title: In vitro and in vivo evaluation of 64Cu-labeled DOTA-linker-bombesin(7-14) analogues containing different amino acid linker moieties.
abstract: The gastrin-releasing peptide receptor (GRPR) is overexpressed on a variety of tumor types and has been targeted with radiolabeled peptides for detection and therapy of these cancers. Analogues of the 14 amino acid bombesin (BN) peptide have been radiolabeled with both gamma- and positron-emitting radionuclides for detection of GRPR-expressing tumors. We have previously evaluated BN analogues radiolabeled with the positron-emitter, copper-64 (64Cu), that contained various aliphatic linkers placed between the BN peptide and the 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelator. These studies showed that the analogues could be used for positron-emission tomographic (PET) imaging of GRPR-positive tumors in mice but clinical translation would be hindered by significant uptake in background tissues. Therefore, the purpose of this study was to determine if the use of amino acid linkers placed between the DOTA chelate and the BN peptide would reduce nontarget tissue uptake, while maintaining good prostate tumor uptake. The linkers studied utilized three amino acid combinations of glycine (G), serine (S), or glutamic acid (E). In vitro assays in PC-3 cells showed that the glutamic acid-containing linkers had poor binding and internalization, while the other analogues had IC50 values <100 nM and good internalization. In vivo, these same analogues demonstrated tumor-specific uptake and good imaging characteristics that were comparable to, or better than the previously reported 64Cu-labeled DOTA-BN analogues. Overall, this study shows that BN analogues containing amino acid linkers can be used for the PET imaging of GRPR-expressing prostate cancer and that these linkers lead to lower background tissue uptake.
authors.affiliation: Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Jesse J
authors.initials: JJ
authors.lastname: Parry
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Kelly
authors.forename: Rebecca
authors.initials: R
authors.lastname: Andrews
authors.forename: Buck E
authors.initials: BE
authors.lastname: Rogers
mesh_terms: D000818:Animals; D001839:Bombesin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000737:chemistry / Q000493:pharmacokinetics; D003301:Copper Radioisotopes; D005260:Female; D018698:Glutamic Acid / Q000737:chemistry / Q000493:pharmacokinetics; D005998:Glycine / Q000737:chemistry / Q000493:pharmacokinetics; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000175:diagnosis / Q000000981:diagnostic imaging / Q000378:metabolism; D011877:Radionuclide Imaging; D012694:Serine / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: D002614:Chelating Agents; D003301:Copper Radioisotopes; D006573:Heterocyclic Compounds, 1-Ring; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D018698:Glutamic Acid; D012694:Serine; D001839:Bombesin; D005998:Glycine