Exploring Hydrophilic PD-L1 Radiotracers Utilizing Phosphonic Acids: Insights Into Unforeseen Pharmacokinetics


Exploring Hydrophilic PD-L1 Radiotracers Utilizing Phosphonic Acids: Insights Into Unforeseen Pharmacokinetics

Krutzek, F.; Donat, C.; Stadlbauer, S.

Immune checkpoint inhibitor therapy targeting the PD-1/PD-L1 axis in cancer patients holds promise as an oncological treatment. However, the number of non-responders remains high. Consequently, clinicians need a diagnostic tool to predict treatment outcomes. PET imaging can play an important role in supporting therapy decisions by offering whole-body scan while quantitatively assessing PD-L1 expression. In multi-step organic synthesis, four PD-L1 radiolig-ands containing a linker-chelator system for radiometallation, along with three hydrophilizing units – one sulfonic acid and two phosphonic acids – were synthesized. After labeling with 64Cu, log D7.4 values of below –3.03 were determined and proteolytic stability studies were conducted confirming stabilities over 94% after 48 hours. Binding affinities studies were conducted using two different binding assays revealing high affinities up 13 nM. µPET/CT imaging was performed in tumor-bearing mice to investigate PD-L1 specific tumor uptake and the pharmacokinetic profile. The µPET images revealed an unexpected in vivo behavior, including low tumor uptake in PD-L1 positive tumors, high liver uptake, and accumulation in bone/bone marrow/joints. These effects were attributed to Ca2+-affinity and/or binding to macrophages. Despite phosphonic acids offering a high degree of water-solubility, their incorporation must be carefully considered to avoid ex-acerbating the radioligands’ pharmacokinetic behaviors.

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Publ.-Id: 37446