Glia Imaging Differentiates Multiple System Atrophy from Parkinson's Disease: A Positron Emission Tomography Study with [11 C]PBR28 and Machine Learning Analysis.

BACKGROUND: The clinical diagnosis of multiple system atrophy (MSA) is challenged by overlapping features with Parkinson's disease (PD) and late-onset ataxias. Additional biomarkers are needed to confirm MSA and to advance the understanding of pathophysiology. Positron emission tomography (PET) imaging of the translocator protein (TSPO), expressed by glia cells, has shown elevations in MSA. OBJECTIVE: In this multicenter PET study, we assess the performance of TSPO imaging as a diagnostic marker for MSA. METHODS: We analyzed [11 C]PBR28 binding to TSPO using imaging data of 66 patients with MSA and 24 patients with PD. Group comparisons were based on regional analysis of parametric images. The diagnostic readout included visual reading of PET images against clinical diagnosis and machine learning analyses. Sensitivity, specificity, and receiver operating curves were used to discriminate MSA from PD and cerebellar from parkinsonian variant MSA. RESULTS: We observed a conspicuous pattern of elevated regional [11 C]PBR28 binding to TSPO in MSA as compared with PD, with "hotspots" in the lentiform nucleus and cerebellar white matter. Visual reading discriminated MSA from PD with 100% specificity and 83% sensitivity. The machine learning approach improved sensitivity to 96%. We identified MSA subtype-specific TSPO binding patterns. CONCLUSIONS: We found a pattern of significantly increased regional glial TSPO binding in patients with MSA. Intriguingly, our data are in line with severe neuroinflammation in MSA. Glia imaging may have potential to support clinical MSA diagnosis and patient stratification in clinical trials on novel drug therapies for an α-synucleinopathy that remains strikingly incurable. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Brain exposure of the ATM inhibitor AZD1390 in humans-a positron emission tomography study.

BACKGROUND: The protein kinase ataxia telangiectasia mutated (ATM) mediates cellular response to DNA damage induced by radiation. ATM inhibition decreases DNA damage repair in tumor cells and affects tumor growth. AZD1390 is a novel, highly potent, selective ATM inhibitor designed to cross the blood-brain barrier (BBB) and currently evaluated with radiotherapy in a phase I study in patients with brain malignancies. In the present study, PET was used to measure brain exposure of 11C-labeled AZD1390 after intravenous (i.v.) bolus administration in healthy subjects with an intact BBB. METHODS: AZD1390 was radiolabeled with carbon-11 and a microdose (mean injected mass 1.21 µg) was injected in 8 male subjects (21-65 y). The radioactivity concentration of [11C]AZD1390 in brain was measured using a high-resolution PET system. Radioactivity in arterial blood was measured to obtain a metabolite corrected arterial input function for quantitative image analysis. Participants were monitored by laboratory examinations, vital signs, electrocardiogram, adverse events. RESULTS: The brain radioactivity concentration of [11C]AZD1390 was 0.64 SUV (standard uptake value) and reached maximum 1.00% of injected dose at Tmax[brain] of 21 min (time of maximum brain radioactivity concentration) after i.v. injection. The whole brain total distribution volume was 5.20 mL*cm-3. No adverse events related to [11C]AZD1390 were reported. CONCLUSIONS: This study demonstrates that [11C]AZD1390 crosses the intact BBB and supports development of AZD1390 for the treatment of glioblastoma multiforme or other brain malignancies. Moreover, it illustrates the potential of PET microdosing in predicting and guiding dose range and schedule for subsequent clinical studies.

Population Pharmacokinetic Modeling With Enterohepatic Circulation for AZD3241 in Healthy Subjects and Patients With Multiple System Atrophy.

AZD3241 is a potent and selective myeloperoxidase inhibitor potentially for the treatment of a number of neurodegenerative disorders, including multiple system atrophy (MSA). The objectives of this work were to develop a population pharmacokinetic (PopPK) model for AZD3241 and to investigate the correlation between AZD3241 exposure and myeloperoxidase inhibition. The PopPK model was developed using AZD3241 data from one phase 1 study in healthy subjects and one phase 2 study in patients with MSA. A one-compartment model incorporating a gallbladder compartment for enterohepatic circulation, sequential zero-first order absorption, and first-order elimination adequately described the AZD3241 concentration profiles. The apparent clearance and central volume of distribution were 63.1 L/h (interindividual variability: 34.8%) and 121.9 L (interindividual variability: 44.0%), respectively. The enterohepatic circulation model reasonably captured the second peak of AZD3241, and high-fat food increased the absorption rate by 69%. A linear regression model was applied to describe the relationship between AZD3241 exposure and percentage change from baseline in myeloperoxidase-specific activity. The developed PopPK model was consistent with known pharmacokinetic characteristics of AZD3241. This model can be used to estimate AZD3241 exposure in patients with MSA and could be applied to future pharmacokinetic-pharmacodynamic analyses of AZD3241 in clinical development.