Radiolabeled NGR-Based Heterodimers for Angiogenesis Imaging: A Review of Preclinical Studies

SIMPLE SUMMARY: The increasing prevalence of malignant diseases and related metastases warrants the need for the establishment of specific diagnostic vectors that ensure timely as well as selective tumor identification. Since the application of multivalent ligands serves as an effective way to increase the binding ability of peptide-based molecular vectors, multi-target imaging is emerging as an intensively investigated area of cancer research. Given the colocalization of asparagine-glycine-arginine (NGR tripeptide) motif with angiogenesis-related Aminopeptidase N (APN/CD13), radiolabelled NGR-containing bispecific compounds may be valuable tools in the molecular diagnostics of APN/CD13 overexpressing tumors. Overall, the establishment of vascular-homing heterobivalent probes would not only broaden the horizon of cancer diagnostics but also contribute to the ultimate goal of the establishment of personalized tumor imaging. ABSTRACT: Since angiogenesis/neoangiogenesis has a major role in tumor development, progression and metastatic spread, the establishment of angiogenesis-targeting imaging and therapeutic vectors is of utmost significance. Aminopeptidase N (APN/CD13) is a pivotal biomarker of angiogenic processes abundantly expressed on the cell surface of active vascular endothelial and various neoplastic cells, constituting a valuable target for cancer diagnostics and therapy. Since the asparagine–glycine–arginine (NGR) sequence has been shown to colocalize with APN/CD13, the research interest in NGR-peptide-mediated vascular targeting is steadily growing. Earlier preclinical experiments have already demonstrated the imaging and therapeutic feasibility of NGR-based probes labeled with different positron emission tomography (PET) and single-photon emission computed tomography (SPECT) radionuclides, including Gallium-68 ((68)Ga), Copper-64 ((64)Cu), Technetium-99m ((99m)Tc), Lutetium-177 ((177)Lu), Rhenium-188 ((188)Re) or Bismuth-213 ((213)Bi). To improve the tumor binding affinity and the retention time of single-receptor targeting peptides, NGR motifs containing heterodimers have been introduced to identify multi-receptor overexpressing malignancies. Preclinical studies with various tumor-bearing experimental animals provide useful tools for the investigation of the in vivo imaging behavior of NGR-based heterobivalent ligands. Herein, we review the reported preclinical achievements on NGR heterodimers that could be highly relevant for the development of further target-specific multivalent compounds in diagnostic and therapeutic settings.