Brier Matthew R, Hamdi Mahdjoub, Rajamanikam Jayashree, Zhao Haiyang, Mansor Syahir, Jones Lynne A, Rahmani Farzaneh, Jindal Saurabh, Koudelis Deborah, Perlmutter Joel S, Wong Dean F, Nickels Michael, Ippolito Joseph E, Gropler Robert J, Schindler Thomas H, Laforest Richard, Tu Zhude, Benzinger Tammie L S
Department of Neurology, Washington University, St. Louis, Missouri.
Mallinckrodt Institute of Radiology, Washington University, St. Louis, Missouri.
J Nucl Med. 2022 Nov;63(11):1775-1782. doi: 10.2967/jnumed.121.263189. Epub 2022 Mar 24.
This study evaluated the safety, dosimetry, and characteristics of 3-((2-fluoro-4-(5-(2'-methyl-2-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)(methyl-C)amino)propanoic acid (C-CS1P1), a radiotracer targeting sphingosine-1-phosphate receptor (S1PR) 1 (S1PR1). S1PR1 is of clinical interest because of its role in multiple sclerosis (and other conditions), with an expanding class of S1PR modulators approved for relapsing multiple sclerosis. C-CS1P1 binds S1PR1 with high specificity and has shown promise in animal models of inflammatory diseases. C-CS1P1 was injected into 5 male and 6 female healthy participants. Ten participants were imaged with PET using a multipass whole-body continuous-bed-motion acquisition, and one had dedicated head and neck PET and MRI. Participants were continuously monitored for safety events. Organ time-activity curve data were collected, integrated, and normalized to the injected activity. Organ radiation doses and effective dose were computed using the adult male and female models in OLINDA, version 2.2. SUV images were evaluated for qualitative biodistribution. No adverse events were observed after the dose, including no bradycardia. The liver was the critical organ from dosimetry analysis (mean ± SD: female, 23.12 ± 5.19 μSv/MBq; male, 21.06 ± 1.63 μSv/MBq). The whole-body effective dose (as defined by International Commission on Radiological Protection publication 103) was 4.18 ± 0.30 μSv/MBq in women and 3.54 ± 0.14 μSv/MBq in men. Using a maximum delivered dose of 740 MBq (20 mCi), the effective dose for women would be 3.1 mSv (0.31 rem), with a liver dose of 17.1 mSv (1.7 rem); the effective dose for men would be 2.6 mSv (0.26 rem), with a liver dose of 15.6 mSv (1.56 rem). Brain uptake was seen predominantly in gray matter and correlated with regional S1PR1 RNA expression ( = 0.84). These results support the safety of C-CS1P1 for evaluation of inflammation in human clinical populations. Dosimetry permits repeated measures in the same participants. Brain uptake correlates well with known target topography.
本研究评估了3-((2-氟-4-(5-(2'-甲基-2-(三氟甲基)-[1,1'-联苯]-4-基)-1,2,4-恶二唑-3-基)苄基)(甲基-C)氨基)丙酸(C-CS1P1)的安全性、剂量学及特性，C-CS1P1是一种靶向鞘氨醇-1-磷酸受体(S1PR)1(S1PR1)的放射性示踪剂。S1PR1因其在多发性硬化症(及其他病症)中的作用而具有临床意义，目前已有越来越多的S1PR调节剂被批准用于复发型多发性硬化症。C-CS1P1与S1PR1具有高特异性结合，且在炎症性疾病动物模型中已显示出前景。向5名男性和6名女性健康参与者注射了C-CS1P1。10名参与者采用多程全身连续床动采集进行PET成像，1名参与者进行了头部和颈部专用PET及MRI检查。持续监测参与者的安全事件。收集、整合器官时间-活度曲线数据，并将其归一化至注射活度。使用OLINDA 2.2版中的成年男性和女性模型计算器官辐射剂量和有效剂量。评估SUV图像的定性生物分布。注射剂量后未观察到不良事件，包括无心动过缓。剂量学分析显示肝脏是关键器官(平均值±标准差：女性，23.12±5.19μSv/MBq；男性，21.06±1.63μSv/MBq)。全身有效剂量(按照国际放射防护委员会第103号出版物定义)女性为4.18±0.30μSv/MBq，男性为3.54±0.14μSv/MBq。使用最大给药剂量740MBq(20mCi)，女性的有效剂量将为3.1mSv(0.31rem)，肝脏剂量为17.1mSv(1.7rem)；男性的有效剂量将为2.6mSv(0.26rem)，肝脏剂量为15.6mSv(1.56rem)。脑摄取主要见于灰质，且与区域S1PR1 RNA表达相关(=0.84)。这些结果支持C-CS1P1在人类临床群体中评估炎症的安全性。剂量学允许在同一参与者中进行重复测量。脑摄取与已知的靶点拓扑结构相关性良好。
