[18F]5-(6-Fluorohexyn-1-yl)-3-[2(S)-2-azetidinylmethoxy]pyridine

Excerpt

Neuronal α4β2 nicotinic cholinergic receptors (nAChRs) are part of a heterogeneous family of ligand-gated ion channels expressed in the central nervous system, where their activation by acetylcholine and nicotine causes a rapid increase in cellular permeability to ions such as Na⁺ and Ca²⁺ (1-3). Nicotinic receptors exist as pentamers (homomeric or heteromeric) in various brain regions and ganglia. There are nine subtypes of ligand-binding α receptors (α2 to α10) and four subtypes of structural β receptors (β2 to β5). nAChRs have been found to be involved in cognitive processes such as learning, memory, and control of movement in normal subjects. nAChR dysfunction has been implicated in a number of human diseases such as schizophrenia, Huntington's disease, Alzheimer's disease, and Parkinson's disease. nAChRs also play a significant role in nicotine addiction and other health problems associated with tobacco smoking.

3-[2(S)-2-Azetidinylmethoxy]pyridine (A-85380) is a highly potent and selective α4β2 nAChR agonist with subnanomolar affinity (4, 5). 6-[¹⁸F]Fluoro-A-85380 and 2-[¹⁸F]fluoro-A-85380 have been studied in humans as positron emission tomography (PET) agents for α4β2 nAChR imaging in the brain. A-85380 has also been labeled as 5-[¹²³I]iodo-A-85380 (5-[¹²³I]IA), which has been developed as a single-photon emission computed tomography (SPECT) agent for the noninvasive study of α4β2 nAChR in the brain. However, prolonged imaging times (>5 h) are required for reliable quantification because of the slow kinetics of this agent. 5-(6-Hydroxyhexyn-1-yl)-A-85380 (sazetidine-A), a derivative of A-85380, has been shown to be a potent and selective β2 nAChR agonist for α4β2 nAChR with subnanomolar affinity (6). [¹⁸F]5-(6-Fluorohexyn-1-yl)-A-85380 ([¹⁸F]ZW-104) is being developed as a PET agent for the noninvasive study of α4β2 nAChR in the brain (7).