Clickable Albumin Binders for Modulating the Tumor Uptake of Targeted Radiopharmaceuticals

The intentional binding of radioligands to albumin gains increasing attention in the context of radiopharmaceutical cancer therapy as it can lead to an enhanced radioactivity uptake into the tumor lesions and, thus, to a potentially improved therapeutic outcome. However, the influence of the radioligand's albumin-binding affinity on the time profile of tumor uptake has been only partly addressed so far. Based on the previously identified N-epsilon-4-(4-iodophenyl)butanoyl-lysine scaffold, we designed clickable lysine-derived albumin binders (cLABs) and determined their dissociation constants toward albumin by novel assay methods. Structure-activity relationships were derived, and selected cLABs were applied for the modification of the somatostatin receptor subtype 2 ligand (Tyr3)octreotate. These novel conjugates were radiolabeled with copper-64 and subjected to a detailed in vitro and in vivo radiopharmacological characterization. Overall, the results of this study provide an incentive for further investigations of albumin binders for applications in endoradionuclide therapies.

Automated summary

The intentional binding of radioligands to albumin in the context of cancer therapy has potential benefits in enhancing radioactivity uptake into tumor lesions. This study designed clickable albumin binders and applied them to modify a somatostatin receptor ligand for radiopharmacological characterization, providing motivation for further investigation in endoradionuclide therapies.