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The Non-Anhydrous, Minimally Basic Synthesis of the Dopamine D2 Agonist [18F]MCL-524. 多巴胺D2激动剂[18F]MCL-524的非无水、最低碱性合成。
IF 2.1 Q3 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2021-09-01 Epub Date: 2021-09-09 DOI: 10.3390/chemistry3030075
James A H Inkster, Anna W Sromek, Vamsidhar Akurathi, John L Neumeyer, Alan B Packard

The dopamine D2 agonist MCL-524 is selective for the D2 receptor in the high-affinity state (D2high), and, therefore, the PET analogue, [18F]MCL-524, may facilitate the elucidation of the role of D2high in disorders such as schizophrenia. However, the previously reported synthesis of [18F]MCL-524 proved difficult to replicate and was lacking experimental details. We therefore developed a new synthesis of [18F]MCL-524 using a "non-anhydrous, minimally basic" (NAMB) approach. In this method, [18F]F- is eluted from a small (10-12 mg) trap-and-release column with tetraethylammonium tosylate (2.37 mg) in 7:3 MeCN:H2O (0.1 mL), rather than the basic carbonate or bicarbonate solution that is most often used for [18F]F- recovery. The tosylated precursor (1 mg) in 0.9 mL anhydrous acetonitrile was added directly to the eluate, without azeotropic drying, and the solution was heated (150 °C/15 min). The catechol was then deprotected with the Lewis acid In(OTf)3 (10 equiv.; 150 °C/20 min). In contrast to deprotection with protic acids, Lewis-acid-based deprotection facilitated the efficient removal of byproducts by HPLC and eliminated the need for SPE extraction prior to HPLC purification. Using the NAMB approach, [18F]MCL-524 was obtained in 5-9% RCY (decay-corrected, n = 3), confirming the utility of this improved method for the multistep synthesis of [18F]MCL-524 and suggesting that it may applicable to the synthesis of other 18F-labeled radiotracers.

多巴胺D2激动剂MCL-524对处于高亲和力状态(D2high)的D2受体是选择性的,因此,PET类似物[18F]MCL-524,可以促进阐明D2high在精神分裂症等疾病中的作用。然而,先前报道的[18F]MCL-524的合成被证明难以复制,并且缺乏实验细节。因此,我们使用“非无水、最低碱性”(NAMB)方法开发了[18F]MCL-524的新合成方法。在该方法中,[18F]F-用在7:3MeCN:H2O(0.1mL)中的甲苯磺酸四乙基铵(2.37mg)从小型(10-12mg)捕获和释放柱中洗脱,而不是最常用于[18F]F-回收的碱性碳酸盐或碳酸氢盐溶液。将甲苯磺酰化的前体(1 mg)在0.9 mL无水乙腈中直接加入洗脱液中,无需共沸干燥,并加热溶液(150°C/15分钟)。然后用路易斯酸In(OTf)3(10当量;150°C/20分钟)对邻苯二酚进行脱保护。与用质子酸脱保护相反,基于路易斯酸的脱保护促进了通过HPLC有效去除副产物,并消除了在HPLC纯化之前对SPE提取的需要。使用NAMB方法,在5-9%RCY(衰变校正,n=3)中获得[18F]MCL-524,证实了这种改进方法在[18F]MCL-524的多步合成中的实用性,并表明它可以应用于其他18F标记的放射性示踪剂的合成。
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