title: Synthesis and radiopharmacological evaluation of ⁶⁴Cu-labeled bombesin analogs featuring a bis(2-pyridylmethyl)-1,4,7-triazacyclononane chelator.
abstract: The bifunctional chelating agent 2-[4,7-bis(2-pyridylmethyl)-1,4,7-triazacyclononan-1-yl]acetic acid, DMPTACN-COOH, has been found to bind strongly to copper(II), resulting in a radiocopper(II)-ligand complex that exhibits high in vivo stability. The pendant carboxylic acid group enables this derivative to be conjugated to the N-terminal amino acid residues of peptides. Exploiting this, two stabilized bombesin (BBN) derivatives, βAla-βAla-[Cha(13),Nle(14)]BBN(7-14) and βhomo-Glu-βAla-βAla-[Cha(13),Nle(14)]BBN(7-14) have been coupled to DMPTACN-COOH and radiolabeled with the positron emitter copper-64 ((64)Cu-1 and (64)Cu-3). The in vitro binding characteristics of the [(64)Cu]Cu-labeled bombesin conjugates in gastrin-releasing peptide receptor (GRPR) over-expressing prostate cancer (PC-3) cells have been evaluated. Biodistribution studies performed in Wistar rats indicate a specific uptake in the GRPR-rich pancreas and rapid renal elimination for both (64)Cu-1 and (64)Cu-3. Small animal PET imaging studies performed in NMRI nu/nu mice bearing the human prostate tumor PC-3 demonstrated a very high degree of tumor accumulation for (64)Cu-1 and (64)Cu-3. Incorporation of a single additional glutamic acid residue within the spacer between bombesin and the radiolabeled complex ((64)Cu-3) leads to a higher tumor-to-muscle uptake ratio (amounting to >30 at 100 min post injection) compared to (64)Cu-1.
authors.affiliation: Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, P.O. Box 510119, 01314 Dresden, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Bergmann
authors.forename: A
authors.initials: A
authors.lastname: Ruffani
authors.forename: B
authors.initials: B
authors.lastname: Graham
authors.forename: L
authors.initials: L
authors.lastname: Spiccia
authors.forename: J
authors.initials: J
authors.lastname: Steinbach
authors.forename: J
authors.initials: J
authors.lastname: Pietzsch
authors.forename: H
authors.initials: H
authors.lastname: Stephan
mesh_terms: D000818:Animals; D001839:Bombesin / Q000737:chemistry / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000737:chemistry / Q000493:pharmacokinetics; D003301:Copper Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D011471:Prostatic Neoplasms / Q000737:chemistry* / Q000175:diagnosis / Q000378:metabolism; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D018004:Receptors, Bombesin / Q000096:biosynthesis; D014018:Tissue Distribution
chemical_list: D002614:Chelating Agents; D003301:Copper Radioisotopes; D019275:Radiopharmaceuticals; D018004:Receptors, Bombesin; D001839:Bombesin
keywords: Bombesin (BBN); Copper-64; Gastrin-releasing peptide receptors; Human prostate adenocarcinoma cells (PC-3); JBGKGUKDMCUNFQ-UHFFFAOYSA-N; QFPVUEQQDDAEQA-UHFFFAOYSA-N; Small animal positron emission tomography; XMGBKKSMXQSOJK-UHFFFAOYSA-N