**2.5 Imaging the cholinergic system**

The abnormal aggregation of amyloid and tau proteins in AD pathophysiology is accompanied by concomitant decline of neurotransmitter systems, primarily the cholinergic system (Bierer, et al., 1995; Bohnen, et al., 2005; Contestabile, 2011; Francis, et al., 1999; Terry and Buccafusco, 2003). Thus, from a diagnostic perspective, there is interest in being able to image the cholinergic system with PET. To date, efforts have focused upon developing radiolabeled analogs of acetylcholine that are substrates for acetylcholinesterase. Acetylcholinesterase (AChE) is the enzyme responsible for the degradation of acetylcholine, leading to the termination of cholinergic neurotransmission. AChE deficits in *post-mortem* AD brain samples have been observed, suggesting that cholinergic decline is part of the complex neurodegenerative cascade that occurs in AD. Therefore, radiopharmaceuticals suitable for quantifying AChE *in vivo* have potential for tracking the progression of the cholinergic aspect of this cascade in AD patients. The synthetic acetylcholinesterase substrate, 1-[11C]methylpiperidin-4-yl propionate ([11C]PMP) (Shao, et al., 2003; Snyder, et al., 1998), is currently in routine clinical use as a radiopharmaceutical for the study of AChE function in AD patients, and results from such studies have been encouraging (K. A. Frey, et al., 1997; Iyo, et al., 1997; Koeppe, et al., 1997; Kuhl, et al., 1996). For example, statistically significant decreases in the cortical hydrolysis rate of [11C]PMP in AD brains, versus agematched controls, have been detected, and correlations identified (Bohnen, et al., 2005; Iyo, et al., 1997; Kilbourn, et al., 1996; Kuhl, et al., 1996). Similar results have also been obtained using [11C]-*N*-methyl-4-piperidyl-acetate ([11C]AMP) (Namba, et al., 1994).
