title: In vivo enzyme inhibition improves the targeting of [177Lu]DOTA-GRP(13-27) in GRPR-positive tumors in mice.
abstract: BACKGROUND
  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 (111)In-labeling. In this study, the authors evaluated the most promising from these series, DOTA-GRP(13-27), after radiolabeling with (177)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 [(177)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.
  
  
  CONCLUSIONS
  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 [(177)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.
authors.affiliation: 1 Molecular Radiopharmacy, INRASTES, NSCR Demokritos , Athens, Greece .
authors.forename: Panteleimon J
authors.initials: PJ
authors.lastname: Marsouvanidis
authors.forename: Marleen
authors.initials: M
authors.lastname: Melis
authors.forename: Erik
authors.initials: E
authors.lastname: de Blois
authors.forename: Wout A P
authors.initials: WA
authors.lastname: Breeman
authors.forename: Eric P
authors.initials: EP
authors.lastname: Krenning
authors.forename: Theodosia
authors.initials: T
authors.lastname: Maina
authors.forename: Berthold A
authors.initials: BA
authors.lastname: Nock
authors.forename: Marion
authors.initials: M
authors.lastname: de Jong
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D019886:Gastrin-Releasing Peptide / Q000493:pharmacokinetics; D006020:Glycopeptides / Q000494:pharmacology*; D064593:Heterografts; D006801:Humans; D008187:Lutetium / Q000737:chemistry; D008297:Male; D051379:Mice; D008819:Mice, Nude; D015260:Neprilysin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010446:Peptide Fragments / Q000493:pharmacokinetics; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging* / Q000201:enzymology / Q000378:metabolism*; D011480:Protease Inhibitors / Q000494:pharmacology; D011868:Radioisotopes / Q000737:chemistry; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D018004:Receptors, Bombesin / Q000096:biosynthesis* / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D006020:Glycopeptides; D010446:Peptide Fragments; D011480:Protease Inhibitors; D011868:Radioisotopes; D019275:Radiopharmaceuticals; D018004:Receptors, Bombesin; D008187:Lutetium; D019886:Gastrin-Releasing Peptide; D015260:Neprilysin; C008890:phosphoramidon
keywords: enzyme inhibition; in vivo stability; lysine; neutral endopeptidase; phosphoramidon; radiolabeled gastrin-releasing peptide; radionuclide therapy; renal retention