IC-P-142: [¹¹ C]MK-6884 PET TRACER FOR M4 MUSCARINIC CHOLINERGIC RECEPTORS IN ALZHEIMER'S DISEASE: COMPARISON WITH [¹⁸ F]FDG PET

Cholinergic neuron loss has long been known to be a hallmark of AD. The largest class of therapeutic agents targets acetylcholinesterase in order to increase acetylcholine availability. In order to evaluate regional cholinergic tone in individual patients and measure target engagement for potential therapies, it would be helpful to image muscarinic receptors in vivo. Several imaging tracers have been developed over the years to image cholinergic receptors, but the findings with these agents have been either negative or too subtle to be of use. Recently, a M4 muscarinic cholinergic receptor PET tracer has been developed that shows good imaging characteristics. We report on the first group of AD patients to be studied with this tracer, [11C]MK-6884. Nine patients with Alzheimer's disease (MMSE=15.2±5.2), aged from 60 to 76 years old (mean=68.9±5.5 years, five women), underwent [11C]MK-6884 M4 receptor and [18F]FDG metabolism PET. Immediately after a bolus injection of approximately 370 MBq of [11C]MK-6884, images were acquired during 90 minutes. Standardized uptake value ratios (SUVRs) were calculated between 5 to 15 minutes using the cerebellum grey matter as the reference region. [18F]FDG SUVRs were calculated following standard procedures, using the cerebellum grey matter as the reference region between 40 to 60 min. As expected, [11C]MK-6884 showed good uptake in the basal ganglia, with low values in thalamus. Cortical uptake was reduced mostly in parieto-temporal association cortex, corresponding well with the clinical syndrome: patients with a predominant language problem had greater loss in the left hemisphere and the opposite was true for those with visuospatial skills impairment. Frontal lobes were also affected, but not as much as the posterior structures. There was a concordance in cortical [11C]MK-6884 and [18F]FDG PET values, indicating that the [11C]MK-6884 binding was disease specific, but also discordant areas, highlighting the potential specificity of [11C]MK-6884. The initial experience with [11C]MK-6884 suggests that this tracer may prove useful to image muscarinic receptors in AD.