Search

Abstract: Inflammatory mechanisms, like microglial activation, could be involved in the pathogenesis of Alzheimer''s disease (AD). (R)-[11C]PK11195 (1-(2-chlorophenyl)-N-methyl-N-1(1-methylpropyl)-3-isoquinolinecarboxamide), a positron emission tomography (PET) ligand, can be used to quantify microglial activation in vivo. The purpose of this study was to assess whether increased (R)-[11C]PK11195 binding is present in AD and mild cognitive impairment (MCI), currently also known as “prodromal AD.” Methods: Nineteen patients with probable AD, 10 patients with prodromal AD (MCI), and 21 healthy control subjects were analyzed. Parametric images of binding potential (BPND) of (R)-[11C]PK11195 scans were generated using receptor parametric mapping (RPM) with supervised cluster analysis. Differences between subject groups were tested using mixed model analysis, and associations between BPND and cognition were evaluated using Pearson correlation coefficients. Results: Voxel-wise statistical parametric mapping (SPM) analysis showed small clusters of significantly increased (R)-[11C]PK11195 BPND in occipital lobe in AD dementia patients compared with healthy control subjects. Regions of interest (ROI)-based analyses showed no differences, with large overlap between groups. There were no differences in (R)-[11C]PK11195 BPND between clinically stable prodromal AD patients and those who progressed to dementia, and BPND did not correlate with cognitive function. Conclusion: Microglial activation is a subtle phenomenon occurring in AD. [Copyright &y& Elsevier]

Aims: HTL0018318 is a selective M 1 receptor partial agonist currently under development for the symptomatic treatment of cognitive and behavioural symptoms in Alzheimer's disease and other dementias. We investigated safety, tolerability, pharmacokinetics and exploratory pharmacodynamics (PD) of HTL0018318 following single ascending doses., Methods: This randomized, double-blind, placebo-controlled study in 40 healthy younger adult and 57 healthy elderly subjects, investigated oral doses of 1-35 mg HTL0018318. Pharmacodynamic assessments were performed using a battery of neurocognitive tasks and electrophysiological measurements. Cerebrospinal fluid concentrations of HTL0018318 and food effects on pharmacokinetics of HTL0018318 were investigated in an open label and partial cross-over design in 14 healthy subjects., Results: Pharmacokinetics of HTL0018318 were well-characterized showing dose proportional increases in exposure from 1-35 mg. Single doses of HTL0018318 were associated with mild dose-related adverse events of low incidence in both younger adult and elderly subjects. The most frequently reported cholinergic AEs included hyperhidrosis and increases in blood pressure up to 10.3 mmHg in younger adults (95% CI [4.2-16.3], 35-mg dose) and up to 11.9 mmHg in elderly subjects (95% CI [4.9-18.9], 15-mg dose). There were no statistically significant effects on cognitive function but the study was not powered to detect small to moderate effect sizes of clinical relevance., Conclusion: HTL0018318 showed well-characterized pharmacokinetics and following single doses were generally well tolerated in the dose range studied. These provide encouraging data in support of the development for HTL0018318 for Alzheimer's disease and other dementias., (© 2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

The methylguanidine derivative 11 C-GMOM ( 11 C-labeled N -(2-chloro-3-thiomethylphenyl)- N '-(3-methoxyphenyl)- N '-methylguanidine) has been used successfully to quantify N -methyl-d-aspartate (NMDA) receptor binding in humans. The purpose of the present study was to estimate the 11 C-GMOM radiation dose in healthy humans. Methods: After 11 C-GMOM injection, 3 female and 2 male subjects underwent 10 consecutive whole-body PET scans in approximately 77 min. Seven source organs were defined manually, scaled to a sex-specific reference, and residence times were calculated for input into OLINDA/EXM software. Accepted tissue-weighting factors were used to calculate the effective dose. Results: The mean absorbed radiation doses in source organs ranged from 7.7 μGy·MBq -1 in the brain to 12.7 μGy·MBq -1 in the spleen. The effective dose (±SD) was 4.5 ± 0.5 μSv·MBq -1 Conclusion: The effective dose of 11 C-GMOM is at the lower end of the range seen for other 11 C-labeled ligands, allowing for serial PET scanning in a single subject., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)