Development and In Vivo Preclinical Imaging of Fluorine-18-Labeled Synaptic Vesicle Protein 2A (SV2A) PET Tracers
Development and In Vivo Preclinical Imaging of Fluorine-18-Labeled Synaptic Vesicle Protein 2A (SV2A) PET Tracers
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DOI：
10.1007/s11307-018-1260-5
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发表时间：
2019-06-01
影响因子：
3.1
通讯作者：
Barret, Olivier
中科院分区：
文献类型：
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作者：
Constantinescu, Cristian C.;Tresse, Cedric;Barret, Olivier
目的突触囊泡蛋白2A是突触密度的生物标志物，其正电子发射断层扫描(PET)可作为评估神经退行性疾病进展的一种手段。已经初步报道了两种示踪剂，并在体内进行了表征：[C-11]UCB-J和[F-18]UCB-H。在早期的人体研究中，[C-11]UCB-J显示了令人振奋的结果，而其F-18标记的类似物[F-18]UCB-H与[C-11]UCB-J相比，显示出不太理想的特定信号。考虑到[C-11]UCB-J在配备回旋加速器的设施中的使用有限，拥有F-18变种将有助于进行大型、多中心成像试验。我们已经在非人类灵长类动物中筛选了几个UCB-J的F-18衍生物，并确定了一个有前途的F-18 PET候选者[F-18]MNI-1126，并对外消旋体[F-18]MNI-1038进行了进一步的研究，提供了与[C-11]UCB-J类似的信号。经过筛选，[F-18]MNI-1038(外消旋体)和[F-18]MNI-1126(R-对映体)信号最高，动力学有利，并被选择用于进一步的成像。使用代谢物校正的动脉输入函数对PET数据进行动力学建模，采用单组织和双组织间隔模型，以及线性方法。用左乙拉西坦(Lev，10，30 mg/kg，iv)进行阻断前扫描，以确定示踪剂对SV2A的体内特异性。用[F-18]MNI-1038对1只雄性和1只雌性恒河猴进行了两次全身PET研究，并用Olinda/Exm 2.0软件估算了辐射吸收剂量和有效剂量(ED，ICRP-103)。结果所有筛选的化合物都具有很好的脑渗透性，无血浆比例接近40%。[F-18]MNI-1126和[F-18]MNI-1038的摄取和分布与UCB-J最一致，而其他衍生物的摄取和分布结果较差，摄取与[F-18]UCB-H相似或更低。[F-18]MNI-1126和[F-18]MNI-1038的V-T在所有灰质区都很高(动物平均值接近30ml/cm(3))，并与[C-11]UCB-J(r>；0.99)高度相关。用LEV预先阻断[F-18]MNI-1126或[F-18]MNI-1038显示出在所有灰质区域的强健占有率，与报道的[C-11]UCB-J相似(30 mg/kg时类似85%，10 mg/kg时类似65%)。以半卵圆中心为参照区，[F-18]MNI-1126的BPND值比[C-11]UCB-J报告的值高出近30%至40%。[F-18]MNI-1038的平均ED值为22.3Sv/MBq，示踪剂通过尿路和肝胆途径被清除。结论我们已鉴定出一种F-18标记的示踪剂([F-18]MNI-1126)，该示踪剂在非人类灵长类动物中具有与[C-11]UCB-J相似的体内特性和特异性，这使得[F-18]MNI-1126有希望成为一种在人体试验中成像SV2A的PET示踪剂。
PurposeSynaptic vesicle protein 2A (SV2A) serves as a biomarker of synaptic density and positron emission tomography (PET) imaging of SV2A could provide a tool to assess progression of neurodegenerative diseases. Two tracers have primarily been reported and characterized in vivo: [C-11]UCB-J and [F-18]UCB-H. In early human studies, [C-11]UCB-J showed promising results, while its F-18-labeled analogue [F-18]UCB-H showed suboptimal specific signal in comparison to [C-11]UCB-J. Considering the limited use of [C-11]UCB-J to facilities with a cyclotron, having a F-18 variant would facilitate large, multicenter imaging trials. We have screened several F-18 derivatives of UCB-J in non-human primates and identified a promising F-18 PET candidate, [F-18]MNI-1126, with additional investigations of the racemate [F-18]MNI-1038, affording a signal comparable to [C-11]UCB-J.ProceduresF-18 derivatives of UCB-J and UCB-H were synthesized and administered to non-human primates for microPET imaging. Following screenings, [F-18]MNI-1038 (racemate) and [F-18]MNI-1126 (R-enantiomer) were identified with the highest signal and favorable kinetics and were selected for further imaging. Kinetic modeling with one- and two-tissue compartmental models, and linear methods were applied to PET data using metabolite-corrected arterial input function. Pre-block scans with levetiracetam (LEV, 10, 30mg/kg, iv) were performed to determine the tracers' in vivo specificity for SV2A. Two whole-body PET studies were performed with [F-18]MNI-1038 in one male and one female rhesus, and radiation absorbed dose estimates and effective dose (ED, ICRP-103) were estimated with OLINDA/EXM 2.0.ResultsAll compounds screened displayed very good brain penetration, with a plasma-free fraction of similar to 40%. [F-18]MNI-1126 and [F-18]MNI-1038 showed uptake and distribution the most consistent with UCB-J, while the other derivatives showed suboptimal results, with similar or lower uptake than [F-18]UCB-H. V-T of [F-18]MNI-1126 and [F-18]MNI-1038 was high in all gray matter regions (within animal averages similar to 30ml/cm(3)) and highly correlated with [C-11]UCB-J (r>0.99). Pre-blocking of [F-18]MNI-1126 or [F-18]MNI-1038 with LEV showed robust occupancy across all gray matter regions, similar to that reported with [C-11]UCB-J (similar to 85% at 30mg/kg, similar to 65% at 10mg/kg). Using the centrum semiovale as a reference region, BPND of [F-18]MNI-1126 reached values of up to similar to 30 to 40% higher than those reported for [C-11]UCB-J. From whole-body imaging average ED of [F-18]MNI-1038 was estimated to be 22.3Sv/MBq, with tracer being eliminated via both urinary and hepatobiliary pathways.ConclusionsWe have identified a F-18-labeled tracer ([F-18]MNI-1126) that exhibits comparable in vivo characteristics and specificity for SV2A to [C-11]UCB-J in non-human primates, which makes [F-18]MNI-1126 a promising PET radiotracer for imaging SV2A in human trials.