Update on Preclinical Development and Clinical Translation of Cholecystokinin-2 Receptor Targeting Radiopharmaceuticals

Elisabeth Von Guggenberg,Christof Rottenburger,Renata Mikołajczak,Petra Kolenc,Alicja Hubalewska-Dydejczyk

doi:10.3390/cancers13225776

Abstract

Simple SummaryPeptide analogs, derived from the natural peptide hormone gastrin, are promising candidates for improving the visualization and treatment of tumors. Gastrin specifically binds to the cholecystokinin-2 receptor, a G-protein-coupled receptor expressed on the cell surface of different tumors. This enables specific targeting of tumor cells using gastrin analogs, labeled with radioisotopes. The receptor is expressed at high incidence in medullary thyroid carcinoma, a rare form of thyroid cancer lacking effective treatments at an advanced stage. Different radiolabeled gastrin analogs as well as nonpeptidic compounds targeting CCK2R have been developed. Specific modifications have been introduced in order to safely deliver the radiation to the tumor site. In this review, recent strategies applied to improve the targeting properties are described. These developments enabled the introduction of new radiolabeled peptide analogs for imaging and therapy in cancer patients. In addition to highlighting the current clinical trials, the perspectives for future applications are given.The cholecystokinin-2 receptor (CCK2R) has been a target of interest for molecular imaging and targeted radionuclide therapy for two decades. However, so far CCK2R targeted imaging and therapy has not been introduced in clinical practice. Within this review the recent radiopharmaceutical development of CCK2R targeting compounds and the ongoing clinical trials are presented. Currently, new gastrin derivatives as well as nonpeptidic substances are being developed to improve the properties for clinical use. A team of specialists from the field of radiopharmacy and nuclear medicine reviewed the available literature and summarized their own experiences in the development and clinical testing of CCK2R targeting radiopharmaceuticals. The recent clinical trials with novel radiolabeled minigastrin analogs demonstrate the potential for both applications, imaging as well as targeted radiotherapy, and reinforce the clinical applicability within a theranostic concept. The intense efforts in optimizing CCK2R targeting radiopharmaceuticals has led to new substances for clinical use, as shown in first imaging studies in patients with advanced medullary thyroid cancer. The first clinical results suggest that the wider clinical implication of CCK2R-targeted radiopharmaceuticals is reasonable.

Highlights

The cholecystokinin-2 receptor (CCK2R) is a promising target for theranostic use in nuclear medicine, and has been in the focus of the radiopharmaceutical development over the last twenty years
First scintigraphic visualization of tumor lesions in a patient with metastasised medullary thyroid carcinoma (MTC) using 131 I-labeled gastrin was undertaken by Thomas Behr in 1998 [5]
The clinical comparison of three different 111 In- and 99m Tc-labeled derivatives of human minigastrin (MG) and cholecystokinin-8 demonstrated the need for further radiopharmaceutical development to enable CCK2R-based peptide receptor radionuclide therapy (PRRT) [10]

Summary

Introduction

The cholecystokinin-2 receptor (CCK2R) is a promising target for theranostic use in nuclear medicine, and has been in the focus of the radiopharmaceutical development over the last twenty years. The difficulties in the development of clinically useful radiolabeled CCK2R targeting peptide analogs became clear These were related either to high kidney uptake, leading to nephrotoxicity during therapeutic application, or low enzymatic stability, limiting the tumor targeting properties [8,9]. The clinical comparison of three different 111 In- and 99m Tc-labeled derivatives of human minigastrin (MG) and cholecystokinin-8 demonstrated the need for further radiopharmaceutical development to enable CCK2R-based peptide receptor radionuclide therapy (PRRT) [10]. BM0607 on Targeted Radionuclide Therapy, twelve different CCK2R targeting peptide analogs were preclinically evaluated, with the major aim of finding a promising new candidate for PRRT [11–13] These joint efforts triggered further clinical studies and gave new directions to the ongoing preclinical research. Perspectives on the application of this new group of radiopharmaceuticals in patients with CCK2R expressing tumors and on the goals to be pursued in future clinical studies are given

Current Radiopharmaceutical Development

Tumor Imaging with Radiolabeled Gastrin Analogs

Perspectives

Findings

Conclusions