SYNTHESIS AND PRELIMINARY EVALUATION OF AN IODOVINYL-TETRABENAZINE ANALOG AS A MARKER FOR THE VESICULAR MONOAMINE TRANSPORTER
SYNTHESIS AND PRELIMINARY EVALUATION OF AN IODOVINYL-TETRABENAZINE ANALOG AS A MARKER FOR THE VESICULAR MONOAMINE TRANSPORTER
复制标题
DOI：
10.1002/jlcr.2580330413
复制
发表时间：
1993-04-01
影响因子：
1.8
通讯作者：
KUNG, HF
中科院分区：
文献类型：
--
作者：
CANNEY, DJ;GUO, YZ;KUNG, HF
合成了一种含碘乙烯基的丁苯那嗪衍生物（TBZ，1）（I-TBZ，3b），作为囊泡单胺转运蛋白的潜在放射性示踪剂。以TBZ为原料，经乙炔化反应合成了3a。 乙炔基衍生物4转化为相应的乙烯基锡烷5。然后在室温下用氯仿中的I2处理乙烯基锡烷中间体，得到碘代乙烯基化合物（3a，I-TBZ）。无载体添加的（[I]I-TBZ）-I-125（3b）通过处理5.在H2 O2存在下与碘化钠[I-125]反应。静脉注射后，（[I]I-TBZ）-I-125（3b）可轻易穿过血脑屏障并定位于脑中（2 min和30 min时分别为0.92%和0.36%剂量/器官）。然而，未观察到配体的特定区域摄取。使用从3b的手性HPLC分离获得的两个良好分离的峰进行的后续生物分布研究证明，馏分I显示出比后一个峰（馏分II，0.3%剂量/器官，20 min）更高的脑摄取（0.6%剂量/器官，20 min）。馏分I也表现出一定程度的特异性纹状体，可以通过预处理与丁苯那嗪阻断。3a的高亲脂性（组分1和II的P（o/B）分别为1723和1395）可能有助于体内高非特异性结合，并导致该化合物观察到的低靶/非靶比。碘乙烯基-TBZ类似物3b作为囊泡单胺转运蛋白的SPECT显像剂是一个很差的候选者。
A derivative of tetrabenazine (TBZ, 1) containing an iodovinyl group (I-TBZ, 3b) was prepared as a potential radiotracer for the vesicular monoamine transporter. The synthesis of 3a was achieved by ethynylation of TBZ. The ethynyl derivative 4, was converted to the corresponding vinylstannane 5. The vinylstannane intermediate was then treated with I2 in chloroform at room temperature, to afford the iodovinyl compound (3a, I-TBZ). The no-carrier-added ([I]I-TBZ)-I-125 (3b) was prepared by treating an ethanolic solution of 5. with sodium[I-125]iodide in the presence of H2O2. Following i.v. injection, ([I]I-TBZ)-I-125 (3b) can readily cross the blood brain barrier and localize in the brain (0.92 and 0.36 % dose/organ, at 2 min and 30 min, respectively). However, no specific regional uptake of the ligand was observed. Subsequent biodistribution studies performed using two well resolved peaks obtained from chiral HPLC separation of 3b, demonstrated that Fraction I displayed higher brain uptake (0.6 % dose/organ, 20 min) than the latter peak (Fraction II, 0.3 % dose/organ, 20 min). Fraction I also exhibited a modest degree of specificity for the striatum which could be blocked by pretreatment with tetrabenazine. The high lipophilicity of 3a (P(o/b) for Fraction 1 and II = 1723 and 1395, respectively) may contribute to high nonspecific binding in vivo, and result in the low target/nontarget ratio observed for this compound. Iodovinyl-TBZ analog 3b is a poor candidate as a SPECT imaging agent for the vesicular monoamine transporter.