^99mTc Radiotracers Based on Human GRP(18-27): Synthesis and Comparative Evaluation

Abstract

Gastrin-releasing peptide receptors (GRPRs) expressed on human tumors can serve as molecular targets for radiolabeled peptide analogs based on the frog tetradecapeptide bombesin (BBN). We have recently expanded this approach toward human GRP(18-27) sequences and introduced 99m Tc-demomedin C, our first radiotracer based on , showing favorable biologic characteristics during preclinical evaluation in rodents. We now present a series of 99m Tc-demomedin C analogs, generated by single-Gly 24 or double-Gly 24 /Met 27 substitutions in the peptide chain, and compare their performance in GRPR-positive in vitro and in vivo models. at 4 h after injection). 99m Tc-SARNC6 displayed the highest tumor-to-nontumor ratios followed by 99m Tc-SARNC2. Conclusion: This structure-activity relationship study has shown the impact of single-Gly 24 or double-Gly 24 /Met 27 substitutions in the 99m Tc-SARNC1 motif on key biologic parameters, including GRPR affinity, internalization efficiency, and in vivo stability, which eventually determine the pharmacokinetic profile of resulting radiopeptides. By revealing improved analogs, this study has strengthened the applicability perspectives of radioligands based on human GRP sequences in the detection and therapy of GRPRexpressing tumors in humans.

In Vivo Enzyme Inhibition Improves the Targeting of [177Lu]DOTA-GRP(13–27) in GRPR-Positive Tumors in Mice

“…18 This radiotracer, once exposed to proteolytic enzymes within the body, was rapidly degraded due to the higher number of possible cleavage sites in the natural peptide motif compared to the GRP (18)(19)(20)(21)(22)(23)(24)(25)(26)(27) peptide analog ([ 99m Tc]Demomedin C). 19 Increased resistance to such proteolytic activity might translate into prolonged circulation of radiolabeled peptide analogs preferably leading to higher receptor targeting as well as higher tumor uptake of radioactivity in tumor lesions. One of the most prominent proteases in the degradation process of radiopeptides from different peptide families is the enzyme neutral endopeptidase (NEP, EC 3.4.24.11).…”

Theranostic Perspectives in Prostate Cancer with the Gastrin-Releasing Peptide Receptor Antagonist NeoBOMB1: Preclinical and First Clinical Results

“…The first-generation radiopeptides developed for such purposes were GRPR agonists derived from C-terminal fragments of the amphibian tetradecapeptide bombesin (BBN) (7)(8)(9)(10)(11)(12) or the respective human 27mer peptide GRP (13)(14)(15). The use of resulting radioligands in humans was soon linked to undesirable effects after agonist-induced GRPR activation (16).…”

“…Following this rationale, we have initially developed 99m Tcdemobesin 1 ( 99m Tc-DB1), a GRPR antagonist radioligand for SPECT imaging, labeled with 99m Tc and containing the [DPhe 6 , Leu-NHEt 13 ,des-Met 14 ]BBN (6)(7)(8)(9)(10)(11)(12)(13)(14) peptide fragment (17,18). To allow labeling with other clinically relevant radiometals, we then replaced the acyclic tetraamine chelator of DB1 by the universal chelator DOTA.…”

“…Truncation of C-terminal Met 14 -NH 2 and alkylation of the Leu 13 NH 2 amide is only one of many C-terminus modifications in the BBN (6)(7)(8)(9)(10)(11)(12)(13)(14) motif, shown to convey antagonistic properties to resulting receptor ligands. For example, replacement of the C-terminal Leu 13 -Met 14 -NH 2 dipeptide by Sta 13 -Leu 14 -NH 2 and coupling of DOTA has recently fostered the development of promising GRPR radioantagonists (20,21,25).…”

GEP-NETs update: Functional localisation and scintigraphy in neuroendocrine tumours of the gastrointestinal tract and pancreas (GEP-NETs)

“…Not only somatostatin receptor agonists but also receptor antagonists are being studied (96). Other peptide receptors might also be interesting targets for receptor imaging, such as the gastrin-releasing peptide or bombesin receptors (97,98,99).…”