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首页> 外文期刊>Neurochemistry International: The International Journal for the Rapid Publication of Critical Reviews, Preliminary and Original Research Communications in Neurochemistry >Synthesis and preliminary evaluation of ((18)F)-fluoro-(2S)-Exaprolol for imaging cerebral beta-adrenergic receptors with PET.
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Synthesis and preliminary evaluation of ((18)F)-fluoro-(2S)-Exaprolol for imaging cerebral beta-adrenergic receptors with PET.

机译：合成和初步评估（（18）F）-氟-（2S）-依帕洛尔用于用PET成像脑β-肾上腺素能受体。

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Cerebral beta-adrenergic receptors (beta-ARs) are of interest in several disorders including Parkinson's disease, Alzheimer's disease and in particular major depressive disorder. Development of a positron emission tomography (PET) ligand for imaging beta-ARs would allow the quantification of these receptors in the living human brain so as to better understand both the pathophysiology of depression and how to improve treatment. Currently there are no radioligands suitable for this purpose. In an attempt to achieve this goal, we prepared [(18)F]-labeled (2S)-1-(1-fluoropropan-2-ylamino)-3-(2-cyclohexylphenoxy)propan-2-ol (fluoro-Exaprolol; (2S)-1). Radiolabeling with fluorine-18 was accomplished via preparation of a precursor containing a tosyl leaving group (10), and utilizes the 2-oxazolidinone group to simultaneously protect both the amine and hydroxy groups. The oxazolidinone was readily removed with lithium aluminum hydride following a nucleophilic [(18)F]-fluoride for tosyl displacement to prepare [(18)F]-(2S)-1 in 31% radiochemical yield (uncorrected for decay), with >98% radiochemical purity in <1h. The specific activity of the formulated product was 927mCi/mumol and the logP (pH 7.4) was 2.97. Preliminary biological evaluations in conscious rats indicated that [(18)F]-(2S)-1 had good brain uptake for imaging (0.8-1.3% injected dose/gram (% ID/g) of wet tissue, 5min post-injection of the radiotracer) with a slow washout (>0.5% ID/g at 60min post-injection) in all brain regions. Pharmacological challenges indicate that the binding is largely non-specific, as administration of Propranolol, authentic (2S)-1, or WAY 100635 prior to injection of [(18)F]-(2S)-1 did not block uptake of the radiotracer. These results indicate that [(18)F]-(2S)-1 is not a suitable candidate for PET imaging of cerebral beta-ARs.
机译：脑β-肾上腺素能受体（β-ARs）在包括帕金森氏病，阿尔茨海默氏病，尤其是重度抑郁症在内的多种疾病中令人关注。开发用于对β-AR成像的正电子发射断层扫描（PET）配体将可以量化人类大脑中的这些受体，从而更好地了解抑郁症的病理生理学以及如何改善治疗。当前没有适合此目的的放射性配体。为了实现此目标，我们制备了[（18）F]标记的（2S）-1-（1-氟丙-2-基氨基）-3-（2-环己基苯氧基）丙-2-醇（氟-Exaprolol ;（2S）-1）。氟18的放射性标记是通过制备含有甲苯磺酰基离去基团（10）的前体来完成的，并利用2-恶唑烷酮基团同时保护胺和羟基。亲核性[[18] F]-氟化物用于甲苯磺酰基置换后，很容易用氢化铝锂去除甲苯唑啉酮，以31％的放射化学产率（未校正衰变）制备[（18）F]-（2S）-1，其中> <1h内放射化学纯度达到98％。配制产品的比活为927mCi / mumol，logP（pH 7.4）为2.97。在清醒大鼠中的初步生物学评估表明，[（18）F]-（2S）-1具有良好的大脑摄取以进行成像（湿组织注射剂量为0.8-1.3％/克（％ID / g），注射后5分钟）放射性示踪剂）在所有脑区域均具有较慢的冲洗速度（注射后60分钟时> 0.5％ID / g）。药理学挑战表明该结合在很大程度上是非特异性的，因为在注射[（18）F]-（2S）-1之前服用普萘洛尔，真实的（2S）-1或WAY 100635不会阻止放射性示踪剂的吸收。这些结果表明，[（18F）]-（2S）-1不适合用于大脑β-AR的PET成像。

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