5-(6-(5-[C]methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin-3-yl)-1H-indole

The nicotinic acetylcholine receptors (nAChR) are pentameric ligand-gated cation channels that are found primarily in the central nervous system of mammals and are composed of α and β subunits arranged in various homomeric or heteromeric stoichiometric arrangements (for details, see dos Santos Coura and Granon (1)). The nAChRs have a high affinity for both nicotine and acetylcholine; binding of a ligand to the receptor facilitates the passage of cations into the cell, which alters the polarity of the cell membrane and activates the signal transduction pathways that culminate in a cellular response (2). These receptors are believed to be involved in a variety of cognitive functions and memory (1), neuroprotection in Parkinson’s disease (3), Alzheimer’s disease (AD) (4), and the progression of certain cancers (5). The heteromeric α4β2 and the homomeric α7 are the most commonly expressed nAChRs in the brain, and the β2 subunit is a component of most heteromeric nicotinic receptors in the central nervous system. There is much evidence that α4β2-nAChR is involved in normal cognitive functions in animals; it is also implicated in addiction (e.g., smoking) and the cognitive impairments observed in AD, attention deficit hyperactivity disorder, and schizophrenia (6). α7-nAChR participates in cognition and has a reduced expression in the human schizophrenic brain, and there are indications that it has a therapeutic role in the treatment of AD (7). Although some radiolabeled compounds can be used with positron emission tomography (PET) to visualize α4β2-nAChR in the human brain these radio-ligands exhibit slow kinetics and a low binding potential in the brain which limits their use to investigate nAChR in humans (8). Therefore, no suitable tracer(s) are available for the noninvasive imaging of α7-nAChR in humans (7). In an effort to develop new ligands for α7-nAChR two compounds, 5-(6-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin-3-yl)-1H-indole (A-833834) and 2-(6-methyl-3,6-diazabicyclo[3.2.0]heptan-3-yl)-7-(6-methyl-3,6-diazabicyclo[3.2.0]heptan-3-yl)-9H-fluoren-9-one (A-752274) were synthesized, labeled with C (to obtain [C]A-833834 and [C]A-752274, respectively), and evaluated in mice (7). The biodistribution of both tracers was investigated in the mouse brain, and [C]A-752274 was also evaluated for use with PET imaging of a baboon brain. This chapter presents results obtained with [C]A-833834. The biodistribution and PET imaging characteristics of [C]A-752274 are discussed in a separate chapter in MICAD (www.micad.nih.gov) (9).