Optimization of next-generation CXCR4 ligands for radiotheranostic applications

Radiotheranostic agents enable paired diagnostic imaging and targeted radiopharmaceutical therapy through the selection of appropriate radioisotopes. Radiotheranostics are typically composed of a targeting vector, a chelator or prosthetic group for radiolabeling and an optional linker for optimizing their pharmacokinetic properties. The chemokine receptor 4 (CXCR4) is a promising target for molecular imaging and therapy across a broad range of pathological conditions, including cancer, cardiovascular disorders, infectious and autoimmune diseases. The elucidation of CXCR4 crystal structures, together with extensive structure-activity relationship studies, has accelerated the design of novel small molecule and peptide-based CXCR4-targeted radiopharmaceuticals. These molecules have served as scaffolds that can be chemically modified to optimize their pharmacokinetic properties and maximize accumulation at the target organ. In oncology, the peptide-based theranostic pair Pentixafor/Pentixather has advanced into early-stage clinical evaluations for imaging and therapy. This review summarizes the current landscape of CXCR4 radiopharmaceuticals, and highlights key structural features and chemical modifications that lead to enhanced receptor affinity as well as improved pharmacokinetic and in vivo targeting properties for theranostic applications.