Nuclear Imaging of Prostate Cancer with Gastrin-Releasing-Peptide- Receptor Targeted Radiopharmaceuticals

Abstract

Prostate cancer is one of the most common causes of cancer in men. Evaluating the different stages of prostate cancer with conventional imaging techniques still proves difficult. Nuclear imaging might provide a technique that is able to evaluate prostate cancer, but clinical application has been limited due to lack of accuracy of current radiopharmaceuticals. The development of radiopharmaceuticals that can be targeted to specific antigens, overexpressed in prostate cancer, but sparse in normal tissue, is crucial. Peptides are of particular interest because of their favourable characteristics, leading to increased attention for nuclear imaging of the gastrin-releasing-peptide-receptor (GRPR) with radiolabelled bombesin-like peptides. Several derivatives of bombesin and its truncated form have been prepared for imaging with single photon emission computed tomography (SPECT) or positron emission tomography (PET), thereby delivering potent candidates for further clinical evaluation. This article provides an overview of the development and preclinical evaluation of radiolabelled bombesin analogues for in vivo targeting of GRPR in prostate cancer. The effect of the radionuclide, chelator, spacer and unnatural amino acids on affinity, metabolic stability and image quality are discussed, as well as agonistic or antagonistic properties. Potent candidates are proposed based on these selection criteria: (I) high affinity for GRPR, with rapid and specific tumour uptake (II) high hydrophilicity resulting in the preferred renal-urinary mode of excretion and low hepatobiliary excretion, (III) high stability, but relatively rapid clearance from blood. Also, a summary is made of clinical studies that report on the detection of prostate cancer with GRPR targeted radiopharmaceuticals.

Alpha- versus Beta-Particle Radiopeptide Therapy in a Human Prostate Cancer Model (213Bi-DOTA-PESIN and 213Bi-AMBA versus177Lu-DOTA-PESIN)

“…However, in the present study, no significant decrease in renal uptake was noted after either of these pretreatments because 213 Bi-DOTA-PESIN renal uptake is relatively low (highest tumor-to-kidney ratios among bombesin analogues; ref. 30).…”

“…Despite these promising results, there are potentially limiting factors that have to be taken into account when considering therapeutic applications of GRP analogues. Preliminary results in clinical studies have shown a high accumulation in the small/large intestine and relatively low uptake in tumor lesions when labeled with 99m Tc (30). The low accumulation in tumor lesions may be due to a low metabolic stability of these radiopeptides, and excretion via the hepatobiliary tract is caused by high lipophilicity.…”

PSMA, EpCAM, VEGF, and GRPR as imaging targets in locally recurrent prostate cancer after radiotherapy.

“…Staining of normal prostate and muscle with the anti-GRPR antibody has been described in the literature by other authors [60][61][62], and at first glance, this might pose a problem for the future use of GRPR as a target for new therapeutic or diagnostic modalities. However, pre-clinical and clinical studies have shown very low uptake of GRPR-targeted bombesin-like radiopharmaceuticals in muscle with high tumor-to-muscle ratios [70].…”

“…Several clinical studies with PSMA as the target have been reported with encouraging results [71,72]. Bombesin-like radiopharmaceuticals, which are natural ligands of GRPR, can be relatively easy synthesized in large quantities and have shown promising results in several clinical studies [70]. However, due to its background staining, more careful selection of the protocol may be required for optimal targeting.…”

New Agonist- and Antagonist-Based Treatment Approaches for Advanced Prostate Cancer

“…32 Tc-bombesin, a radioactive signal was found in the prostate tumour region within 4 min after intravenous administration of 0.7 µg 99m Tc-bombesin. 36 To 38 Cytotoxic analogues of bombesin are also being investigated because receptors for bombesin-like peptides are present on a wide variety of tumours, including prostate cancer tumours. 15 AN-215, a cytotoxic analogue of bombesin, has been shown to have a powerful inhibitory effect on the growth of PC-3 androgen-independent prostate cancers.…”