Optimization, biological evaluation and microPET imaging of copper-64-labeled bombesin agonists, [64Cu-NO2A-(X)-BBN(7-14)NH2], in a prostate tumor xenografted mouse model.

Abstract

UNLABELLED:

Gastrin-releasing peptide receptors (GRPr) are a member of the bombesin (BBN) receptor family. GRPr are expressed in high numbers on specific human cancers, including human prostate cancer. Therefore, copper-64 ((64)Cu) radiolabeled BBN(7-14)NH(2) conjugates could have potential for diagnosis of human prostate cancer via positron-emission tomography (PET). The aim of this study was to produce [(64)Cu-NO2A-(X)-BBN(7-14)NH(2)] conjugates for prostate cancer imaging, where X=pharmacokinetic modifier (beta-alanine, 5-aminovaleric acid, 6-aminohexanoic acid, 8-aminooctanoic acid, 9-aminonanoic acid or para-aminobenzoic acid) and NO2A=1,4,7-triazacyclononane-1,4-diacetic acid [a derivative of NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid)].

METHODS:

[(X)-BBN(7-14)NH(2)] Conjugates were synthesized by solid-phase peptide synthesis (SPPS), after which NOTA was added via manual conjugation. The new peptide conjugates were radiolabeled with (64)Cu radionuclide. The receptor-binding affinity was determined in human prostate PC-3 cells, and tumor-targeting efficacy was determined in PC-3 tumor-bearing severely combined immunodeficient (SCID) mice. Whole-body maximum intensity microPET/CT images of PC-3 tumor-bearing SCID mice were obtained 18 h postinjection (pi).

RESULTS:

Competitive binding assays in PC-3 cells indicated high receptor-binding affinity for the [NO2A-(X)-BBN(7-14)NH(2)] and [(nat)Cu-NO2A-(X)-BBN(7-14)NH(2)] conjugates. In vivo biodistribution studies of the [(64)Cu-NO2A-(X)-BBN(7-14)NH(2)] conjugates at 1, 4 and 24 h pi showed very high uptake of the tracer in GRPr-positive tissue with little accumulation and retention in nontarget tissues. High-quality, high-contrast microPET images were obtained, with xenografted tumors being clearly visible at 18 h pi.

CONCLUSIONS:

NO2A chelator sufficiently stabilizes copper(II) radiometal under in vivo conditions, producing conjugates with very high uptake and retention in targeted GRPr. Preclinical evaluation of these new peptide conjugates in tumor-bearing mice provides some impetus for clinical evaluation in human patients.

• Authors: Stephanie R Lane, Prasanta Nanda, Tammy L Rold, Gary L Sieckman, Said D Figueroa, Timothy J Hoffman, Silvia S Jurisson, Charles J Smith
• Journal: Nuclear medicine and biology (Nucl Med Biol) Vol. 37 Issue 7 Pg. 751-61 (Oct 2010) ISSN: 1872-9614 [Electronic] United States
• PMID: 20870150 (Publication Type: Evaluation Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2010 Elsevier Inc. All rights reserved.

Chemical References

• Copper Radioisotopes
• Heterocyclic Compounds, 1-Ring
• Radiopharmaceuticals
• Bombesin

Topics

• Animals
• Bombesin (chemistry)
• Copper Radioisotopes
• Heterocyclic Compounds, 1-Ring
• Humans
• Male
• Mice
• Mice, Nude
• Positron-Emission Tomography
• Prostatic Neoplasms (diagnostic imaging, metabolism)
• Radiopharmaceuticals
• Tissue Distribution
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays