Xing D, Chen P, Keil R, Kilts C D, Shi B, Camp V M, Malveaux G, Ely T, Owens M J, Votaw J, Davis M, Hoffman J M, BaKay R A, Subramanian T, Watts R L, Goodman M M
Emory Center for Positron Emission Tomography and Departments of Radiology, Psychiatry and Behavior Sciences, Neurology, and Neurosurgery, Emory University, Atlanta, Georgia 30320, USA.
J Med Chem. 2000 Feb 24;43(4):639-48. doi: 10.1021/jm9902234.
2beta-(R)-Carbo-1-fluoro-2-propoxy-3beta-(4-chlorophenyl) tro pane ((R)-FIPCT, R-6) and 2beta-(S)-carbo-1-fluoro-2-propoxy-3beta-(4-chlorophenyl) tro pane ((S)-FIPCT, S-6) were prepared and evaluated in vitro and in vivo for dopamine transporter (DAT) selectivity and specificity. High specific activity (18)F-FIPCT and (18)F-FIPCT were synthesized in 5% radiochemical yield (decay-corrected to end of bombardment (EOB)) by preparation of the precursors 2beta-carbo-R-1-mesyloxy-2-propoxy-3beta-(4-chlorop hen yl)tropane (R-12) and 2beta-carbo-S-1-mesyloxy-2-propoxy-3beta-(4-chlorop hen yl)tropane (S-12) followed by treatment with no carrier-added potassium[(18)F]fluoride and kyrptofix K222 in acetonitrile. Competition binding in cells stably expressing the transfected human DAT and serotonin transporter (SERT) labeled by [(3)H]WIN 35428 and [(3)H]citalopram, respectively, demonstrated the following order of DAT affinity (K(i) in nM): GBR 12909 (0.36) > CIT (0.48) > (S)-FIPCT (0.67) >> (R)-FIPCT (3.2). The affinity of (S)-FIPCT and (R)-FIPCT for SERT was 127- and 20-fold lower, respectively, than for DAT. In vivo biodistribution studies were performed in male rats and demonstrated that the brain uptake of (18)F-FIPCT and (18)F-FIPCT were selective and specific for DAT rich regions (caudate and putamen). PET brain imaging studies in monkeys demonstrated high (18)F-FIPCT and (18)F-FIPCT uptake in the caudate and putamen which resulted in caudate-to-cerebellum and putamen-to-cerebellum ratios of 2.5-3.5 at 115 min. (18)F-FIPCT uptake in the caudate/putamen achieved transient equilibrium at 75 min. In an imaging experiment with (18)F-FIPCT in a rhesus monkey with its left hemisphere lesioned with MPTP, radioactivity was reduced to background in the caudate and putamen of the lesioned hemisphere. The high specific activity one-step radiolabeling preparation and high specificity and selectivity of (18)F-FIPCT and (18)F-FIPCT for DAT indicate (18)F-FIPCT and (18)F-FIPCT are potential radioligands for mapping brain DAT in humans using PET.
制备了2β-(R)-碳-1-氟-2-丙氧基-3β-(4-氯苯基)托烷((R)-FIPCT，R-6)和2β-(S)-碳-1-氟-2-丙氧基-3β-(4-氯苯基)托烷((S)-FIPCT，S-6)，并在体外和体内对其多巴胺转运体(DAT)的选择性和特异性进行了评估。通过制备前体2β-碳-R-1-甲磺酰氧基-2-丙氧基-3β-(4-氯苯基)托烷(R-12)和2β-碳-S-1-甲磺酰氧基-2-丙氧基-3β-(4-氯苯基)托烷(S-12)，然后在乙腈中用无载体添加的氟化钾[(18)F]和穴醚K222处理，以5%的放射化学产率(衰变校正至轰击结束(EOB))合成了高比活度的(18)F-FIPCT和(18)F-FIPCT。分别用[(3)H]WIN 35428和[(3)H]西酞普兰标记稳定表达转染人DAT和5-羟色胺转运体(SERT)细胞的竞争结合实验表明，DAT亲和力顺序如下(Ki，单位为nM)：GBR 12909(0.36)>CIT(0.48)>(S)-FIPCT(0.67)>>(R)-FIPCT(3.2)。(S)-FIPCT和(R)-FIPCT对SERT的亲和力分别比对DAT低127倍和20倍。在雄性大鼠中进行了体内生物分布研究，结果表明(18)F-FIPCT和(18)F-FIPCT在脑中的摄取对富含DAT的区域(尾状核和壳核)具有选择性和特异性。在猴子身上进行的PET脑成像研究表明，(18)F-FIPCT和(18)F-FIPCT在尾状核和壳核中摄取量很高，在115分钟时尾状核与小脑以及壳核与小脑的比值为2.5至3.5。(18)F-FIPCT在尾状核/壳核中的摄取在75分钟时达到瞬时平衡。在一只左侧半球用MPTP损伤的恒河猴身上进行的(18)F-FIPCT成像实验中，损伤半球的尾状核和壳核中的放射性降低至本底水平。(18)F-FIPCT和(18)F-FIPCT的高比活度一步放射性标记制备以及对DAT的高特异性和选择性表明，(18)F-FIPCT和(18)F-FIPCT是使用PET在人体中绘制脑DAT图谱的潜在放射性配体。
