PDF(Pubmed)
Abstract：
OBJECTIVE: 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.
METHODS: 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.
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 (VT) at equilibrium across all regions of interest was 0.512 mL/cm3, no difference in VT 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.
CONCLUSIONS: 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).
METHODS: 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.
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 (VT) at equilibrium across all regions of interest was 0.512 mL/cm3, no difference in VT 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.
CONCLUSIONS: 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).
摘要：
目的：Minzasolmin（UCB0599）是口服给药，ASYN错误折叠的小分子抑制剂在发展中作为帕金森病的潜在疾病改善疗法。在这里，我们描述了放射性标记示踪剂的临床前发展，以及使用示踪剂研究minzasolmin脑分布的1期研究的结果。
方法：在临床前研究中，在minzasolmin（UCB2713）的S-对映体上研究了两个放射性标记位置：[11C]甲胺UCB2713（[11C-N-CH3]UCB2713）和[11C]羰基UCB2713（[11C-CO]UCB2713）。雄性C57黑6小鼠（N=10）接受静脉注射[11C-N-CH3]UCB2713；评估脑匀浆的放射性，并通过高效液相色谱法分析血浆样品。正电子发射断层扫描-计算机断层扫描（PET-CT）用于对小鼠子集（n=3）的大脑进行成像。在开放标签中，第一阶段研究，健康志愿者在注射[11C]minzasolmin放射性示踪剂（≤10µg）后用PET-CT扫描两次，首先没有，然后口服非放射性标记的minzasolmin360mg。
目的：确定minzasolmin在人脑中的生物分布；次要目的包括minzasolmin的安全性/耐受性。
结果：临床前数据支持在临床研究中使用[11C]minzasolmin。在第一阶段的研究中，PET数据显示在健康志愿者(N=4)的脑中有大量的药物信号。在所有感兴趣区域的平衡状态下，平均估计的全脑总分布体积（VT）为0.512mL/cm3，在施用360mg的minzasolmin后未观察到VT差异。75％（n=3）的参与者报告了因治疗引起的不良事件（TEAE）。没有药物相关的TEAE,死亡,严重不良事件,或报告停业。
结论：在N-甲基标记的PET示踪剂的临床前阳性结果之后，[11C]minzasolmin用于第一阶段研究，这表明minzasolmin容易穿过血脑屏障，并在整个大脑中分布良好。安全性和药代动力学结果与先前的早期研究（如UP0077，NCT04875962）一致。
方法：在临床前研究中，在minzasolmin（UCB2713）的S-对映体上研究了两个放射性标记位置：[11C]甲胺UCB2713（[11C-N-CH3]UCB2713）和[11C]羰基UCB2713（[11C-CO]UCB2713）。雄性C57黑6小鼠（N=10）接受静脉注射[11C-N-CH3]UCB2713；评估脑匀浆的放射性，并通过高效液相色谱法分析血浆样品。正电子发射断层扫描-计算机断层扫描（PET-CT）用于对小鼠子集（n=3）的大脑进行成像。在开放标签中，第一阶段研究，健康志愿者在注射[11C]minzasolmin放射性示踪剂（≤10µg）后用PET-CT扫描两次，首先没有，然后口服非放射性标记的minzasolmin360mg。
目的：确定minzasolmin在人脑中的生物分布；次要目的包括minzasolmin的安全性/耐受性。
结果：临床前数据支持在临床研究中使用[11C]minzasolmin。在第一阶段的研究中，PET数据显示在健康志愿者(N=4)的脑中有大量的药物信号。在所有感兴趣区域的平衡状态下，平均估计的全脑总分布体积（VT）为0.512mL/cm3，在施用360mg的minzasolmin后未观察到VT差异。75％（n=3）的参与者报告了因治疗引起的不良事件（TEAE）。没有药物相关的TEAE,死亡,严重不良事件,或报告停业。
结论：在N-甲基标记的PET示踪剂的临床前阳性结果之后，[11C]minzasolmin用于第一阶段研究，这表明minzasolmin容易穿过血脑屏障，并在整个大脑中分布良好。安全性和药代动力学结果与先前的早期研究（如UP0077，NCT04875962）一致。
