Approaches to Multireceptor Targeting: Hybrid Radioligands, Radioligand Cocktails, and Sequential Radioligand Applications

Abstract

Modern drug discovery highly depends on the identification and validation of the drug targets. Using the method of in vitro quantitative receptor autoradiography, we demonstrated that-for instance, in neuroendocrine tumors-up to 3 receptors can be coexpressed at a relatively high density. In addition, nonendocrine tumors such as breast, prostate, and brain tumors concomitantly express several G protein-coupled receptors at a high density. We propose 3 strategies for exploiting these findings for multireceptor targeting in vivo: use of heterobivalent or heteromultivalent ligands, which may bind simultaneously or monovalently to their different molecular targets; coinjection of a cocktail of radioligands; and sequential injection of different radioligands. Any of these strategies may help to remedy some of the major problems in cancer targeting: heterogeneity, change in phenotype during disease progression, and resistance.

Design, Synthesis, In Vitro, and Initial In Vivo Evaluation of Heterobivalent Peptidic Ligands Targeting Both NPY(Y1)- and GRP-Receptors—An Improvement for Breast Cancer Imaging?

“…Radiolabeled heterobivalent peptide ligands (HBPLs) on the other hand—by their ability to specifically target more than one receptor type—have been proposed to be better-suited agents for tumor imaging as they enable the visualization of the tumor by different receptor types potentially overexpressed by the target cells [ 1 , 2 ].…”

“…To be able to develop a HBPL being able to more efficiently target tumor tissues than the respective peptide monomers, it is necessary to know the receptor expression profile on the target tumor type. Regarding this point, some excellent systematical work has been carried out, determining the presence of certain receptor types and their densities on different human malignancies [ 2 , 4 , 5 , 6 ].…”

Overview of Radiolabeled Somatostatin Analogs for Cancer Imaging and Therapy

“…In this context, as already demonstrated with some analogs, use of somatostatin-based radiopharmaceuticals might be of interest in pulmonary or hepatic cancers, warranting further studies. The development of bivalent radiotracers to target several receptors concomitantly expressed could be of interest to improve targeting [ 237 ]. Similarly, improved detection and sensitivity could be achieved using bimodal agents [ 238 ].…”

The Future of Nuclear Medicine as an Independent Specialty

“…PET imaging can interrogate the whole body for the expression of therapeutic targets (61). The presence and degree of target expression are associated with a therapy response.…”