title: Radiolabeled high affinity peptidomimetic antagonist selectively targets alpha(v)beta(3) receptor-positive tumor in mice.
abstract: OBJECTIVE
  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)ethyloxy]benzoyl-2-(S)-aminoethylsulfonyl-amino-beta-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 (111)In. The (111)In labeled IA and IAC were subjected to in vitro receptor binding, biodistribution and imaging studies using nude mice bearing the receptor-positive M21 human melanoma xenografts.
  
  
  RESULTS
  The (111)In-labeled IA (40%) and -IAC (72%) specifically bound in vitro to alpha(v)beta(3) (0.8 microM) 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 (111)In-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 (111)In-labeled IA at 0.33 and 2 h. The tumor uptakes were inhibited by the co-injection of 200 microg of IA, indicating that the uptake was receptor mediated. These antagonists were excreted primarily via the renal system. The (111)In activity retained in the whole body was quite comparable between the (111)In-labeled IA (24% ID) and the (111)In-labeled IAC (33% ID) at 2 h. The higher peak tumor uptake and longer retention resulted in higher tumor-to-background ratios for the (111)In-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 (111)In-labeled IAC also clearly visualized the receptor-positive tumor at 4 h.
  
  
  CONCLUSIONS
  The (111)In-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.
authors.affiliation: Department of Nuclear Medicine, Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Beom-Su
authors.initials: BS
authors.lastname: Jang
authors.forename: Esther
authors.initials: E
authors.lastname: Lim
authors.forename: Seung
authors.initials: S
authors.lastname: Hee Park
authors.forename: In Soo
authors.initials: IS
authors.lastname: Shin
authors.forename: S Narasimhan
authors.initials: SN
authors.lastname: Danthi
authors.forename: In Sook
authors.initials: IS
authors.lastname: Hwang
authors.forename: Nhat
authors.initials: N
authors.lastname: Le
authors.forename: Sarah
authors.initials: S
authors.lastname: Yu
authors.forename: Jianwu
authors.initials: J
authors.lastname: Xie
authors.forename: King C P
authors.initials: KC
authors.lastname: Li
authors.forename: Jorge A
authors.initials: JA
authors.lastname: Carrasquillo
authors.forename: Chang H
authors.initials: CH
authors.lastname: Paik
mesh_terms: D000818:Animals; D006801:Humans; D007205:Indium Radioisotopes; D007274:Injections, Intraperitoneal; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D007553:Isotope Labeling; D008546:Melanoma, Experimental / Q000188:drug therapy; D051379:Mice; D008819:Mice, Nude; D018716:Molecular Mimicry; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D013449:Sulfonamides / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: C521825:4-(2-(3,4,5,6-tetrahydropyrimidin-2-ylamino)ethyloxy)benzoyl-2-(N-(3-aminoneopenta-1-carbonyl))aminoethylsulfonylamino-beta-alanine; C521824:4-(2-(3,4,5,6-tetrahydropyrimidin-2-ylamino)ethyloxy)benzoyl-2-aminoethylsulfonylamino-beta-alanine; D007205:Indium Radioisotopes; D039302:Integrin alphaVbeta3; D019275:Radiopharmaceuticals; D013449:Sulfonamides; D015091:beta-Alanine