[¹⁸F]NOS PET Brain Imaging Suggests Elevated Neuroinflammation in Idiopathic Parkinson’s Disease

Neuroinflammation is implicated as a key pathologic mechanism in many neurodegenerative diseases and is thought to be mediated in large part by microglia, native phagocytic immune cells of the CNS. Abnormal aggregation of the protein α-synuclein after phagocytosis by microglia is one possible neuropathophysiological mechanism driving Parkinson’s disease (PD). We conducted a human pilot study to evaluate the feasibility of targeting the inducible isoform of nitric oxide synthase using the [18F]NOS radiotracer to measure neuroinflammation in idiopathic PD. Ten adults consisting of 6 PD patients and 4 healthy controls (HC) underwent one hour of dynamic [18F]NOS positron emission tomography (PET) brain imaging with arterial blood sampling. We observed increased [18F]NOS whole brain distribution volume (VT) in PD patients compared to age-matched healthy controls (p p = 0.72). These findings suggest elevated oxidative stress, a surrogate marker of inflammation, is present in early-stage idiopathic PD and indicate that [18F]NOS PET imaging is a promising, non-invasive method to measure neuroinflammation

Molecular imaging of pulmonary inflammation in electronic and combustible cigarette users: a pilot study.

Electronic cigarette (EC) use has increased dramatically, particularly among adolescents and young adults, which, like cigarette use, can cause pulmonary inflammation and increase the risk of lung disease. This preliminary study used positron emission tomography with F-6-(1/2)(2-fluoro-propyl)-4-methylpyridin-2-amine (F-NOS) to quantify inducible nitric oxide synthase (iNOS) expression to characterize oxidative stress and inflammation in the lungs in vivo in three age- and sex-matched groups: (1) 5 EC users, (2) 5 cigarette smokers, and (3) 5 never smoke/vape controls. EC users showed greater F-NOS non-displaceable binding potential (BPND) than cigarette smokers ( = 0.03) and never smoke/vape controls ( = 0.01); whereas BPND in cigarette smokers did not differ from controls (p> 0.1). F-NOS lung tissue delivery and iNOS distribution volume did not significantly differ between groups. Although there were no group differences in peripheral inflammatory biomarker concentrations, F-NOS BPND correlated with the pro-inflammatory cytokine tumor necrosis factor-α concentrations (rs= 0.87, = 0.05) in EC users. Additionally, when EC users and cigarette smokers were pooled together, vaping episodes/cigarettes per day correlated with interleukin-6 levels (rs= 0.86, = 0.006). This is the first PET imaging study to compare lung inflammation between EC and cigarette users in vivo. We found preliminary evidence EC users had greater pulmonary inflammation than cigarette smokers and never smoke/vape controls, with a positive association between pulmonary and peripheral measures of inflammation

In vivo visualization of PARP inhibitor pharmacodynamics

BACKGROUND [18F]FluorThanatrace ([18F]FTT) is a radiolabeled poly (adenosine diphosphate-ribose) polymerase inhibitor (PARPi) that enables noninvasive quantification of PARP with potential to serve as a biomarker for patient selection for PARPi therapy. Here we report for the first time to our knowledge noninvasive in vivo visualization of drug-target engagement during PARPi treatment.METHODS Two single-arm, prospective, nonrandomized clinical trials were conducted at the University of Pennsylvania from May 2017 to March 2020. PARP expression in breast cancer was assessed in vivo via [18F]FTT PET before and after initiation of PARPi treatment and in vitro via [125I]KX1 (an analog of [18F]FTT) binding to surgically removed breast cancer.RESULTS Thirteen patients had baseline [18F]FTT PET. Nine of these then had resection and in vitro evaluation of [18F]FTT uptake with an analog and uptake was blocked with PARPi. Of the other 4 patients, 3 had [18F]FTT PET uptake, and all had uptake blocked with treatment with a therapeutic PARPi. Initial in vivo [18F]FTT tumor uptake ranged from undetectable to robust. Following initiation of PARPi therapy, [18F]FTT uptake was not detectable above background in all cases. In vitro tumor treatment with a PARPi resulted in 82% reduction in [125I]KX1 binding.CONCLUSION [18F]FTT noninvasively quantifies PARP-1 expression. Early results indicate ability to visualize PARPi drug-target engagement in vivo and suggest the utility of further study to test [18F]FTT PET as a predictive and pharmacodynamic biomarker.TRIAL REGISTRATION ClinicalTrials.gov identifiers NCT03083288 and NCT03846167.FUNDING Metavivor Translational Research Award, Susan G. Komen for the Cure (CCR 16376362), Department of Defense BC190315, and Abramson Cancer Center Breakthrough Bike Challenge

Decreased Nicotinic Receptor Availability in Smokers with Slow Rates of Nicotine Metabolism

The nicotine metabolite ratio (NMR), a stable measure of hepatic nicotine metabolism via the CYP2A6 pathway and total nicotine clearance, is a predictive biomarker of response to nicotine replacement therapy, with increased quit rates in slower metabolizers. Nicotine binds directly to nicotinic acetylcholine receptors (nAChRs) to exert its psychoactive effects. This study examined the relationship between NMR and nAChR availability (α4β2* subtype) using positron emission tomography (PET) imaging of the radiotracer 2-(18)F-FA-85380 (2-(18)F-FA). METHODS: Twenty four smokers, 12 slow metabolizers (NMR <0.26) and 12 normal metabolizers (NMR ≥0.26), underwent 2-(18)F-FA-PET brain imaging following overnight nicotine abstinence (18 hours prior to scanning), using a validated bolus plus infusion protocol. Availability of nAChRs was compared between NMR groups in a priori volumes of interest (VOIs), with total distribution volume (V(T)/f(P)) being the measure of nAChR availability. Cravings to smoke were assessed prior to and following the scans. RESULTS: Thalamic nAChR α4β2* availability was significantly reduced in slow (versus normal) nicotine metabolizers (P=0.04). Slow metabolizers exhibited greater reductions in craving than normal metabolizers from pre- to post-scanning; however, craving was unrelated to availability. CONCLUSION: The rate of nicotine metabolism is associated with thalamic nAChR availability. Additional studies could examine whether altered nAChR availability underlies differences in treatment response between slow and normal metabolizers of nicotine