PET Diagnostic Molecules Utilizing Multimeric Cyclic RGD Peptide Analogs for Imaging Integrin αvβ3 Receptors

Abstract

Multimeric ligands consisting of multiple pharmacophores connected to a single backbone have been widely investigated for diagnostic and therapeutic applications. In this review, we summarize recent developments regarding multimeric radioligands targeting integrin αvβ3 receptors on cancer cells for molecular imaging and diagnostic applications using positron emission tomography (PET). Integrin αvβ3 receptors are glycoproteins expressed on the cell surface, which have a significant role in tumor angiogenesis. They act as receptors for several extracellular matrix proteins exposing the tripeptide sequence arginine-glycine-aspartic (RGD). Cyclic RDG peptidic ligands c(RGD) have been developed for integrin αvβ3 tumor-targeting positron emission tomography (PET) diagnosis. Several c(RGD) pharmacophores, connected with the linker and conjugated to a chelator or precursor for radiolabeling with different PET radionuclides (18F, 64Cu, and 68Ga), have resulted in multimeric ligands superior to c(RGD) monomers. The binding avidity, pharmacodynamic, and PET imaging properties of these multimeric c(RGD) radioligands, in relation to their structural characteristics are analyzed and discussed. Furthermore, specific examples from preclinical studies and clinical investigations are included.

There is a world beyond αvβ3-integrin: Multimeric ligands for imaging of the integrin subtypes αvβ6, αvβ8, αvβ3, and α5β1 by positron emission tomography

“…This conceptual change was consequently transferred to clinical investigations. Radiolabeled 'RGD-peptides' were frequently applied for tumor imaging, e.g., as a possible alternative to [ 18 F]FDG, quietly disregarding the question whether a tracer uptake might actually be related to angiogenesis or not [ 2 , 7 ]. It, however, seems to consolidate that the average αvβ3-integrin expression density on tumor cells and -endothelium is simply not sufficient to guarantee a clinical impact comparable to somatostatin receptor (SSTR)-, PSMA-, or fibroblast activating protein (FAP) targeted radiopharmaceuticals.…”

“…In view of the popularity of cyclic pentapeptides of the cyclo[RGDxK] (x = y, f) type, it is hard to imagine that a greater variety of conjugates has been generated for any other small-molecule targeting motif. The same might apply to multimers thereof [ 2 ]. The impact of multiplicity has been evaluated for c[RGDxK]'s in several systematic studies, which invariantly showed that a higher degree of multiplicity increased the affinity of the constructs [ 78 – 85 ] and frequently resulted in improved in vivo targeting properties, i.e., higher target-specific uptake [ 86 , 87 ].…”

“…Although the discussed molecular design strategies yielded convincing results in rodent models, it is all but obvious that the enhanced performance of the trimeric radiopeptides or -peptidomimetics actually translates to a higher diagnostic value in a clinical setting [ 2 ]. αvβ3-integrin PET with 68 Ga-Avebetrin nonetheless showed a good image contrast and enabled, for example, the localization of a PDAC lesion (Fig.…”

“…Multimerization is a venerable concept, and its theoretical foundations have been established decades ago [ 1 ]. There is no general doubt about the potential benefits of combining more than one targeting moiety (receptor ligands, enzyme inhibitors, antibodies or -fragments, or others), in view of a solid body of evidence that multimers invariantly exhibit a higher avidity than monomers [ 1 , 2 ]. Böhmer et al nevertheless pointed out that in despite of the long-known, huge potential of multimers and a lot of pertinent research, such compounds have made no impact in molecular imaging beyond the in vitro or preclinical levels [ 1 ], aside from full-size antibodies which are natural dimers of targeting proteins.…”

“…Two decades ago, the development [ 10 ] and first successful clinical applications of the positron emission tomography (PET) radiopharmaceutical 18 F-Galacto-RGD [ 3 – 5 ] caused a veritable enthusiasm and unleashed an avalanche of similar agents, which were initially celebrated as a new class of highly promising peptidic radioligands for imaging of (tumor) angiogenesis [ 11 , 12 ]. These days, however, one cannot help noticing a certain fatigue or even resignation because none of the many integrin tracers, even of the respective multimers which occasionally showed superior in vivo properties [ 6 ], has become clinically relevant [ 2 ].…”