[11C]LBT-999:: A suitable radioligand for investigation of extra-striatal dopamine transporter with PET
[11C]LBT-999:: A suitable radioligand for investigation of extra-striatal dopamine transporter with PET
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DOI：
10.1002/syn.20337
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发表时间：
2007-01-01
期刊：
影响因子：
2.3
通讯作者：
Bottlaender, Michel
中科院分区：
文献类型：
--
作者：
Saba, Wadad;Valette, Heric;Bottlaender, Michel
一种新的tropane衍生物，(E)- n-（4-氟丁-2-烯基）-2 β -碳甲氧基3 β -(4'-tolyl)nortropane (LBT-999)，在狒狒中被评估为碳-11放射性配体，用于使用正电子发射断层扫描（PET）研究多巴胺转运体（DAT）。注射后30分钟，纹状体的脑摄取高（壳核和尾状核分别为17和13% ID/100 mL组织），中脑和丘脑为中等（5和3% ID/100 mL组织），皮层和小脑为低（2% ID/100 mL组织）。纹状体与小脑的比例很高（注射后110 min为30）。在用DAT拮抗剂GBR12909 （5mg /kg静脉注射）或PE2I （1mg /kg静脉注射）预处理后，特异性结合被完全阻断。这些拮抗剂降低了[C-11]LBT-999在壳核（分别为- 79%和-92%）、尾状核（分别为- 80%和-91%）、中脑（分别为- 73%和-78%）和丘脑（分别为- 34%和-46%）的摄取。血清素转运体（SERT）拮抗剂西酞普兰（5mg /kg静脉注射）或去甲肾上腺素转运体拮抗剂马普替林（5mg /kg静脉注射）对LBT特异性结合没有影响。用PE2I （1 mg/kg静脉注射）引起壳核（-97%）、尾状核（-96%）、中脑（-96%）和丘脑（-81%）特异性结合的快速且几乎完全降低，证实了[C-11]LBT-999结合的可变性。[C-11]LBT-999的高脑摄取及其低非特异性结合（反映在非常高的脑结构与小脑的比例）表明，这种放射性示踪剂是体内定量DAT的极好候选物，特别是在纹状体外结构，如中脑。
A new tropane derivative, (E)-N-(4-fluorobut-2-enyl)-2 beta-carbomethoxy3 beta-(4'-tolyl)nortropane (LBT-999), was evaluated in baboons as a carbon-11 radioligand for studies of the dopamine transporter (DAT) using positron emission tomography (PET). Brain uptake was high in the striatum (17 and 13% ID/100 mL tissue in the putamen and the caudate, respectively), moderate in the midbrain and thalamus (5 and 3% ID/100 mL tissue, respectively), and low in the cortex and cerebellum (2% ID/100 mL tissue) at 30 min post injection. The striatum-to-cerebellum ratio was high (30 at 110 min post injection). Specific binding was completely blocked following pretreatment with the DAT antagonists GBR12909 (5 mg/kg i.v.) or PE2I (1 mg/kg i.v.). The [C-11]LBT-999 uptake was decreased by these antagonists in the putamen (-79 and -92%, respectively), caudate (-80 and -91%, respectively), midbrain (-73 and -78%, respectively), and thalamus (-34 and -46%, respectively). The serotonin transporter (SERT) antagonist citalopram (5 mg/kg i.v.) or the norepinephrine transporter antagonist maprotiline (5 mg/kg i.v.) had no effect on LBT specific binding. Pharmacological challenge with PE2I (1 mg/kg i.v.) induced a rapid and almost complete decrease of the specific binding in the putamen (-97%), caudate (-96%), midbrain (-96%), and thalamus (-81%), confirming the reversibility of [C-11]LBT-999 binding. The high brain uptake of [C-11]LBT-999 together with its low nonspecific binding (reflected by the very high brain structure-to-cerebellum ratio) indicate that this radio-tracer is an excellent candidate for in vivo quantification of the DAT, especially in extra-striatal structures, such as the midbrain.