[64Cu-NOTA-8-Aoc-BBN(7-14)NH2] targeting vector for positron-emission tomography imaging of gastrin-releasing peptide receptor-expressing tissues.

Abstract

Radiolabeled peptides hold promise as diagnostic/therapeutic targeting vectors for specific human cancers. We report the design and development of a targeting vector, [(64)Cu-NOTA-8-Aoc-BBN(7-14)NH(2)] (NOTA = 1,4,7-triazacyclononane-1,4,7-triacetic acid, 8-Aoc = 8-aminooctanoic acid, and BBN = bombesin), having very high selectivity and affinity for the gastrin-releasing peptide receptor (GRPr). GRPrs are expressed on a variety of human cancers, including breast, lung, pancreatic, and prostate, making this a viable approach toward site-directed localization or therapy of these human diseases. In this study, [NOTA-X-BBN(7-14)NH(2)] conjugates were synthesized, where X = a specific pharmacokinetic modifier. The IC(50) of [NOTA-8-Aoc-BBN(7-14)NH(2)] was determined by a competitive displacement cell-binding assay in PC-3 human prostate cancer cells using (125)I-[Tyr(4)]-BBN as the displacement ligand. An IC(50) of 3.1 +/- 0.5 nM was obtained, demonstrating high binding affinity of [NOTA-8-Aoc-BBN] for the GRPr. [(64)Cu-NOTA-X-BBN] conjugates were prepared by the reaction of (64)CuCl(2) with peptides in buffered aqueous solution. In vivo studies of [(64)Cu-NOTA-8-Aoc-BBN(7-14)NH(2)] in tumor-bearing PC-3 mouse models indicated very high affinity of conjugate for the GRPr. Uptake of conjugate in tumor was 3.58 +/- 0.70% injected dose (ID) per g at 1 h postintravenous injection (p.i.). Minimal accumulation of radioactivity in liver tissue (1.58 +/- 0.40% ID per g, 1 h p.i.) is indicative of rapid renal-urinary excretion and suggests very high in vivo kinetic stability of [(64)Cu-NOTA-8-Aoc-BBN(7-14)NH(2)] with little or no in vivo dissociation of (64)Cu(2+) from the NOTA chelator. Kidney accumulation at 1 h p.i. was 3.79 +/- 1.09% ID per g. Molecular imaging studies in GRPr-expressing tumor models produced high-contrast, high-quality micro-positron-emission tomography images.

• Authors: Adam F Prasanphanich, Prasant K Nanda, Tammy L Rold, Lixin Ma, Michael R Lewis, Jered C Garrison, Timothy J Hoffman, Gary L Sieckman, Said D Figueroa, Charles J Smith
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 104 Issue 30 Pg. 12462-7 (Jul 24 2007) ISSN: 0027-8424 [Print] United States
• PMID: 17626788 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• 64Cu-1,4,7-triazacyclononane-1,4,7-triacetic acid-8-aminooctanoic acid-bombesin(7-14)amide
• Boron Compounds
• Heterocyclic Compounds, 1-Ring
• Methacrylates
• Methylmethacrylates
• Peptide Fragments
• Receptors, Bombesin
• Super-bond

Topics

• Animals
• Boron Compounds
• Cell Line, Tumor
• Heterocyclic Compounds, 1-Ring (chemistry, isolation & purification, pharmacokinetics)
• Humans
• Methacrylates
• Methylmethacrylates
• Mice
• Mice, SCID
• Molecular Structure
• Neoplasms (diagnosis, metabolism)
• Organ Specificity (drug effects)
• Peptide Fragments (chemistry, isolation & purification, pharmacokinetics)
• Positron-Emission Tomography (methods)
• Receptors, Bombesin (metabolism)
• Xenograft Model Antitumor Assays