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

Abstract

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.

[18F]ALX5406: A Brain-Penetrating Prodrug for GlyT1-Specific PET Imaging

“…4 was radiolabeled using the protocol for copper mediated alcohol-enhanced 18 F-fluorination previously developed in our group (Scheme ). − Accordingly, [ 18 F]­fluoride trapped on an anion exchange resin was eluted with a solution of Et 4 NHCO 3 in n- BuOH directly into a solution of the radiolabeling precursor 4 and [Cu­(OTf) 2 (py) 4 ] in DMA. The reaction mixture was heated for 10 min at 110 °C, furnishing the corresponding radiolabeled ester [ 18 F]­ALX5406.…”

18F-Fluorination Using Tri-Tert-Butanol Ammonium Iodide as Phase-Transfer Catalyst: An Alternative Minimalist Approach

“…Organic PTCs were reported for the elution of [ 18 F]fluoride using MeOH as a solvent [ 22 ]. Importantly, TBMA-I has an excellent solubility in MeOH and could be used for the elution of [ 18 F]fluoride without employing an additional base.…”

“…Aromatic18 F-Fluorination: Radiosynthesis of [ 18 F]]fluoride was eluted according to the reported procedure of Zlatopolskiy et al[22]: [ 18 F]fluoride was eluted directly into the reaction vial, using a methanolic solution of TEAB (20.9 mM, 500 µL) and MeOH was removed at 85 • C under a stream of helium. 6-Benzothiazole boronic acid pinacol ester (5, 4.2 mg, 16.1 µmol) and [Cu(OTf) 2 (py) 4 ] (9.9 mg, 14.6 µmol) in solution with DMA:n-BuOH (2:1, 500 µL) was added and the reaction was stirred at 110 • C for 20 min under air.…”

Imaging Cholinergic Receptors in the Brain by Positron Emission Tomography

“…Nevertheless, the study provided important information to support the clinical development of GSK1034702. More recently, a 18 F-labeled regioisomer of GSK1034702, [ 18 F] 23 , has been developed, but no preclinical evaluation has been reported yet . The preparation of [ 18 F] 23 was achieved via alcohol-enhanced Cu-mediated radiofluorination with a moderate yield of 17%.…”