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Rationale : Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive disease characterized by dyspnea and loss of lung function. Transforming growth factor-beta (TGF-β) activation mediated by α v integrins is central to the pathogenesis of IPF. Bexotegrast (PLN 74809) is an oral, once-daily, dual-selective inhibitor of α v β 6 and α v β 1 integrins under investigation for the treatment of IPF. Positron emission tomography (PET) using an α v β 6 -specific PET tracer could confirm target engagement of bexotegrast in the lungs of participants with IPF. Objectives : This Phase 2 study (NCT04072315) evaluated α v β 6 receptor occupancy in the lung, as assessed by changes from baseline in α v β 6 PET tracer uptake, following single dose administration of bexotegrast to participants with IPF. Methods : In this open-label, single-center, single-arm study, adults with IPF received up to 2 single doses of bexotegrast, ranging from 60 to 320 mg with or without background IPF therapy (pirfenidone or nintedanib). At baseline and approximately 4 hours after each orally administered bexotegrast dose, a 60-minute dynamic PET/CT scan was conducted following administration of an α v β 6 -specific PET probe ([ 18 F]FP-R 0 1-MG-F2). α v β 6 receptor occupancy by bexotegrast was estimated from the changes in PET tracer uptake following bexotegrast. Pharmacokinetics, safety, and tolerability of bexotegrast were also assessed. Results : Eight participants completed the study. Total and unbound plasma bexotegrast concentrations increased in a dose-dependent manner, and regional PET volume of distribution (V T ) values decreased in a dose- and concentration-dependent manner. The V T data fit a simple saturation model, producing an unbound bexotegrast EC 50 estimate of 3.32 ng/mL. Estimated maximum receptor occupancy was 35%, 53%, 71%, 88%, and 92% following single 60, 80, 120, 240, and 320-mg doses of bexotegrast, respectively. No treatment-emergent adverse events related to bexotegrast were reported. Conclusions : Dose- and concentration-dependent α v β 6 receptor occupancy by bexotegrast was observed by PET imaging, supporting once-daily 160 to 320 mg dosing to evaluate efficacy in clinical trials of IPF. Trial registration number: NCT04072315 Primary source of funding: Pliant Therapeutics, Inc. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Purpose: Minzasolmin (UCB0599) is an orally administered, small molecule inhibitor of ASYN misfolding in development as a potential disease-modifying therapy for Parkinson's disease. Here we describe the preclinical development of a radiolabeled tracer and results from a phase 1 study using the tracer to investigate the brain distribution of minzasolmin., Procedures: In the preclinical study, two radiolabeling positions were investigated on the S-enantiomer of minzasolmin (UCB2713): [ 11 C]methylamine UCB2713 ([ 11 C-N-CH 3 ]UCB2713) and [ 11 C]carbonyl UCB2713 ([ 11 C-CO]UCB2713). Male C57 black 6 mice (N = 10) received intravenous [ 11 C-N-CH 3 ]UCB2713; brain homogenates were assessed for radioactivity and plasma samples analyzed by high-performance liquid chromatography. Positron emission tomography-computed tomography (PET-CT) was used to image brains in a subset of mice (n = 3). In the open-label, phase 1 study, healthy volunteers were scanned twice with PET-CT following injection with [ 11 C]minzasolmin radiotracer (≤ 10 µg), first without, then with oral dosing with non-radiolabeled minzasolmin 360 mg., Primary Objective: to determine biodistribution of minzasolmin in the human brain; secondary objectives included minzasolmin safety/tolerability., Results: Preclinical data supported the use of [ 11 C]minzasolmin in clinical studies. In the phase 1 study, PET data showed substantial drug signal in the brain of healthy volunteers (N = 4). The mean estimated whole brain total distribution volume (V T ) at equilibrium across all regions of interest was 0.512 mL/cm 3 , no difference in V T was observed following administration of minzasolmin 360 mg. Treatment-emergent adverse events (TEAEs) were reported by 75% (n = 3) of participants. No drug-related TEAEs, deaths, serious adverse events, or discontinuations were reported., Conclusion: Following positive preclinical results with the N-methyl labeled PET tracer, [ 11 C]minzasolmin was used in the phase 1 study, which demonstrated that minzasolmin readily crossed the blood-brain barrier and was well distributed throughout the brain. Safety and pharmacokinetic findings were consistent with previous early-phase studies (such as UP0077, NCT04875962)., (© 2023. The Author(s).)

Persistent inflammation is described in people with HIV (PWH) on antiretroviral treatment (ART). Early ART initiation is associated with reduced inflammation. We aimed to evaluate neuroinflammation, using translocator protein (TSPO) [ 11 C]PBR28 PET neuroimaging in PWH who initiated ART during acute HIV (aPWH) versus chronic HIV infection (cPWH) versus a control population. This was a cross-sectional, observational study. All participants underwent [ 11 C]PBR28 PET-CT neuroimaging. Using a two-tissue compartment model, total volume of distribution (V T ) and distribution volume ratios (DVR) using cortical grey matter as a pseudo-reference region at 20 regions of interest (ROIs) were calculated. Differences in V T and DVR were compared between groups using the Kruskall-Wallis test. Seventeen neuro-asymptomatic male PWH on ART (9 aPWH, 8 cPWH) and 8 male control participants (CPs) were included. Median (interquartile range, IQR) age was 40 (30, 46), 44 (41, 47) and 21 (20, 25) years in aPWH, cPWH and CPs, respectively. Median (IQR) CD4 (cells/µL) and CD4:CD8 were 687 (652, 1014) and 1.37 (1.24, 1.42), and 700 (500, 720) and 0.67 (0.64, 0.82) in aPWH and cPWH, respectively. Overall, no significant difference in V T and DVR were observed between the three groups at any ROIs. cPWH demonstrated a trend towards higher mean V T compared with aPWH and CPs at most ROIs. No significant differences in neuroinflammation, using [ 11 C]PBR28 binding as a proxy, were identified between cPWH, aPWH and CPs. A trend towards lower absolute [ 11 C]PBR28 binding was seen amongst aPWH and CPs, suggesting early ART may mitigate neuroinflammation., (© 2024. The Author(s).)

Background: Microglial activation contributes to both inflammatory damage and repair in experimental ischemic stroke. However, because of the logistical challenges, there have been few clinical imaging studies directly describing inflammatory activation and its resolution after stroke. The purpose of our pilot study was to describe the spatio-temporal profile of brain inflammation after stroke using 18kD translocator protein (TSPO) positron emission tomography (PET) with magnetic resonance (MR) co-registration in the subacute and chronic stage after stroke., Methods: Three patients underwent magnetic resonance imaging (MRI) and PET scans with TSPO ligand [ 11 C]PBR28 15 ± 3 and 90 ± 7 days after an ischaemic stroke. Regions of interest (ROI) were defined on MRI images and applied to the dynamic PET data to derive regional time-activity curves. Regional uptake was quantified as standardised uptake values (SUV) over 60 to 90 min post-injection. ROI analysis was applied to identify binding in the infarct, and in frontal, temporal, parietal, and occipital lobes and cerebellum excluding the infarcted area., Results: The mean age of participants was 56 ± 20.4 years and mean infarct volume was 17.9 ± 18.1 ml. [ 11 C]PBR28 showed increased tracer signal in the infarcted area compared to non-infarcted areas of the brain in the subacute phase of stroke (Patient 1 SUV 1.81; Patient 2 SUV 1.15; Patient 3 SUV 1.64). [ 11 C]PBR28 uptake returned to the level of non-infarcted areas at 90 days Patient 1 SUV 0.99; Patient 3 SUV 0.80). No additional upregulation was detected elsewhere at either time point., Conclusions: The neuroinflammatory reaction after ischaemic stroke is limited in time and circumscribed in space suggesting that post-ischaemic inflammation is tightly controlled but regulatory mechanisms., (© 2023. The Author(s).)

Microglia activation, an indicator of central nervous system inflammation, is believed to contribute to the pathology of Huntington's disease. Laquinimod is capable of regulating microglia. By targeting the translocator protein, 11 C-PBR28 PET-CT imaging can be used to assess the state of regional gliosis in vivo and explore the effects of laquinimod treatment. This study relates to the LEGATO-HD, multi-centre, double-blinded, Phase 2 clinical trial with laquinimod (US National Registration: NCT02215616). Fifteen patients of the UK LEGATO-HD cohort (mean age: 45.2 ± 7.4 years; disease duration: 5.6 ± 3.0 years) were treated with laquinimod (0.5 mg, N = 4; 1.0 mg, N = 6) or placebo ( N = 5) daily. All participants had one 11 C-PBR28 PET-CT and one brain MRI scan before laquinimod (or placebo) and at the end of treatment (12 months apart). PET imaging data were quantified to produce 11 C-PBR28 distribution volume ratios. These ratios were calculated for the caudate and putamen using the reference Logan plot with the corpus callosum as the reference region. Partial volume effect corrections (Müller-Gartner algorithm) were applied. Differences were sought in Unified Huntington's Disease Rating Scale scores and regional distribution volume ratios between baseline and follow-up and between the two treatment groups (laquinimod versus placebo). No significant change in 11 C-PBR28 distribution volume ratios was found post treatment in the caudate and putamen for both those treated with laquinimod ( N = 10) and those treated with placebo ( N = 5). Over time, the patients treated with laquinimod did not show a significant clinical improvement. Data from the 11 C-PBR28 PET-CT study indicate that laquinimod may not have affected regional translocator protein expression and clinical performance over the studied period., Competing Interests: M.F.G., B.B., G.R., J.-M.S. and M.R.H. were employees of Teva Pharmaceutical Industries at the time the research was conducted., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)