Synthesis and radiopharmacological evaluation of 64Cu-labeled bombesin analogs featuring a bis(2-pyridylmethyl)-1,4,7-triazacyclononane chelator

Ralf Bergmann, A Ruffani, Bimbil Graham, Leone Spiccia, Jorg Steinbach, J Pietzsch, Holger Stephan

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27 Citations (Scopus)


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, ?Ala-?Ala-[Cha 13,Nle14]BBN(7-14) and ?homo-Glu-?Ala-?Ala- [Cha13,Nle14]BBN(7-14) have been coupled to DMPTACN-COOH and radiolabeled with the positron emitter copper-64 (64Cu-1 and 64Cu-3). The in vitro binding characteristics of the [ 64Cu]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 64Cu-1 and 64Cu-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 64Cu-1 and 64Cu-3. Incorporation of a single additional glutamic acid residue within the spacer between bombesin and the radiolabeled complex ( 64Cu-3) leads to a higher tumor-to-muscle uptake ratio (amounting to >30 at 100 min post injection) compared to 64Cu-1.
Original languageEnglish
Pages (from-to)434 - 446
Number of pages13
JournalEuropean Journal of Medicinal Chemistry
Publication statusPublished - 2013

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