Design, Synthesis, and Biological Evaluation of Small-Molecule-Based Radioligands with Improved Pharmacokinetic Properties for Imaging of Programmed Death Ligand 1

Small molecules offer some advantages for developing
positron emission
tomography (PET) tracers and are therefore a promising approach for
imaging and therapy monitoring of programmed death ligand 1 (PD-L1)
positive tumors. Here, we report six biphenyl PD-L1 radioligands using
the NODA-GA-chelator for efficient copper-64 complexation. These radioligands
contain varying numbers of sulfonic and/or phosphonic acid groups,
serving as hydrophilizing units to lower the log D7.4 value down to −4.28. The binding affinities
of compounds were evaluated using saturation binding and a real-time
binding assay, with a highest binding affinity of 21 nM. Small-animal
PET imaging revealed vastly different pharmacokinetic profiles depending
on the quantity and type of hydrophilizing units. Of the investigated
radioligands, [64Cu]Cu-3 showed the most favorable
kinetics in vitro. This was also found in vivo, with a predominantly
renal clearance and a specific uptake in the PD-L1-overexpressing
tumor. With further modifications, this compound could be a promising
candidate for the imaging of PD-L1 in the clinical setting.