Cerebral Acetylcholinesterase Imaging: Development of the Radioprobes

Abstract

Cerebral acetylcholinesterase (AChE) imaging is not only useful for diagnosis of dementia disorders but also for therapeutic monitoring of the effects of cholinesterase (ChE) inhibitors and for decision of the appropriate clinical dosage of newly developed ChE inhibitors. Several ChE inhibitors or the derivatives such as 1,2,3,4-tetrahydro-9-methylaminoacridine (MTHA), donepezil, physostigmine, CP126,998 and 2-fluoro-CP118,954 have been labeled with positron emitters for mapping cerebral AChE by positron emission tomography (PET). When [(11)C]MTHA or [(11)C]donepezil was injected in animals, the uptake poorly reflect the regional distribution of AChE in the brain because of high non-specific binding and/or less specific to AChE in vivo in the brain tissue. [(11)C]physostigmine, [(11)C]CP126,998 and 2-[(18)F]fluoro-CP118,954 were distributed corresponding well to the regional AChE activity in animals, and also former two probes were successfully applied to clinical PET trial. The other approach is measuring cerebral AChE activity with radiolabeled acetylcholine analogue substrates. We have developed the principle for measuring cerebral enzyme activity by PET and radiolabeled N-methylpiperidinyl esters for quantitative measurement of cerebral AChE activity. N-[(11)C]methylipiperidin-4-yl acetate (MP4A) and N-[(11)C]methylpiperidin-4-yl propionate (MP4P) have been used for clinical studies of other demented disorders including Alzheimer's disease (AD), and the probes have demonstrated not only the reduction of AChE activity in the cerebral cortex of patients with AD but also the inhibitory effects of donepezil and rivastigmine on AChE activity in the brain of AD patients. Following this succession, widely available [(18)F]-labeled derivatives of MP4A and MP4P have been developed based on the structure-activity relationships between AChE and piperidinol esters.

Synthesis and Preliminary Evaluation of Piperidinyl and Pyrrolidinyl Iodobenzoates as Imaging Agents for Butyrylcholinesterase

“…As a result, all three iodobenzoate esters are selective for BuChE over AChE. Their affinities for BuChE (Table 1) are comparable to the extensively studied substrate for the enzyme, butyrylthiocholine (30.9 μM) [36].…”

Neuroimaging in Dementia

“…In AD, where the cholinergic deficit has been shown in vitro , the cholinergic system can be evaluated using a variety of agents that interact with acetylcholine receptors and acetylcholinesterase, a key enzyme whose function decreases in AD [73]. PET imaging has potential as a tool for monitoring treatment, as it has been used to demonstrate significant increases in 11 C-nicotine binding sites after 3 months of treatment with rivastigmine, with the increases positively correlated with improvements in the performance of attentional tasks at 12 months [74].…”

Human Brain Imaging of Acetylcholine Receptors

“…Over the past three decades, numerous radiotracers have been developed for the evaluation of the cholinergic system in the human brain by SPECT and PET (Eckelman, 2006;Giboureau et al, 2010;Horti and Villemagne, 2006;Kikuchi et al, 2007;Toyohara et al, 2010b). These include several radioligands suitable for mapping mAChR and nAChR, presynaptic vesicular ACh transporter, and AChE.…”