Akkermans Jordy, Miranda Alan, Verhaeghe Jeroen, Elvas Filipe, Zajicek Franziska, Bard Jonathan, Liu Longbin, Khetarpal Vinod, Doot Robert, Staelens Steven, Bertoglio Daniele
Molecular Imaging Center Antwerp (MICA), Universiteitsplein 1, University of Antwerp, Antwerp, Belgium.
μNEURO Research Centre of Excellence, Universiteitsplein 1, University of Antwerp, Antwerp, Belgium.
EJNMMI Res. 2024 Dec 27;14(1):126. doi: 10.1186/s13550-024-01188-1.
Huntington's disease (HD) is a rare neurodegenerative disorder caused by an expansion of the CAG trinucleotide repeat in the huntingtin gene which encodes the mutant huntingtin protein (mHTT) that is associated with HD-related neuropathophysiology. Noninvasive visualization of mHTT aggregates in the brain, with positron emission tomography (PET), will allow to reliably evaluate the efficacy of therapeutic interventions in HD. This study aimed to assess the radiation burden of [F]CHDI-650, a novel fluorinated mHTT radioligand, in humans based on both in vivo and ex vivo biodistribution in mice and subsequent determination of dosimetry for dosing in humans.
Wild-type male and female CD-1 Swiss mice (n = 15/sex) were used to assess in vivo PET imaging-based and ex vivo biodistribution-based tracer distribution of [F]CHDI-650 at 30-, 60-, 120-, 240- and 360-min post-injection. Three-dimensional volumes of interest of the organs were drawn on the co-registered PET/CT image and organs were collected after dissection. Organ radioactivity levels were determined using both modalities. The residence time was calculated and extrapolated to human phantoms. The absorbed and effective doses were computed with OLINDA/EXM 2.2 and IDAC-Dose2.1. Ex vivo and PET-imaging biodistribution of [F]CHDI-650 showed rapid washout after 30 min in most of the organs with the highest uptake in the gallbladder and urine in mice. Extrapolation of the data to human phantoms with OLINDA showed a total mean in vivo based effective dose of 21.7 μSv/MBq with the highest equivalent organ dose in the urinary bladder wall (4.52 μSv/MBq). The total mean ex vivo based effective dose was calculated to be 20.6 μSv/MBq. The highest equivalent organ dose ex vivo in the urinary bladder wall was estimated to be 4.22 μSv/MBq. The predicted exposure in humans using IDAC-Dose correlated well to those obtained with OLINDA for both in vivo and ex vivo measurements (r = 0.9320 and r = 0.9368, respectively).
Dosimetry analysis indicated absorbed and effective doses of [F]CHDI-650 are well below the recommended limits, suggesting that the radioligand is suitable for clinical assessment. Based on the highest effective dose estimates, an injection of 370 MBq in humans would result in a radiation dose of 8.03 mSv.
亨廷顿舞蹈症（HD）是一种罕见的神经退行性疾病，由亨廷顿基因中CAG三核苷酸重复序列的扩增引起，该基因编码与HD相关神经病理生理学相关的突变型亨廷顿蛋白（mHTT）。利用正电子发射断层扫描（PET）对大脑中的mHTT聚集体进行无创可视化，将有助于可靠地评估HD治疗干预措施的疗效。本研究旨在基于小鼠体内和体外生物分布以及随后确定人体给药剂量学，评估新型氟化mHTT放射性配体[F]CHDI-650对人体的辐射负担。
使用野生型雄性和雌性CD-1瑞士小鼠（n = 15/性别），评估注射后30、60、120、240和360分钟时[F]CHDI-650基于体内PET成像和体外生物分布的示踪剂分布。在配准的PET/CT图像上绘制器官的三维感兴趣区，解剖后收集器官。使用两种方法确定器官放射性水平。计算停留时间并外推至人体模型。使用OLINDA/EXM 2.2和IDAC-Dose2.1计算吸收剂量和有效剂量。[F]CHDI-650的体外和PET成像生物分布显示，30分钟后大多数器官中的放射性迅速清除，小鼠胆囊和尿液中的摄取量最高。用OLINDA将数据外推至人体模型显示，基于体内的总平均有效剂量为21.7 μSv/MBq，膀胱壁中的等效器官剂量最高（4.52 μSv/MBq）。计算得出基于体外的总平均有效剂量为20.6 μSv/MBq。估计膀胱壁体外最高等效器官剂量为4.22 μSv/MBq。使用IDAC-Dose预测的人体暴露量与OLINDA在体内和体外测量中获得的暴露量相关性良好（分别为r = 0.9320和r = 0.9368）。
剂量学分析表明，[F]CHDI-650的吸收剂量和有效剂量远低于推荐限值，表明该放射性配体适用于临床评估。根据最高有效剂量估计，人体注射370 MBq将导致辐射剂量为8.03 mSv。
