Chapter 26. In Vivo Diagnostics for Alzheimer's Disease Based on the Acetylcholine Transporter

Publisher Summary This chapter discusses the ACh transporter (AChT). The chapter also discusses the current status of efforts to develop ligands for the AChT that can be used in single photon emission computed tomography (SPECT) or positron emission tomography (PET) to map the density of cholinergic nerve terminals in living human brain. Degeneration of cholinergic terminals in the hippocampus and frontal cortex are among the earliest deficits in this neurodegenerative disease. A sensitive in vivo diagnostic that determines the functional status and/or density of cholinergic nerve terminals in brain might provide a means to detect the onset of Alzheimer's disease before cognitive deficits occur. An early diagnostic probably must probe a concentrated target found only in the cholinergic presynapse. The characteristic function of cholinergic nerve terminals, which constitutes about 6% of the cortical terminals in mammalian brain, is to synthesize and release acetylcholine (ACh). The sodium-dependent high affinity choline uptake transporter in the cytoplasmic membrane, choline acetyltransferase in the cytoplasm, and the ACh transporter in the membrane of synaptic vesicles are key proteins in the synthesis and release of ACh. Among the proteins that carry out presynaptic metabolism of ACh, AChT complex has the most highly developed pharmacology. A potent family of compounds that binds allosterically to the AChT is known. Most of the compounds are relatively easily synthesized and many of them exhibit favorable pharmacokinetics in vivo . Despite the various shortcomings of the available analogs, the utility of the vesamicol family for the visualization of cholinergic nerve terminals has been demonstrated. Thus, this approach to the diagnosis of Alzheimer's disease has great promise, but better ligands are needed. Because of its modularity, the chemical structure of vesamicol is amenable to extensive structure–activity analysis.