[C-11]MK-6884 PET: CHARACTERIZING BRAIN M4 RECEPTORS IN HEALTHY ELDERLY VOLUNTEERS AND ACETYLCHOLINESTERASE INHIBITORS-TREATED AD PATIENTS

The M4 muscarinic cholinergic receptor may play important roles in the pathophysiology and treatment of Alzheimer's disease (AD). This study aimed to assess the utility of [11C]MK-6884, a novel PET radiotracer targeting the M4 allosteric modulator binding sites, in characterizing brain M4 receptors in both healthy elderly volunteers (HEV) and AD patients receiving standard-of-care treatment for cognitive impairment with acetylcholinesterase inhibitors (AChEIs). Seven HEVs (age: 63 ± 5.4) and ten AD patients (age: 68 ± 5.2, MMSE: 14 ± 5.7) underwent dynamic brain PET scans after IV injections of [11C]MK-6884 (dose: ∼370 MBq). Retest PET scans were performed in 6 of the 7 HEVs for assay validation purposes. All AD patients were stably maintained on either donepezil or rivastigmine therapy for at least 4 weeks prior to study. The cerebellum was validated and used as the non-displaceable reference region to estimate target region binding potential (BPND). Single IV doses of [11C]MK-6884 were safe and well tolerated in both HEV and AD, with no serious adverse events associated with treatment. With the reference-region based method, acceptable test-retest reproducibility (TRV) was obtained in HEV (e.g., BPND TRV of 11% in striatum and 16% in frontal cortex). Overall, tracer kinetics in AD brains were similar to those of HEV, but with substantial regional differences. The striatal BPND values, highest among all brain regions, are comparable between AD (0.98 ± 0.20) and HEV (0.96 ± 0.13); the cortical BPND values, however, are significantly lower in AD patients. Among cortical regions, frontal cortex showed the highest BPND (0.74 ± 0.20) in AD, which is ∼20% lower (p=0.03, two-tailed Welch's t-test) than that in HEV (0.92 ± 0.15). The parametric [11C]MK-6884 PET images suggested notable cortical heterogeneity and bi-lateral asymmetry of M4 receptor binding in AD patients’ brains (Fig. 1).