Kung Mei-Ping, Hou Catherine, Goswami Rajesh, Ponde Datta E, Kilbourn Michael R, Kung Hank F
Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Nucl Med Biol. 2007 Apr;34(3):239-46. doi: 10.1016/j.nucmedbio.2006.12.005.
Labeling derivatives of dihydrotetrabenazine (DTBZ) with F-18 (T(1/2)=110 min) instead of C-11 (T(1/2)=20 min) would improve their utility and availability for imaging vesicular monoamine transporters (VMAT2) in clinical settings. The successful synthesis, reported previously, of two novel 9-fluoroalkyl(+/-)-DTBZ ligands prompted us to study the optically resolved active ligand 9-fluoropropyl-(+)-DTBZ (FP-(+)-DTBZ), which may have more promising characteristics. The inhibition constant (K(i)) estimated for FP-(+)-DTBZ (using (3)H-DTBZ as the labeled ligand in rat striatal homogenates) showed a lower value as compared to the racemic FP-(+/-)-DTBZ (0.10+/-0.01 vs 0.19+/-0.04 nM). The inactive isomer, FP-(-)-DTBZ, displayed a much lower binding affinity with a K(i) value >3000 nM. Biodistribution studies in mice after an iv injection of [(18)F]FP-(+)-DTBZ exhibited a ratio of striatum (ST, target) to cerebellum (CB, background) of 4.51 at 30 min postinjection, which is a higher value than previously obtained with the racemic ligand [(18)F]FP-(+/-)-DTBZ (ST/CB=2.95). Brain extraction at 30 min after the tracer injection in mice showed that >95% of the radioactivity corresponded to the parent, nonmetabolized, compound remaining in the ST, suggesting that the tracer has an excellent in vivo stability. Furthermore, localization of the tracer in the brain examined with ex vivo autoradiography displayed a typical distribution pattern consistent with VMAT2 sites. The highest labeling was observed in monoaminergic neuron regions (caudate putamen, olfactory tubercle, nucleus accumbens, substantia nigra, dorsal raphe and locus coerules). We also tested the selective labeling of this tracer at the dopamine neurons in unilateral-lesioned mice (treated with 6-hydroxydopamine). When [(18)F]FP-(+)-DTBZ and [(125)I]IPT ((N-(3'-iodopropen-2'-yl)-2-beta-carbomethoxy-3-beta-(4-chlorophenyl)tropane, a selective marker for dopamine transporters (DATs) in dopaminergic neurons) were simultaneously injected into lesioned mice, we observed an excellent correlation (r=0.95) for these tracers. From these findings, we conclude that [(18)F]FP-(+)-DTBZ is a sensitive and selective tracer for VMAT2 binding sites and it may be useful for in vivo evaluation of diseases relating to changes of monoamine neuronal integrity.
用氟 - 18（半衰期(T(1/2)=110)分钟）而非碳 - 11（半衰期(T(1/2)=20)分钟）标记二氢丁苯那嗪（DTBZ）的衍生物，将提高其在临床环境中用于成像囊泡单胺转运体（VMAT2）的效用和可及性。先前报道成功合成了两种新型的9 - 氟烷基（±） - DTBZ配体，这促使我们研究光学拆分的活性配体9 - 氟丙基 - （+） - DTBZ（FP - （+） - DTBZ），其可能具有更有前景的特性。用[³H]（±） - DTBZ作为标记配体在大鼠纹状体匀浆中估算的FP - （+） - DTBZ的抑制常数（(K_i)）与外消旋的FP - （±） - DTBZ相比显示出较低的值（(0.10 ± 0.01)对(0.19 ± 0.04) nM）。无活性异构体FP - （ - ） - DTBZ表现出低得多的结合亲和力，其(K_i)值(>3000) nM。静脉注射[¹⁸F]FP - （+） - DTBZ后在小鼠中的生物分布研究显示，注射后30分钟时纹状体（ST，靶器官）与小脑（CB，背景）的比值为4.51，这一值高于先前用外消旋配体[¹⁸F]FP - （±） - DTBZ获得的值（ST/CB = 2.95）。在小鼠中注射示踪剂后30分钟时的脑摄取显示，超过95%的放射性对应于留在纹状体中的母体、未代谢的化合物，这表明该示踪剂在体内具有出色的稳定性。此外，用离体放射自显影检查示踪剂在脑中的定位显示出与VMAT2位点一致的典型分布模式。在单胺能神经元区域（尾状壳核、嗅结节、伏隔核、黑质、中缝背核和蓝斑）观察到最高的标记。我们还在单侧损伤小鼠（用6 - 羟基多巴胺处理）中测试了该示踪剂对多巴胺能神经元的选择性标记。当将[¹⁸F]FP - （+） - DTBZ和[¹²⁵I]IPT（N - （3'-碘丙烯 - 2'-基） - 2 - β - 甲氧基羰基 - 3 - β - （4 - 氯苯基）托烷，多巴胺能神经元中多巴胺转运体（DAT）的选择性标记物）同时注射到损伤小鼠中时，我们观察到这些示踪剂之间具有极好的相关性（(r = 0.95)）。基于这些发现，我们得出结论，[¹⁸F]FP - （+） - DTBZ是VMAT2结合位点的敏感且选择性示踪剂，它可能有助于对与单胺神经元完整性变化相关疾病的体内评估。
