PT - JOURNAL ARTICLE AU - David J. Donnelly AU - R. Adam Smith AU - Paul Morin AU - Daša Lipovšek AU - Jochem Gokemeijer AU - Daniel Cohen AU - Virginie Lafont AU - Tritin Tran AU - Erin L. Cole AU - Martin Wright AU - Joonyoung Kim AU - Adrienne Pena AU - Daniel Kukral AU - Douglas D. Dischino AU - Patrick Chow AU - Jinping Gan AU - Olufemi Adelakun AU - Xi-Tao Wang AU - Kai Cao AU - David Leung AU - Samuel J. Bonacorsi, Jr. AU - Wendy Hayes TI - Synthesis and Biologic Evaluation of a Novel <sup>18</sup>F-Labeled Adnectin as a PET Radioligand for Imaging PD-L1 Expression AID - 10.2967/jnumed.117.199596 DP - 2018 Mar 01 TA - Journal of Nuclear Medicine PG - 529--535 VI - 59 IP - 3 4099 - http://jnm.snmjournals.org/content/59/3/529.short 4100 - http://jnm.snmjournals.org/content/59/3/529.full SO - J Nucl Med2018 Mar 01; 59 AB - The programmed death protein (PD-1) and its ligand (PD-L1) play critical roles in a checkpoint pathway cancer cells exploit to evade the immune system. A same-day PET imaging agent for measuring PD-L1 status in primary and metastatic lesions could be important for optimizing drug therapy. Herein, we have evaluated the tumor targeting of an anti–PD-L1 adnectin after 18F-fluorine labeling. Methods: An anti–PD-L1 adnectin was labeled with 18F in 2 steps. This synthesis featured fluorination of a novel prosthetic group, followed by a copper-free click conjugation to a modified adnectin to generate 18F-BMS-986192. 18F-BMS-986192 was evaluated in tumors using in vitro autoradiography and PET with mice bearing bilateral PD-L1–negative (PD-L1(–)) and PD-L1–positive (PD-L1(+)) subcutaneous tumors. 18F-BMS-986192 was evaluated for distribution, binding, and radiation dosimetry in a healthy cynomolgus monkey. Results: 18F-BMS-986192 bound to human and cynomolgus PD-L1 with a dissociation constant of less than 35 pM, as measured by surface plasmon resonance. This adnectin was labeled with 18F to yield a PET radioligand for assessing PD-L1 expression in vivo. 18F-BMS-986192 bound to tumor tissues as a function of PD-L1 expression determined by immunohistochemistry. Radioligand binding was blocked in a dose-dependent manner. In vivo PET imaging clearly visualized PD-L1 expression in mice implanted with PD-L1(+), L2987 xenograft tumors. Two hours after dosing, a 3.5-fold-higher uptake (2.41 ± 0.29 vs. 0.82 ± 0.11 percentage injected dose per gram, P &lt; 0.0001) was observed in L2987 than in control HT-29 (PD-L1(–)) tumors. Coadministration of 3 mg/kg ADX_5322_A02 anti–PD-L1 adnectin reduced tumor uptake at 2 h after injection by approximately 70%, whereas HT-29 uptake remained unchanged, demonstrating PD-L1–specific binding. Biodistribution in a nonhuman primate showed binding in the PD-L1–rich spleen, with rapid blood clearance through the kidneys and bladder. Binding in the PD-L1(+) spleen was reduced by coadministration of BMS-986192. Dosimetry estimates indicate that the kidney is the dose-limiting organ, with an estimated human absorbed dose of 2.20E–01 mSv/MBq. Conclusion: 18F-BMS-986192 demonstrated the feasibility of noninvasively imaging the PD-L1 status of tumors by small-animal PET studies. Clinical studies with 18F-BMS-986192 are under way to measure PD-L1 expression in human tumors.