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): [¹¹C]methylamine UCB2713 ([¹¹C-N-CH₃]UCB2713) and [¹¹C]carbonyl UCB2713 ([¹¹C-CO]UCB2713). Male C57 black 6 mice (N = 10) received intravenous [¹¹C-N-CH₃]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 [¹¹C]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 [¹¹C]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/cm³, 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, [¹¹C]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).

Keywords: Alpha-synuclein; Brain distribution; Minzasolmin; PET tracers; PET-imaging; Parkinson’s disease; Phase 1 study.

Fig. 1

a Chemical structure of minzasolmin. UPAC Nomenclature: N-[(1R)-1-(1H-indol-3-ylmethyl)pentyl]-2-(4-methylpiperazin-1-yl)thiazole-5-carboxamide. Molecular weight: 425.6, b Radiosynthesis of [¹¹C-N-CH₃]UCB2713 on the N-piperazine site (i) and [¹¹C-CO]UCB2713 by [¹¹C]aminocarbonylation (ii). Compound 1 N-[(1R)-1-(1H-indol-3-ylmethyl)pentyl]-2-piperazin-1-yl-thiazole-5-carboxamide, Compound 2 5-iodo-2-(4-methylpiperazin-1-yl)thiazole, Compound 3 (2S)-1-(1H-indol-3-yl)hexan-2-amine, [¹¹C-CO]UCB2713 [¹¹C]carbonyl UCB2713, [¹¹C-N-CH₃]UCB2713 [¹¹C]methylamine UCB2713, DMF dimethylformamide, Et₃N triethylamine.

Fig. 2

Study design figure for TM0017. *PK samples were taken at 0 h (up to 5 min before dosing), and 0.25 h, 0.5 h, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h, 12 h, 15 h, 24 h, 36 h, and 48 h after 360 mg oral minzasolmin. h hours, min minutes, PET-CT positron emission tomography-computed tomography, PK pharmacokinetics.

Fig. 3

[¹¹C]UCB2713 time activity curve in the brain (mouse) and ex vivo brain activity. In vivo experiments included PET/CT scan of the brain, performed on the three mice euthanized at 90 min post-administration of [¹¹C]UCB2713; ex vivo experiments were performed on all 10 mice with samples of brain homogenate. min minute, PET-CT positron emission tomography-computed tomography, SD standard deviation, SUV standard uptake volume.

Fig. 4

The ratio of parent ([¹¹C]UCB2713) in brain:plasma over time. Median values are included above each group. min minute.

Fig. 5

a TM0017—orthogonal cross-sections of co-registered PET and MR images from a representative participant. From left to right column images are PET Scan 1 (Baseline), PET Scan 2 (approximately 2 h post-dose), and structural (T1 weighted) MRI. The PET images are shown as SUV summed from 10 to 90 min. b Mean V_T of [¹¹C]minzasolmin by selected brain region of participants in the TM0017 phase 1 study (error bars are one standard deviation from the mean). c Mean brain uptake rate for each brain region assessed from total plasma concentrations (least-squares mean, error bars are one standard deviation from the mean). Blue = PET Scan 1, orange = PET Scan 2. d TACs for PET Scan 1 (Baseline) and PET Scan 2 (approximately 2 h post-dose) for selected ROI (striatum, cerebellum, gray matter, and cerebral white matter). h hour, K₁ mean brain influx rate, min minute, MRI magnetic resonance imaging, PET positron emission tomography, ROI region of interest, SUV standard uptake value, T1 longitudinal relaxation time, TAC time activity curve, V_T the estimated whole brain total distribution volume at equilibrium.

Fig. 6

Summary of the preclinical and clinical studies ASYN alpha-synuclein, h hour, K_p partition coefficient, MRI magnetic resonance imaging, PET position emission tomography, SUV standard uptake value.