Preparation of a First ¹⁸F-Labeled Agonist for M₁ Muscarinic Acetylcholine Receptors

M₁ muscarinic acetylcholine receptors (mAChRs) are abundant in postsynaptic nerve terminals of all forebrain regions and have been implicated in the cognitive decline associated with Alzheimer's disease and other CNS pathologies. Consequently, major efforts have been spent in the development of subtype-selective positron emission tomography (PET) tracers for mAChRs resulting in the development of several ¹¹C-labeled probes. However, protocols for the preparation of ¹⁸F-labeled mAChR-ligands have not been published so far. Here, we describe a straightforward procedure for the preparation of an ¹⁸F-labeled M₁ mAChR agonist and its corresponding pinacol boronate radiolabeling precursor and the non-radioactive reference compound. The target compounds were prepared from commercially available aryl fluorides and Boc protected 4-aminopiperidine using a convergent reaction protocol. The radiolabeling precursor was prepared by a modification of the Miyaura reaction and labeled via the alcohol-enhanced Cu-mediated radiofluorination. The developed procedure afforded the radiotracer in a non-decay-corrected radiochemical yield of 17 ± 3% (n = 3) and in excellent radiochemical purity (>99%) on a preparative scale. Taken together, we developed a straightforward protocol for the preparation of an ¹⁸F-labeled M₁ mAChR agonist that is amenable for automation and thus provides an important step towards the routine production of a ¹⁸F-labeled M₁ selective PET tracer for experimental and diagnostic applications.