Wuest F, Berndt M, Strobel K, van den Hoff J, Peng X, Neumeyer J L, Bergmann R
Institut für Radiopharmazie, Forschungszentrum Dresden-Rossendorf, Postfach 510119, 01314 Dresden, Germany.
Bioorg Med Chem. 2007 Jul 1;15(13):4511-9. doi: 10.1016/j.bmc.2007.04.019. Epub 2007 Apr 19.
The fluoroalkyl-containing tropane derivative 2beta-carbo-2'-fluoroethoxy-3beta-(4-bromo-phenyl)tropane (MCL-322) is a highly potent and moderately selective ligand for the dopamine transporter (DAT). The compound was labeled with the short-lived positron emitter (18)F in a single step by nucleophilic displacement of the corresponding tosylate precursor MCL-323 with no-carrier-added [(18)F]fluoride. The positron emission tomography (PET) radiotracer 2beta-carbo-2'-[(18)F]fluoroethoxy-3beta-(4-bromo-phenyl)tropane [(18)F]MCL-322 was obtained in decay-corrected radiochemical yields of 30-40% at a specific radioactivity of 1.6-2.4Ci/mumol (60-90GBq/mumol) at the end-of-synthesis (EOS). Small animal PET, ex vivo and in vivo biodistribution experiments in rats demonstrated a high uptake in the striatum (3.2% ID/g) 5min after injection, which increased to 4.2% ID/g after 60min. The uptake in the cerebellum was 1.8% ID/g and 0.6% ID/g after 5min and 60min post-injection, respectively. Specific binding to DAT of [(18)F]MCL-322 was confirmed by blocking experiments using the high affinity DAT ligand GBR 12909. The radiopharmacological characterization was completed with metabolite and autoradiographic studies confirming the selective uptake of [(18)F]MCL-322 in the striatum. It is concluded that the simple single-step radiosynthesis of [(18)F]MCL-322 and the promising radiopharmacological data make [(18)F]MCL-322 an attractive candidate for the further development of a PET radiotracer potentially suitable for clinical DAT imaging in the human brain.
含氟烷基的托烷衍生物2β-碳-2'-氟乙氧基-3β-(4-溴苯基)托烷（MCL-322）是一种对多巴胺转运体（DAT）具有高效力和适度选择性的配体。通过用无载体添加的[(18)F]氟化物对相应的对甲苯磺酸酯前体MCL-323进行亲核取代，在一步反应中用短寿命正电子发射体(18)F对该化合物进行标记。正电子发射断层扫描（PET）放射性示踪剂2β-碳-2'-[(18)F]氟乙氧基-3β-(4-溴苯基)托烷[(18)F]MCL-322在合成结束时（EOS）的衰变校正放射化学产率为30-40%，比活度为1.6-2.4Ci/μmol（60-90GBq/μmol）。大鼠的小动物PET、离体和体内生物分布实验表明，注射后5分钟纹状体摄取率高（3.2%ID/g），60分钟后增加到4.2%ID/g。注射后5分钟和60分钟时，小脑摄取率分别为1.8%ID/g和0.6%ID/g。使用高亲和力DAT配体GBR 12909进行的阻断实验证实了[(18)F]MCL-322与DAT的特异性结合。通过代谢物和放射自显影研究完成了放射药理学表征，证实了[(18)F]MCL-322在纹状体中的选择性摄取。结论是，[(18)F]MCL-322简单的一步放射性合成方法以及有前景的放射药理学数据使其成为一种有吸引力的候选物，可用于进一步开发可能适用于人脑临床DAT成像的PET放射性示踪剂。
