Targeting prostate cancer with radiolabelled bombesins

Abstract

The fact that a number of common human tumours, including those of breast and prostate, express increased levels of the gastrin-releasing peptide receptor (GRP-R) means that this receptor is a potential target for peptide receptor mediated scintigraphy and targeted radionuclide therapy. Although clinical application is yet in its infancy, there is a considerable literature on preclinical studies aimed at developing suitable radioligands for potential clinical application. This brief review provides an overview of this research and also describes some of the limited clinical studies that have been published.

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).…”

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

“…In recent years, amphibian BBN-based radioligands have been studied at length as molecular tools to diagnose and treat GRPR-positive cancer (e.g., prostate, breast, and lung) in humans (1,2,9,12,15). In principle, this approach can be successful in targeting both primary and metastatic disease not only when the high density of GRPR expression in malignant lesions is maintained but also when the applied radioligands fulfill important prerequisites, such as availability in high specific activity, good receptor affinity and internalization ability, stability in the biologic milieu, and favorable pharmacokinetics to achieve high tumor-to-background ratios.…”

“…Anal ogs of the frog tetradecapeptide bombesin (BBN) have been exploited as molecular vehicles to direct diagnostic and therapeutic radionuclides to human primary and metastatic cancer (1)(2)(3). This approach relies on the high-density expression of gastrin-releasing peptide receptors (GRPRs) in many frequently occurring human cancers, such as prostate cancer, mammary carcinoma, or small cell lung cancer, as opposed to their lower abundance or lack of expression in surrounding healthy tissue (4)(5)(6)(7)(8)(9).…”