Preclinical comparison of Al18F- and 68Ga-labeled gastrin-releasing peptide receptor antagonists for PET imaging of prostate cancer.

Abstract

UNLABELLED:

Gastrin-releasing peptide receptor (GRPR) is overexpressed in human prostate cancer and is being used as a target for molecular imaging. In this study, we report on the direct comparison of 3 novel GRPR-targeted radiolabeled tracers: Al(18)F-JMV5132, (68)Ga-JMV5132, and (68)Ga-JMV4168 (JMV5132 is NODA-MPAA-βAla-βAla-[H-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2], JMV4168 is DOTA-βAla-βAla-[H-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2], and NODA-MPAA is 2-[4-(carboxymethyl)-7-{[4-(carboxymethyl)phenyl]methyl}-1,4,7-triazacyclononan-1-yl]acetic acid).

METHODS:

The GRPR antagonist JMV594 (H-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2) was conjugated to NODA-MPAA for labeling with Al(18)F. JMV5132 was radiolabeled with (68)Ga and (18)F, and JMV4168 was labeled with (68)Ga for comparison. The inhibitory concentration of 50% values for binding GRPR of JMV4168, JMV5132, (nat)Ga-JMV4168, and (nat)Ga-JMV5132 were determined in a competition-binding assay using GRPR-overexpressing PC-3 tumors. The tumor-targeting characteristics of the compounds were assessed in mice bearing subcutaneous PC-3 xenografts. Small-animal PET/CT images were acquired, and tracer biodistribution was determined by ex vivo measurements.

RESULTS:

JMV5132 was labeled with (18)F in a novel 1-pot, 1-step procedure within 20 min, without need for further purification and resulting in a specific activity of 35 MBq/nmol. Inhibitory concentration of 50% values (in nM) for GRPR binding of JMV5132, JMV4168, (nat)Ga-JMV5132, (nat)Ga-JMV4168, and Al(nat)F-JMV5132 were 6.8 (95% confidence intervals [CIs], 4.6-10.0), 13.2 (95% CIs, 5.9-29.3), 3.0 (95% CIs, 1.5-6.0), 3.2 (95% CIs, 1.8-5.9), and 10.0 (95% CIs, 6.3-16.0), respectively. In mice with subcutaneous PC-3 xenografts, all tracers cleared rapidly from the blood, exclusively via the kidneys for (68)Ga-JMV4168 and partially hepatobiliary for (68)Ga-JMV5132 and Al(18)F-JMV5132. Two hours after injection, the uptake of (68)Ga-JMV4168, (68)Ga-JMV5132, and Al(18)F-JMV5132 in PC-3 tumors was 5.96 ± 1.39, 5.24 ± 0.29, 5.30 ± 0.98 (percentage injected dose per gram), respectively. GRPR specificity was confirmed by significantly reduced tumor uptake of the 3 tracers after coinjection of a 100-fold excess of unlabeled JMV4168 or JMV5132. Small-animal PET/CT clearly visualized PC-3 tumors, with the highest resolution observed for Al(18)F-JMV5132.

CONCLUSION:

JMV5132 could be rapidly and efficiently labeled with (18)F. Al(18)F-JMV5132, (68)Ga-JMV5132, and (68)Ga-JMV4168 all showed comparable high and specific accumulation in GRPR-positive PC-3 tumors. These new PET tracers are promising candidates for future clinical translation.

• Authors: Kristell L S Chatalic, Gerben M Franssen, Wytske M van Weerden, William J McBride, Peter Laverman, Erik de Blois, Bouchra Hajjaj, Luc Brunel, David M Goldenberg, Jean-Alain Fehrentz, Jean Martinez, Otto C Boerman, Marion de Jong
• Journal: Journal of nuclear medicine : official publication, Society of Nuclear Medicine (J Nucl Med) Vol. 55 Issue 12 Pg. 2050-6 (Dec 2014) ISSN: 1535-5667 [Electronic] United States
• PMID: 25413139 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Chemical References

• 68Ga-JMV4168
• 68Ga-JMV5132
• Al18F-JMV5132
• Aluminum Compounds
• Coordination Complexes
• Fluorine Radioisotopes
• Gallium Radioisotopes
• Peptides
• Radiopharmaceuticals
• Receptors, Bombesin
• Fluorides
• aluminum fluoride

Topics

• Aluminum Compounds (chemistry)
• Animals
• Cell Line, Tumor
• Coordination Complexes (chemistry, pharmacokinetics)
• Fluorides (chemistry)
• Fluorine Radioisotopes (chemistry)
• Gallium Radioisotopes (chemistry)
• Humans
• Male
• Mice
• Mice, Inbred BALB C
• Peptides (chemistry, pharmacokinetics)
• Positron-Emission Tomography (methods)
• Prostatic Neoplasms (diagnostic imaging)
• Radiopharmaceuticals (chemistry, pharmacokinetics)
• Receptors, Bombesin (antagonists & inhibitors)
• Tissue Distribution
• Whole Body Imaging