Evaluation and Application of a PET Tracer in Preclinical and Phase 1 Studies to Determine the Brain Biodistribution of Minzasolmin (UCB0599)

Abstract Purpose Minzasolmin (UCB0599) is an orally administered, small molecule inhibitor of ASYN misfolding in development as a potential disease-modifying therapy for Parkinson’s disease. Here we describe the preclinical development of a radiolabeled tracer and results from a phase 1 study using the tracer to investigate the brain distribution of minzasolmin. Procedures In the preclinical study, two radiolabeling positions were investigated on the S -enantiomer of minzasolmin (UCB2713): [ 11 C]methylamine UCB2713 ([ 11 C- N -CH 3 ]UCB2713) and [ 11 C]carbonyl UCB2713 ([ 11 C-CO]UCB2713). Male C57 black 6 mice ( N = 10) received intravenous [ 11 C- N -CH 3 ]UCB2713; brain homogenates were assessed for radioactivity and plasma samples analyzed by high-performance liquid chromatography. Positron emission tomography-computed tomography (PET-CT) was used to image brains in a subset of mice ( n = 3). In the open-label, phase 1 study, healthy volunteers were scanned twice with PET-CT following injection with [ 11 C]minzasolmin radiotracer (≤ 10 µg), first without, then with oral dosing with non-radiolabeled minzasolmin 360 mg. Primary objective: to determine biodistribution of minzasolmin in the human brain; secondary objectives included minzasolmin safety/tolerability. Results Preclinical data supported the use of [ 11 C]minzasolmin in clinical studies. In the phase 1 study, PET data showed substantial drug signal in the brain of healthy volunteers ( N = 4 ). The mean estimated whole brain total distribution volume (V T ) at equilibrium across all regions of interest was 0.512 mL/cm 3 , no difference in V T was observed following administration of minzasolmin 360 mg. Treatment-emergent adverse events (TEAEs) were reported by 75% ( n = 3) of participants. No drug-related TEAEs, deaths, serious adverse events, or discontinuations were reported. Conclusion Following positive preclinical results with the N-methyl labeled PET tracer, [ 11 C]minzasolmin was used in the phase 1 study, which demonstrated that minzasolmin readily crossed the blood–brain barrier and was well distributed throughout the brain. Safety and pharmacokinetic findings were consistent with previous early-phase studies (such as UP0077, NCT04875962).