Evaluation of [18F]MNI-1054, a novel PET ligand for lysine-specific histone demethylase 1A (LSD1), in non-human primates

Abstract Background The aim of this study was to characterize the novel LSD1-specific PET radiotracer [18F]MNI-1054 in rhesus monkeys and to utilize it to evaluate occupancy of TAK-418, a novel LSD1 inhibitor. To accomplish this, eleven 180-minute dynamic brain PET scans were performed in two rhesus monkeys (1 male/1 female), including baseline scans and a self-block with unlabeled MNI-1054 (3 mg/kg) to assess total levels of specific binding. Displacement and blocking studies with TAK-418 were performed to confirm irreversible binding and to evaluate the dose-occupancy relationship of TAK-418. Scans were also acquired 24- and 48-hours post-TAK-418 dosing to assess LSD1 repopulation rates. Additional baseline and blocking studies with 3.0 mg/kg TAK-418 were acquired in a male monkey to evaluate peripheral binding and occupancy in the testes, an organ with high LSD1 expression. Lastly, whole-body scans were obtained from two animals (1 male/1 female) to evaluate dosimetry. Results Across studies, [18F]MNI-1054 fraction in plasma was ~42% at 30 min and ~14% at 180 min after injection. Tracer kinetics were accurately modeled using an irreversible two-tissue compartment model, yielding Ki as the binding endpoint. The highest specific signal was found in the cerebellum, and the neuroanatomical signal profile was consistent with that of LSD1 expression. The specific signal was blocked in a dose-dependent fashion by the molecularly distinct LSD1 inhibitor TAK-418, with Omax = 95.6% and ED50 = 0.0224 mg/kg in cerebellum. Scans at later time points yielded an LSD1 repopulation half-life estimate of 12.28 h. Evidence of significant LSD1 expression and occupancy was found in testes with 3.0 mg/kg TAK-418, however point occupancy levels could not be reliably estimated from Ki. The estimated whole-body effective dose was ~0.027 mSv/MBq, with the gallbladder wall being the limiting organ (0.18 mSv/MBq). Conclusions [18F]MNI-1054 displayed acceptable brain penetrance, kinetics and LSD1 specificity as well as an acceptable dosimetry. Overall, these findings show its suitability as a viable PET probe to assess the binding profile of LSD1 inhibitors in the brain and support further evaluation in humans.