The Non-Anhydrous, Minimally Basic Synthesis of the Dopamine D2 Agonist [18F]MCL-524

• Published in: Chemistry an international journal Vol. 3; no. 3; pp. 1047 - 1056
• Main Authors: Inkster, James A. H., Sromek, Anna W., Akurathi, Vamsidhar, Neumeyer, John L., Packard, Alan B.
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 01-09-2021
• Subjects: Acetonitrile; Acids; aporphines; Bicarbonates; Catechol; Dopamine; dopamine D2 agonist; Efficiency; fluorine-18; high-affinity state; Incorporation; Lewis acid; PET; Radioactive tracers; Schizophrenia; Synthesis
• ISSN: 2624-8549; 2624-8549
• DOI: 10.3390/chemistry3030075

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.