Fluoroalkyl derivatives of dihydrotetrabenazine as positron emission tomography imaging agents targeting vesicular monoamine transporters
Fluoroalkyl derivatives of dihydrotetrabenazine as positron emission tomography imaging agents targeting vesicular monoamine transporters
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DOI：
10.1016/j.nucmedbio.2006.05.006
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发表时间：
2006-08-01
影响因子：
3.1
通讯作者：
Kung, Hank F.
中科院分区：
文献类型：
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作者：
Goswami, Rajesh;Ponde, Datta E.;Kung, Hank F.
[C-11]-二氢四苯那嗪（DTBZ）联合正电子发射断层扫描（PET）对脑内水泡单胺转运蛋白2 （VMAT2）的成像已经证明其在诊断和监测神经退行性疾病如帕金森病和亨廷顿病方面的有用性。我们报道了（18）7种DTBZ类似物的开发，它们具有较长的半衰期（t = 110，而C-11为20分钟），以增加VMAT2显像剂在PET常规临床研究中的可用性。成功制备了外消旋9-氟乙基（FE）和9-氟丙基(FP)-9-去甲基- dtbz及其羟基衍生物。采用[1 F-18]氟置换相应甲酰化产物合成无载体外消旋F-18- dtbz衍生物，产率高（30 ~ 40%），比活性高（SA= 1500 ~ 2000 Ci/mmol）。外消旋体(+/-)- fe - dtbz （6a）和(+/-)- fp - dtbz （6b）对大鼠纹状体匀浆中VMAT2结合位点的K-i值分别为0.76和0.56 nM，而已知化合物(+/-)- dtbz和(+/-)-tetrabenazine （TBZ）的K-i值分别为1.7 +/- 0.2和1.3 + +/- 0.1 nM。与此一致的是，消旋子[F-18]6a和[F-18]6b在小鼠纹状体均质物中对VMAT2结合位点的K-d值分别为0.52和0.48 nM（基于2000 Ci/mmol的SA）。这两种试剂的结合密度与[H-3](+/-)- tbz的结合密度相当。[F-18] fib体外放射自显影结果显示，在尾状壳核区有明显的结合，与VMAT2在小鼠脑中的定位一致，该结合被非放射性TBZ有效阻断。静脉注射示踪剂后小鼠的生物分布研究显示，该示踪剂的脑吸收率极好（消旋[F-18]6a和[F-18]6b在2分钟内分别为4.66%和7.08% ID/g）。结果表明，[F-18]6b比[F-18]6a表现出更快的脑冲洗。结果，[F-18]6b产生了更好的靶背景比（静脉注射[F-18]6b和[F-18]6a后30分钟纹状体/小脑分别为3.0和1.7）。非放射性(+/-)- dtbz阻断研究清楚地证实了[F-18]6b结合VMAT2位点的体内竞争性和特异性。总之，这些发现强烈表明，新型外消旋体[F-18]6b作为脑内VMAT2结合位点的分子显像剂具有潜在的用途。需要进一步的研究来评估这些f -18标记的DTBZ衍生物作为PET示踪剂在各种神经退行性疾病诊断中的应用。(c) 2006爱思唯尔公司版权所有。
Imaging of vesicular monoamine transporter 2 (VMAT2) in the brain with [C-11]-dihydrotetrabenazine (DTBZ) in conjunction with positron emission tomography (PET) has demonstrated its usefulness in the diagnosis and monitoring of neurodegenerative diseases such as Parkinson's disease and Huntington's disease. We report on the development of (18)7 analogs of DTBZ with a longer half-life (t = 110 vs. 20 min for C-11) to increase the availability of VMAT2 imaging agents for routine clinical studies with PET. Racemic 9-fluoroethyl (FE) and 9 - fluoropropyl (FP)-9-desmethyl-DTBZ and the corresponding hydroxyl derivatives were successfully prepared. No-carrier-added racemic F-18-DTBZ derivatives were synthesized by an [1 F-18]fluoride displacement of the corresponding mesylates with good yields (30 - 40%) and high specific activity (SA= 1500-2000 Ci/mmol). Racemic (+/-)-FE-DTBZ (6a) and (+/-)-FP-DTBZ (6b) displayed excellent binding affinities (K-i = 0.76 and 0.56 nM, respectively) for VMAT2 binding sites in rat striatal homogenates, whereas the known compounds (+/-)-DTBZ and (+/-)-tetrabenazine (TBZ) showed K-i values of 1.7 +/- 0.2 and 1.3 + +/- 0.1 nM, respectively. Consistently, racernic [F-18]6a and [F-18]6b exhibited K-d values of 0.52 and 0.48 nM, respectively (based on an SA of 2000 Ci/mmol), for VMAT2 binding sites using mouse striatal bomogenates. Both agents showed comparable binding densities with those obtained with [H-3](+/-)-TBZ. Results of in vitro autoradiography with [F-18] fib showed a distinct binding in the caudate putamen region consistent with the localization of VMAT2 in the mouse brain, which was blocked by nonradioactive TBZ efficiently. Biodistribution studies on mice after an intravenous injection of the tracer exhibited excellent brain uptakes (4.66% and 7.08% ID/g at 2 min for racemic [F-18]6a and [F-18]6b, respectively). It was determined that [F-18]6b displayed a faster brain washout than [F-18]6a did. As a result, [F-18]6b yielded a better target-to-background ratio (striatum/cerebellum=3.0 and 1.7 at 30 min after an intravenous injection for [F-18]6b and [F-18]6a, respectively). The blocking study with the nonradioactive (+/-)-DTBZ clearly confirmed the in vivo competition and specificity of [F-18]6b binding for VMAT2 sites. In conclusion, these findings strongly suggest that the novel racemic [F-18]6b is potentially useful as a molecular imaging agent for VMAT2 binding sites in the brain. Further studies are warranted to assess the utility of these F-18-labeled DTBZ derivatives as PET tracers for the diagnosis of various neurodegenerative diseases. (c) 2006 Elsevier Inc. All rights reserved.