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

The dopamine D₂ agonist MCL-524 is selective for the D₂ receptor in the high-affinity state (D₂^high), and, therefore, the PET analogue, [¹⁸F]MCL-524, may facilitate the elucidation of the role of D₂^high 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.