Bombesin Antagonist–Based Radioligands for Translational Nuclear Imaging of Gastrin-Releasing Peptide Receptor–Positive Tumors

Abstract

The chelators do influence the affinity, antagonistic potency, and pharmacokinetics of the conjugates. The promising preclinical results warrant clinical translation of these probes for SPECT and PET.

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

“…This finding was also extended to GRPR antagonists, with the seminal work of Cescato et al (11). Recently, more articles have appeared showing the promise of novel radiolabeled GRPR antagonists for GRPR-positive tumor imaging (12,(16)(17)(18)25). The studies revealed favorable pharmacokinetics of radiolabeled antagonists, including high tumor uptake and fast clearance from nontargeted tissues.…”

“…Several GRPR antagonists have since been developed by the modification of C-terminal residues of GRPR agonists, including the statinbased BBN analog, JMV594 (H-D-Phe-Gln-Trp-Ala-Val-GlyHis-Sta-Leu-NH 2 ) (15). 68 Ga-labeled GRPR antagonists were developed for PET imaging, showing good targeting properties in preclinical studies (12,(16)(17)(18) and recently also in clinical trials (19,20). Clinical evaluation of the 68 Ga-labeled GRPR antagonist BAY86-7548 ( 68 Ga-DOTA-4-amino-1-carboxymethylpiperidine-D-Phe-Gln-TrpAla-Val-Gly-His-Sta-Leu-NH 2 ) has shown a specificity, sensitivity, and accuracy of 88%, 81%, and 83%, respectively, for the detection of primary PCa.…”

Synthesis and Characterization of a High-Affinity NOTA-Conjugated Bombesin Antagonist for GRPR-Targeted Tumor Imaging

“…Bombesin analog NOTA-PEG 2 -[D-Phe 6 ,Sta 13 ,Leu 14 ]bombesin [6][7][8][9][10][11][12][13][14] (further denoted as NOTA-P2-RM26, see Chart) was synthesized by standard manual solid-phase peptide synthesis 17 as described in Supplementary material 1.…”

“…It has been demonstrated earlier that positively charged at the N-terminus bombesin agonists exhibit higher affinities to the GRP receptors, while a negative charge decreases the affinity. 12,22 The overall charge of a complex of dianionic NOTA with indium or gallium is +1. This positive charge can explain the more than 4-fold lower IC 50 values for metal loaded analogs compared with non-loaded peptide in our study.…”

“…To overcome these drawbacks BN antagonistic analogs with growth-inhibitory effect on tumors have been introduced. 12,13 It was found that GRPR antagonists have more binding sites than agonists, which made them preferable for peptide receptor targeting of tumors. 14 More binding sites for radioconjugates may enhance localization accuracy, especially in small lesions and tumors with low receptor-expression.…”