Exploration of the dopamine transporter:: In vitro and in vivo characterization of a high-affinity and high-specificity iodinated tropane derivative (E)-N-(3-iodoprop-2-enyl)-2β-carbomethoxy-3β-(4′-methylphenyl)nortropane (PE2I)

被引:71
作者
Guilloteau, D
Emond, P
Baulieu, JL
Garreau, L
Frangin, Y
Pourcelot, L
Mauclaire, L
Besnard, JC
Chalon, S
机构
[1] INSERM, U316, Lab Biophys Med & Pharmaceut, F-37200 Tours, France
[2] Cis Bio Ind, F-91192 Gif Sur Yvette, France
关键词
dopamine transporter; cocaine; SPECT; tropane;
D O I
10.1016/S0969-8051(97)00224-2
中图分类号
R8 [特种医学]; R445 [影像诊断学];
学科分类号
1002 ; 100207 ; 1009 ;
摘要
For the diagnosis and follow-up of neurodegenerative diseases, many cocaine derivatives have been proposed as radioligands to explore the dopamine transporter. As none of them have all the criteria of specificity and kinetics for human use, we have developed a new derivative, (E)-N-(3-iodoprop-2-enyl)-2 beta- carbomethoxy-3 beta-(4'-methylphenyl)nortropane (PE2I), which displays promising properties. We report the characterization of PE2I in vitro on rat striatal membranes and in vitro in rats and in monkeys. PE2I had a high affinity (Kd = 0.09 +/- 0.01 nM) and high specificity for the dopamine transporter. In rats we observed a high accumulation in the striatum; by contrast, a very low fixation was measured in the cortex. Moreover, a preinjection of a saturating dose of GBR 12909 prevented the striatal accumulation of PE2I by 74%. These results confirmed the specificity of PE2I for the dopamine transporter. In vivo in monkeys, SPECT studies showed a high accumulation in striatum. Moreover, an equilibrium state was obtained 1 h after injection. PE2I seemed to be the most promising ligand for the dopamine transporter exploration by SPECT using a single-day protocol. (C) 1998 Elsevier Science Inc.
引用
收藏
页码:331 / 337
页数:7
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