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

Abstract

International audienceGastrin-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: Al18F-JMV5132, 68Ga-JMV5132, and 68Ga-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 Al18F. JMV5132 was radiolabeled with 68Ga and 18F, and JMV4168 was labeled with 68Ga for comparison. The inhibitory concentration of 50% values for binding GRPR of JMV4168, JMV5132, natGa-JMV4168, and natGa-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 18F 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, natGa-JMV5132, natGa-JMV4168, and AlnatF-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 68Ga-JMV4168 and partially hepatobiliary for 68Ga-JMV5132 and Al18F-JMV5132. Two hours after injection, the uptake of 68Ga-JMV4168, 68Ga-JMV5132, and Al18F-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 Al18F-JMV5132. Conclusion: JMV5132 could be rapidly and efficiently labeled with 18F. Al18F-JMV5132, 68Ga-JMV5132, and 68Ga-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

Radiolabeled B9958 Derivatives for Imaging Bradykinin B1 Receptor Expression with Positron Emission Tomography: Effect of the Radiolabel–Chelator Complex on Biodistribution and Tumor Uptake

“…6 By conjugating Ga-DOTA-dPEG2 (dPEG2: 9-amino-4,7-dioxanonanoic acid) at the N-terminus, we recently reported that B9958 (Lys-[Hyp 4 ,Cpg 6 ,D-Tic 8 ,Cpg 9 ,des-Arg 10 ]kallidin) was superior to B9858 (Lys-[Hyp 4 ,Igl 6 ,D-Igl 8 ,Oic 9 ,des-Arg 10 ]kallidin) and [Hyp 4 ,Cha 6 ,Leu 9 ,desArg 10 ]kallidin as the targeting vector for the design of B1R imaging agents ( 68 Ga-Z02090 vs. 68 Ga-P04158 and 68 Ga-P03034, Table 1). 7 In a separate study by conjugating the AmBF 3 -Mta (4-(N-trifluoroborylmethyl-N,N-dimethylammonio)methyl-1,2,3-triazole-1-acetic acid) moiety at the N-terminus, we further confirmed that the B9958 derivative 18 F-L08060 (previously called 18 F-AmBF 3 -B9958, Table 1) was preferable to the B9858 derivative 18 F-L08064 (previously called 18 F-AmBF 3 -B9858, Table 1) for imaging B1R expression in xenografted tumors. 8 The aim of this study was to investigate if the tumor uptake and tumor-to-background contrast ratios could be further improved via the selection of radiolabel-chelator complexes ( 68 Ga-DOTA, 68 Ga-NODA and 18 F-AlF-NODA) coupled to the preferred B9958 sequence and the cationic linker Pip.…”

“…7 In a separate study by conjugating the AmBF 3 -Mta (4-(N-trifluoroborylmethyl-N,N-dimethylammonio)methyl-1,2,3-triazole-1-acetic acid) moiety at the N-terminus, we further confirmed that the B9958 derivative 18 F-L08060 (previously called 18 F-AmBF 3 -B9958, Table 1) was preferable to the B9858 derivative 18 F-L08064 (previously called 18 F-AmBF 3 -B9858, Table 1) for imaging B1R expression in xenografted tumors. 8 The aim of this study was to investigate if the tumor uptake and tumor-to-background contrast ratios could be further improved via the selection of radiolabel-chelator complexes ( 68 Ga-DOTA, 68 Ga-NODA and 18 F-AlF-NODA) coupled to the preferred B9958 sequence and the cationic linker Pip. Herein, we present the synthesis and comparative evaluation of three new tracers ( Fig.…”

A Novel 111In-Labeled Anti–Prostate-Specific Membrane Antigen Nanobody for Targeted SPECT/CT Imaging of Prostate Cancer

“…Binding of 111 In-JVZ-007-c-myc-his and 111 In-JVZ-007-cys to frozen cryostat section of PDXs and kidneys (mouse/human) was evaluated using autoradiography, as described previously (19). Tissue sections were incubated for 1 h with 111 In-JVZ-007-c-myc-his or 111 In-JVZ-007-cys (10 29 M).…”

Radiopeptides for Imaging and Therapy: A Radiant Future

“…An interesting approach consists of labeling peptides with Al 18 F via radiometalation chemistry. Several peptides have been labeled with Al 18 F, such as octreotide, E[c(RGDyK)] 2 , exendin-4, the bombesin analog NOTA-8-Aoc-BBN(7-14)NH 2 , and the GRPR antagonist JMV4168 (DOTA-bAla-bAla-JMV594) (7,8). The development of a kit-based method for labeling peptides with 18 F would make application of 18 F-labeled peptides possible in a wider range of hospitals.…”