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.
Highlights
Muscarinic acetylcholine receptors in the central and peripheral nervous system participate in autonomic, cognitive, and motor function
Substantial evidence suggests that they are critically involved in cognition and that loss of cholinergic function contributes to the cognitive decline associated with Alzheimer’s disease, schizophrenia, and other neurological and psychiatric disorders [3,4,5]
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Summary
Muscarinic acetylcholine receptors (mAChRs) in the central and peripheral nervous system participate in autonomic, cognitive, and motor function. Substantial evidence suggests that they are critically involved in cognition and that loss of cholinergic function contributes to the cognitive decline associated with Alzheimer’s disease, schizophrenia, and other neurological and psychiatric disorders [3,4,5] These findings have spurred interest into M1 receptors as a target for experimental or clinical applications. 2 of 122 of 12 spurred interest into M1 receptors as a target for experimental or clinical applications In this context, tomography havetechniques an enormous potential positron for in vivo assessment of target engagement functional(PET). (b) 4-amino-N-Boc-piperidine, DIEA, DMF, 70–80 ◦ C, 38 h, 63% and 72% for 5a and 5b, respectively; N2H4·H2O, EtOH, 45 °C, 2 h, 70% and◦ 29% for 6a and 6b, respectively; (d) triphosgene, Et3N, THF, 45. Et3 N, DMF, r.t., 48 h, 6%. r.t.—room temperature
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