MOLECULAR NEUROIMAGING IN ALZHEIMER'S DISEASE: TARGETING BUTYRYLCHOLINESTERASE (BCHE) FOR POSITRON EMISSION TOMOGRAPHY (PET) AND SINGLE PHOTON EMISSION COMPUTED TOMOGRAPHY (SPECT) IMAGING OF THE BRAIN

Abstract

Currently, there are no effective means to definitively diagnose Alzheimer’s disease (AD) during life. Molecular imaging of β-amyloid (Aβ) or tau neurofibrillary tangle (NFT) pathology in the AD brain, though informative, has limited diagnostic value because similar changes are found in brains of ~30% of cognitively normal individuals and in other neurodegenerative disorders. We have recently shown that the enzyme butyrylcholinesterase (BChE), typically present in high levels in the AD cerebral cortex (yet largely absent in normal brain), is a highly sensitive and specific biomarker for the disease and could therefore provide enhanced accuracy as an AD diagnostic. Consequently, we have developed BChE radioligands for positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging of the brain in AD. Rigorous in vivo evaluation of such radiotracers in AD animal models is essential in order to establish a radioligand’s product profile, ultimately advancing the most promising candidates towards clinical trials in humans. The current work develops and implements a multimodal neuroimaging analysis framework using PET, SPECT magnetic resonance imaging (MRI) and computed tomography (CT) to evaluate putative BChE radioligands. One such BChE radioligand for SPECT imaging, N-Methylpiperidin-4-yl 4-[123I]iodobenzoate (TRV6001), was found to cross the blood brain barrier and recapitulate the known histochemical distribution of BChE in an experimental model, effectively distinguishing an AD mouse brain from that of a wild-type control. An essential neuroimaging analysis framework has been developed and implemented, providing an in vivo radioligand development toolkit for the rapid screening of lead BChE radiotracer candidates. Brain imaging of BChE in humans may enhance the accuracy and timely detection of AD not yet possible with current brain imaging methods and could provide a unique opportunity to facilitate evaluation of emerging next generation therapies for AD.