TY - JOUR
T1 - Synthesis and radiopharmacological evaluation of 64Cu-labeled bombesin analogs featuring a bis(2-pyridylmethyl)-1,4,7-triazacyclononane chelator
AU - Bergmann, Ralf
AU - Ruffani, A
AU - Graham, Bimbil
AU - Spiccia, Leone
AU - Steinbach, Jorg
AU - Pietzsch, J
AU - Stephan, Holger
PY - 2013
Y1 - 2013
N2 - 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.
AB - 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.
UR - http://www.sciencedirect.com.ezproxy.lib.monash.edu.au/science/article/pii/S0223523413006545
U2 - 10.1016/j.ejmech.2013.10.013
DO - 10.1016/j.ejmech.2013.10.013
M3 - Article
SN - 0223-5234
VL - 70
SP - 434
EP - 446
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
ER -