Inkster James A H, Sromek Anna W, Akurathi Vamsidhar, Neumeyer John L, Packard Alan B
Division of Nuclear Medicine and Molecular Imaging, Boston Children's Hospital, 300 Longwood Ave., Boston, MA 02115, USA.
Harvard Medical School, 25 Shattuck St., Boston, MA 02115, USA.
Chemistry (Basel). 2021 Sep;3(3):1047-1056. doi: 10.3390/chemistry3030075. Epub 2021 Sep 9.
The dopamine D agonist MCL-524 is selective for the D receptor in the high-affinity state (D), and, therefore, the PET analogue, [F]MCL-524, may facilitate the elucidation of the role of D in disorders such as schizophrenia. However, the previously reported synthesis of [F]MCL-524 proved difficult to replicate and was lacking experimental details. We therefore developed a new synthesis of [F]MCL-524 using a "non-anhydrous, minimally basic" (NAMB) approach. In this method, [F]F is eluted from a small (10-12 mg) trap-and-release column with tetraethylammonium tosylate (2.37 mg) in 7:3 MeCN:HO (0.1 mL), rather than the basic carbonate or bicarbonate solution that is most often used for [F]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) (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, [F]MCL-524 was obtained in 5-9% RCY (decay-corrected, = 3), confirming the utility of this improved method for the multistep synthesis of [F]MCL-524 and suggesting that it may applicable to the synthesis of other F-labeled radiotracers.
多巴胺D激动剂MCL - 524对高亲和力状态的D受体（D）具有选择性，因此，正电子发射断层扫描（PET）类似物[F]MCL - 524可能有助于阐明D在精神分裂症等疾病中的作用。然而，先前报道的[F]MCL - 524的合成方法难以重复且缺乏实验细节。因此，我们采用“非无水、弱碱性”（NAMB）方法开发了一种新的[F]MCL - 524合成方法。在该方法中，[F]F从一个小的（10 - 12毫克）捕集 - 释放柱中用对甲苯磺酸四乙铵（2.37毫克）在7:3的乙腈:水（0.1毫升）中洗脱，而不是最常用于[F]F回收的碱性碳酸盐或碳酸氢盐溶液。将0.9毫升无水乙腈中的对甲苯磺酰化前体（1毫克）直接加入洗脱液中，无需共沸干燥，然后将溶液加热（150℃/15分钟）。然后用路易斯酸三氟甲磺酸铟（In(OTf)，10当量；150℃/20分钟）对儿茶酚进行脱保护。与用质子酸脱保护相比，基于路易斯酸的脱保护有助于通过高效液相色谱（HPLC）有效去除副产物，并且无需在HPLC纯化之前进行固相萃取（SPE）。使用NAMB方法，以5 - 9%的放射性化学产率（衰变校正， = 3）获得了[F]MCL - 524，证实了这种改进方法在[F]MCL - 524多步合成中的实用性，并表明它可能适用于其他F标记放射性示踪剂的合成。
