James A H Inkster, Anna W Sromek, Vamsidhar Akurathi, John L Neumeyer, Alan B Packard
{"title":"The Non-Anhydrous, Minimally Basic Synthesis of the Dopamine D<sub>2</sub> Agonist [18F]MCL-524.","authors":"James A H Inkster, Anna W Sromek, Vamsidhar Akurathi, John L Neumeyer, Alan B Packard","doi":"10.3390/chemistry3030075","DOIUrl":null,"url":null,"abstract":"<p><p>The dopamine D<sub>2</sub> agonist MCL-524 is selective for the D<sub>2</sub> receptor in the high-affinity state (D<sub>2</sub><sup>high</sup>), and, therefore, the PET analogue, [<sup>18</sup>F]MCL-524, may facilitate the elucidation of the role of D<sub>2</sub><sup>high</sup> in disorders such as schizophrenia. However, the previously reported synthesis of [<sup>18</sup>F]MCL-524 proved difficult to replicate and was lacking experimental details. We therefore developed a new synthesis of [<sup>18</sup>F]MCL-524 using a \"non-anhydrous, minimally basic\" (NAMB) approach. In this method, [<sup>18</sup>F]F<sup>-</sup> is eluted from a small (10-12 mg) trap-and-release column with tetraethylammonium tosylate (2.37 mg) in 7:3 MeCN:H<sub>2</sub>O (0.1 mL), rather than the basic carbonate or bicarbonate solution that is most often used for [<sup>18</sup>F]F<sup>-</sup> 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)<sub>3</sub> (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, [<sup>18</sup>F]MCL-524 was obtained in 5-9% RCY (decay-corrected, <i>n</i> = 3), confirming the utility of this improved method for the multistep synthesis of [<sup>18</sup>F]MCL-524 and suggesting that it may applicable to the synthesis of other <sup>18</sup>F-labeled radiotracers.</p>","PeriodicalId":53216,"journal":{"name":"Chemistry-Switzerland","volume":null,"pages":null},"PeriodicalIF":2.4000,"publicationDate":"2021-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10569134/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Chemistry-Switzerland","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.3390/chemistry3030075","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2021/9/9 0:00:00","PubModel":"Epub","JCR":"Q3","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
引用次数: 0
Abstract
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.