Synthesis, structure activity relationship, radiolabeling and preclinical evaluation of high affinity ligands for the ion channel of the N-methyl-D-aspartate receptor as potential imaging probes for positron emission tomography

The N-methyl-d-aspartate receptor (NMDAr) is involved in many neurological and psychiatric disorders including Alzheimer's disease and schizophrenia. Currently, it is not possible to assess NMDAr availability in vivo. The purpose of this study was to develop a positron emission tomography (PET) ligand for the NMDAr ion channel. A series of di- and tri-N-substituted diarylguanidines was synthesized. In addition, in vitro binding affinity for the NMDAr ion channel in rat forebrain membrane fractions was assessed. Compounds 10, 11 and 32 were radiolabeled with either carbon-11 or fluorine-18. Ligands

Synthesis and preclinical evaluation of carbon-11 labelled N-((5-(4-fluoro-2-[C-11]methoxyphenyl) pyridin-3-yl) methyl) cyclopentanamine as a PET tracer for NR2B subunit-containing NMDA receptors

Introduction: The N-methyl-D-Aspartate (NMDA) receptor plays an important role in learning and memory. Overactivation is thought to play an important role in neurodegenerative disorders such as Alzheimer's disease. Currently, it is not possible to assess N-methyl-D-aspartate receptor (NMDAr) bio-availability in vivo. The purpose of this study was to develop a positron emission tomography (PET) ligand for the NR2B binding site of the NMDA receptor. Methods: N-((5-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)methyl)cyclopentanamine was radiolabelled with carbon-11 in the phenyl moiety. Biodistribution and blocking studies were carried out in anaesthetized mice and in non-anaesthetized rats. Results: N-((5-(4-fluoro-2-

Preclinical evaluation of [F-18]PK-209, a new PET ligand for imaging the ion-channel site of NMDA receptors

Introduction: The present study was designed to assess whether [18F]PK-209 (3-(2-chloro-5-(methylthio)phenyl)-1-(3-([18F]fluoromethoxy)phenyl)-1-methylguanidine) is a suitable ligand for imaging the ion-channel site of N-methyl-D-aspartate receptors (NMDArs) using positron emission tomography (PET). Methods: Dynamic PET scans were acquired from male rhesus monkeys over 120min, at baseline and after the acute administration of dizocilpine (MK-801, 0.3mg/kg; n=3/condition). Continuous and discrete arterial blood samples were manually obtained, to generate metabolite-corrected input functions. Parametric volume-of-distribution (VT) images were obtained using Logan analysis. The selectivity profile of PK-209 was assessed in vitro, on a broad screen of 79 targets. Results: PK-209 was at least 50-fold more selective for NMDArs over all other targets examined. At baseline, prolonged retention of radioactivity was observed in NMDAr-rich cortical regions relative to the cerebellum. Pretreatment with MK-801 reduced the VTof [18F]PK-209 compared with baseline in two of three subjects. The rate of radioligand metabolism was high, both at baseline and after MK-801 administration. Conclusions: PK-209 targets the intrachannel site with high selectivity. Imaging of the NMDAr is feasible with [18F]PK-209, despite its fast metabolism. Further in vivo evaluation in humans is warranted

Recovery of dialysis patients with COVID-19: health outcomes 3 months after diagnosis in ERACODA

© The Author(s) 2022.Background. Coronavirus disease 2019 (COVID-19)-related short-term mortality is high in dialysis patients, but longer-term outcomes are largely unknown. We therefore assessed patient recovery in a large cohort of dialysis patients 3 months after their COVID-19 diagnosis. Methods. We analyzed data on dialysis patients diagnosed with COVID-19 from 1 February 2020 to 31 March 2021 from the European Renal Association COVID-19 Database (ERACODA). The outcomes studied were patient survival, residence and functional and mental health status (estimated by their treating physician) 3 months after COVID-19 diagnosis. Complete follow-up data were available for 854 surviving patients. Patient characteristics associated with recovery were analyzed using logistic regression. Results. In 2449 hemodialysis patients (mean ± SD age 67.5 ± 14.4 years, 62% male), survival probabilities at 3 months after COVID-19 diagnosis were 90% for nonhospitalized patients (n = 1087), 73% for patients admitted to the hospital but not to an intensive care unit (ICU) (n = 1165) and 40% for those admitted to an ICU (n = 197). Patient survival hardly decreased between 28 days and 3 months after COVID-19 diagnosis. At 3 months, 87% functioned at their pre-existent functional and 94% at their pre-existent mental level. Only few of the surviving patients were still admitted to the hospital (0.8–6.3%) or a nursing home (∼5%). A higher age and frailty score at presentation and ICU admission were associated with worse functional outcome. Conclusions. Mortality between 28 days and 3 months after COVID-19 diagnosis was low and the majority of patients who survived COVID-19 recovered to their pre-existent functional and mental health level at 3 months after diagnosis