Work

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

Year: 2025

Type: article

Abstract: Background The aim of this study was to characterize the novel LSD1-specific PET radiotracer [ 18 F]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, [ 18 F]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 K i 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 O max = 95.6% and ED 50 = 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 K i . The estimated whole-body effective dose was ~0.027 mSv/MBq, with the gallbladder wall being the limiting organ (0.18 mSv/MBq). Conclusions [ 18 F]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.

Source: EJNMMI Research

DOI: 10.1186/s13550-025-01350-3