“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 Nε-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.