receptors (GRPR) and GRP-derived analogs have attracted attention due to high receptor expression in frequently occurring human neoplasia. The authors recently synthesized a series of GRPR-affine peptide analogs based on the 27-mer GRP and derivatized with the DOTA chelator at the N-terminus for <sup>111</sup>In-labeling. In this study, the authors evaluated the most promising from these series, DOTA-GRP(13-27), after radiolabeling with <sup>177</sup>Lu for future therapeutic applications. In addition, to improve in vivo stability of the peptide against in vivo degradation by the protease neutral endopeptidase (NEP), the authors coinjected [<sup>177</sup>Lu]DOTA-GRP(13-27) with the potent NEP inhibitor phosphoramidon (PA). The authors also aimed at reducing renal uptake by coadministration of lysine. Methods: In vivo stability studies were performed in Swiss albino mice. Biodistribution studies were conducted in NMRI nu/nu mice bearing prostate cancer (PC)-3 xenografts. Ex vivo autoradiography was performed using frozen sections from PC-3 xenografts and kidneys. Results and Discussion: Coadministration of PA significantly increased the percentage of intact radiopeptide in the mouse circulation. From biodistribution and ex vivo autoradiography studies, coadministration of both lysine and PA with [<sup>177</sup>Lu]DOTA-GRP(13-27) appeared to induce a clear improvement of tumor uptake as well as lower levels of renal radioactivity, causing a promising ninefold increase in tumor/kidney ratios.

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Keywords Enzyme inhibition, In vivo stability, Lysine, Neutral endopeptidase, Phosphoramidon, Radiolabeled gastrin-releasing peptide, Radionuclide therapy, Renal retention
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Journal Cancer Biotherapy and Radiopharmaceuticals
Marsouvanidis, I-P, Melis, M.L, de Blois, E, Breeman, W.A.P, Krenning, E.P, Maina, T, … de Jong, M. (2014). In vivo enzyme inhibition improves the targeting of [177Lu]DOTA-GRP(13-27) in GRPR-positive tumors in mice. Cancer Biotherapy and Radiopharmaceuticals, 29(9), 359–367. doi:10.1089/cbr.2014.1706