Cyclotron Research Centre, University of Liège, Liège, Belgium; and.
UCB Pharma, Brussels, Belgium.
J Nucl Med. 2014 Aug;55(8):1336-41. doi: 10.2967/jnumed.113.136143. Epub 2014 Jun 16.
Synaptic vesicle protein 2 isoforms are critical for proper nervous system function and are involved in vesicle trafficking. The synaptic vesicle protein 2A (SV2A) isoform has been identified as the binding site of the antiepileptic levetiracetam (LEV), making it an interesting therapeutic target for epilepsy. (18)F-UCB-H is a novel PET imaging agent with a nanomolar affinity for human SV2A.
Preclinical PET studies were performed with isoflurane-anesthetized rats. The arterial input function was measured with an arteriovenous shunt and a β-microprobe system. (18)F-UCB-H was injected intravenously (bolus of 140 ± 20 MBq).
Brain uptake of (18)F-UCB-H was high, matching the expected homogeneous distribution of SV2A. The distribution volume (Vt) for (18)F-UCB-H was calculated with Logan graphic analysis, and the effect of LEV pretreatment on Vt was measured. In control animals the whole-brain Vt was 9.76 ± 0.52 mL/cm(3) (mean ± SD; n = 4; test-retest), and the reproducibility in test-retest studies was 10.4% ± 6.5% (mean ± SD). The uptake of (18)F-UCB-H was dose dependently blocked by pretreatment with LEV (0.1-100 mg/kg intravenously).
Our results indicated that (18)F-UCB-H is a suitable radiotracer for the imaging of SV2A in vivo. To our knowledge, this is the first PET tracer for the in vivo quantification of SV2A. The necessary steps for the implementation of (18)F-UCB-H production under good manufacturing practice conditions and the first human studies are being planned.
突触小泡蛋白 2 同工型对于正常的神经系统功能至关重要，并参与囊泡运输。突触小泡蛋白 2A（SV2A）同工型已被确定为抗癫痫药左乙拉西坦（LEV）的结合位点，使其成为治疗癫痫的一个有趣的治疗靶点。（18）F-UCB-H 是一种新型 PET 成像剂，对人 SV2A 的亲和力为纳摩尔级。
在异氟烷麻醉的大鼠中进行了临床前 PET 研究。采用动静脉分流和β-微探针系统测量动脉输入函数。（18）F-UCB-H 通过静脉内注射（140 ± 20 MBq 的团注）。
（18）F-UCB-H 的脑摄取量很高，与 SV2A 的预期均匀分布相匹配。（18）F-UCB-H 的分布容积（Vt）通过 Logan 图形分析进行计算，并测量了 LEV 预处理对 Vt 的影响。在对照动物中，全脑 Vt 为 9.76 ± 0.52 mL/cm3（平均值 ± SD；n = 4；测试-复测），测试-复测研究中的重现性为 10.4% ± 6.5%（平均值 ± SD）。（18）F-UCB-H 的摄取被 LEV（静脉内 0.1-100 mg/kg）预处理剂量依赖性地阻断。
我们的结果表明，（18）F-UCB-H 是一种适合用于体内 SV2A 成像的放射性示踪剂。据我们所知，这是第一个用于体内定量 SV2A 的 PET 示踪剂。正在计划实施（18）F-UCB-H 生产的良好生产规范条件和首次人体研究的必要步骤。
