Madras B K, Meltzer P C, Liang A Y, Elmaleh D R, Babich J, Fischman A J
Department of Psychiatry, Harvard Medical School, New England Regional Primate Research Center, Southborough, Massachusetts 01772-9102, USA.
Synapse. 1998 Jun;29(2):93-104. doi: 10.1002/(SICI)1098-2396(199806)29:2<93::AID-SYN1>3.0.CO;2-5.
Increasing evidence suggests that the dopamine transporter is an important marker for physiological and pathological changes in dopamine neurons. Potent dopamine transport inhibitors of the phenyltropane series (e.g., WIN 35,428 or CFT) are particularly suitable for PET (positron emission tomography) or SPECT (single photon emission computed tomography) imaging of the dopamine transporter in living brain. We investigated whether altropane, an N-iodoallyl analog of WIN 35,428 (IACFT:E-N-iodoallyl-2 -carbomethoxy-3beta-(4-fluorophenyl)tropane), displayed in vitro properties suitable for evaluation as a SPECT imaging agent. In brain striatum of cynomolgus monkey (Macaca fascicularis), the unlabeled E-isomer (IC50: 6.62 +/- 0.78 nM) was more potent than the Z-isomer (IC50: 52.6 +/- 0.3 nM) and displayed a relatively high dopamine:serotonin transporter selectivity (28-fold). In radiolabeled form, [125I]altropane bound to sites in the striatum with a single high affinity (KD: 5.33 +/- 0.55 nM) and with a site density (BMAX: 301 pmol/g original wet tissue weight) that was within the density range reported previously for the dopamine transporter in striatum. Drugs inhibited [125I]altropane binding with a rank order of potency that corresponded closely to their potencies for inhibiting [3H]WIN 35,428 binding (r2: 0.99; P < 0.0001) to the blocking dopamine transport. The favorable binding properties of altropane, together with its rapid entry into primate brain and highly localized distribution in dopamine-rich brain regions, suggest it is a suitable iodinated probe for monitoring the dopamine transporter in vitro and in vivo by SPECT or PET imaging.
越来越多的证据表明，多巴胺转运体是多巴胺神经元生理和病理变化的重要标志物。苯托烷系列的强效多巴胺转运抑制剂（如WIN 35,428或CFT）特别适用于在活体大脑中对多巴胺转运体进行正电子发射断层扫描（PET）或单光子发射计算机断层扫描（SPECT）成像。我们研究了WIN 35,428的N-碘代烯丙基类似物altropane（IACFT：E-N-碘代烯丙基-2-甲氧基羰基-3β-（4-氟苯基）托烷）是否具有适合作为SPECT成像剂进行评估的体外特性。在食蟹猴（猕猴）的脑纹状体中，未标记的E-异构体（IC50：6.62±0.78 nM）比Z-异构体（IC50：52.6±0.3 nM）更有效，并且显示出相对较高的多巴胺：5-羟色胺转运体选择性（28倍）。以放射性标记形式，[125I]altropane以单一高亲和力（KD：5.33±0.55 nM）与纹状体中的位点结合，位点密度（BMAX：301 pmol/g原始湿组织重量）在先前报道的纹状体中多巴胺转运体的密度范围内。药物抑制[125I]altropane结合的效力顺序与它们抑制[3H]WIN 35,428结合（r2：0.99；P <0.0001）以阻断多巴胺转运的效力密切相关。altropane良好的结合特性，连同其快速进入灵长类动物大脑以及在富含多巴胺脑区的高度局部分布，表明它是一种适合通过SPECT或PET成像在体外和体内监测多巴胺转运体的碘化探针。
