A heterodimeric [RGD-Glu-[(64)Cu-NO2A]-6-Ahx-RM2] αvβ3/GRPr-targeting antagonist radiotracer for PET imaging of prostate tumors.

Abstract

INTRODUCTION:

In the present study, we describe a (64)Cu-radiolabeled heterodimeric peptide conjugate for dual αvβ3/GRPr (αvβ3 integrin/gastrin releasing peptide receptor) targeting of the form [RGD-Glu-[(64)Cu-NO2A]-6-Ahx-RM2] (RGD: the amino acid sequence [Arg-Gly-Asp], a nonregulatory peptide used for αvβ3 integrin receptor targeting; Glu: glutamic acid; NO2A: 1,4,7-triazacyclononane-1,4-diacetic acid; 6-Ahx: 6-amino hexanoic acid; and RM2: (D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2), an antagonist analogue of bombesin (BBN) peptide used for GRPr targeting).

METHODS:

RGD-Glu-6Ahx-RM2] was conjugated to a NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid) complexing agent to produce [RGD-Glu-[NO2A]-6-Ahx-RM2], which was purified by reversed-phase high-performance liquid chromatography (RP-HPLC) and characterized by electrospray ionization-mass spectrometry (ESI-MS). Radiolabeling of the conjugate with (64)Cu produced [RGD-Glu-[(64)Cu-NO2A]-6-Ahx-RM2 in high radiochemical yield (≥95%). In vivo behavior of the radiolabeled peptide conjugate was investigated in normal CF-1 mice and in the PC-3 human prostate cancer experimental model.

RESULTS:

A competitive displacement receptor binding assay in human prostate PC-3 cells using (125)I-[Tyr(4)]BBN as the radioligand showed high binding affinity of [RGD-Glu-[(nat)Cu-NO2A]-6-Ahx-RM2] conjugate for the GRPr (3.09±0.34 nM). A similar assay in human, glioblastoma U87-MG cells using (125)I-Echistatin as the radioligand indicated a moderate receptor-binding affinity for the αvβ3 integrin (518±37.5 nM). In vivo studies of [RGD-Glu-[(64)Cu-NO2A]-6-Ahx-RM2] showed high accumulation (4.86±1.01 %ID/g, 1h post-intravenous injection (p.i.)) and prolonged retention (4.26±1.23 %ID/g, 24h p.i.) of tracer in PC-3 tumor-bearing mice. Micro-positron emission tomography (microPET) molecular imaging studies produced high-quality, high contrast images in PC-3 tumor-bearing mice at 4h p.i.

CONCLUSIONS:

The favorable pharmacokinetics and enhanced tumor uptake of (64)Cu-NOTA-RGD-Glu-6Ahx-RM2 warrant further investigations for dual integrin and GRPr-positive tumor imaging and possible radiotherapy.

• Authors: Kubra Durkan, Zongrun Jiang, Tammy L Rold, Gary L Sieckman, Timothy J Hoffman, Rajendra Prasad Bandari, Ashley F Szczodroski, Liqin Liu, Yubin Miao, Tamila Stott Reynolds, Charles J Smith
• Journal: Nuclear medicine and biology (Nucl Med Biol) Vol. 41 Issue 2 Pg. 133-9 (Feb 2014) ISSN: 1872-9614 [Electronic] United States
• PMID: 24480266 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Copper Radioisotopes
• Heterocyclic Compounds
• Heterocyclic Compounds, 1-Ring
• Integrin alphaVbeta3
• Oligopeptides
• Radioactive Tracers
• Receptors, Bombesin
• 1,4,7-triazacyclononane-N,N',N''-triacetic acid
• arginyl-glycyl-aspartic acid
• Aminocaproic Acid

Topics

• Aminocaproic Acid
• Animals
• Cell Line, Tumor
• Cell Transformation, Neoplastic
• Copper Radioisotopes
• Dimerization
• Female
• Heterocyclic Compounds (chemistry)
• Heterocyclic Compounds, 1-Ring
• Humans
• Integrin alphaVbeta3 (metabolism)
• Male
• Mice
• Oligopeptides (chemistry, metabolism, pharmacokinetics)
• Positron-Emission Tomography (methods)
• Prostatic Neoplasms (diagnostic imaging, pathology)
• Radioactive Tracers
• Receptors, Bombesin (antagonists & inhibitors, metabolism)