Preclinical Comparison of Al18F- and 68Ga-Labeled Gastrin-Releasing Peptide Receptor Antagonists for PET Imaging of Prostate Cancer

K. Chatalic, G. Franssen, W. van Weerden, W. McBride, P. Laverman, E. de Blois, B. Hajjaj, L. Brunel, D. Goldenberg, J. Fehrentz, J. Martinez, O. Boerman and M. de Jong

Erasmus MC;
dec, 2014



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-ᴅ-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2], JMV4168 is DOTA-βAla-βAla-[H-ᴅ-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).The GRPR antagonist JMV594 (H-ᴅ-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.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(18)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.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.