Cannabinoid Receptor Type 1 in Parkinson's Disease : A Positron Emission Tomography Study with [F-18]FMPEP-d(2)

Background The endocannabinoid system is a widespread neuromodulatory system affecting several biological functions and processes. High densities of type 1 cannabinoid (CB1) receptors and endocannabinoids are found in basal ganglia, which makes them an interesting target group for drug development in basal ganglia disorders such as Parkinson's disease (PD). Objective The aim of this study was to investigate CB1 receptors in PD with [F-18]FMPEP-d(2) positron emission tomography (PET) and the effect of dopaminergic medication on the [F-18]FMPEP-d(2) binding. Methods The data consisted of 16 subjects with PD and 10 healthy control subjects (HCs). All participants underwent a [F-18]FMPEP-d(2) high-resolution research tomograph PET examination for the quantitative assessment of cerebral binding to CB1 receptors. To investigate the effect of dopaminergic medication on the [F-18]FMPEP-d(2) binding, 15 subjects with PD underwent [F-18]FMPEP-d(2) PET twice, both on and off antiparkinsonian medication. Results [F-18]FMPEP-d(2) distribution volume was significantly lower in the off scan compared with the on scan in basal ganglia, thalamus, hippocampus, and amygdala (P < 0.05). Distribution volume was lower in subjects with PD off than in HCs globally (P < 0.05), but not higher than in HCs in any brain region. Conclusions Subjects with PD have lower CB1 receptor availability compared with HCs. PD medication increases CB1 receptor toward normal levels. (c) 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder SocietyPeer reviewe

Ruthenium-Mediated 18F-Fluorination and Preclinical Evaluation of a New CB1 Receptor Imaging Agent [18F]FPATPP

Cannabinoid receptor 1 (CB1R) controls various physiological and pathological conditions, including memory, motivation, and inflammation, and is thus an interesting target for positron emission tomography (PET). Herein, we report a ruthenium-mediated radiolabeling synthesis and preclinical evaluation of a new CB1R specific radiotracer, [18F]FPATPP. [18F]FPATPP was produced with 16.7 ± 5.7% decay-corrected radiochemical yield and >95 GBq/μmol molar activity. The tracer showed high stability, low defluorination, and high specific binding to CB1Rs in mouse brain.</p

Tumor suppressor p53 as a component of the tumor necrosis factor- induced, protein kinase PKR-mediated apoptotic pathway in human promonocytic U937 cells

Despite what is known about the early signaling events in tumor necrosis factor (TNF) α-induced apoptosis, characterization of the downstream events remains largely undefined. It is now known that a crosstalk exists between the interferon and TNF-α pathways. This linkage allows recruitment of the cell proliferation suppressor PKR (dsRNA-dependent protein kinase) from the interferon pathway to play a pivotal role in TNF-α-induced apoptosis. In this study, we took advantage of the differential TNF-α susceptibilities of human promonocytic U937 subclones, deficient in or overexpressing PKR, to further characterize the role of PKR in apoptosis. By reverse transcription- polymerase chain reaction, we demonstrated that TNF-α transiently induces the tumor suppressor p53 in U937 cells. This p53 induction lags behind the TNF-α induction of PKR by 1 h. By cell viability determination, ultrastructural studies, apoptotic DNA laddering, and antisense techniques, it was shown that inhibition of p53 expression in PKR-overexpressing U937 cells abrogates the TNF-α-induced apoptosis in these cells. Conversely, overexpressing wild type p53 in PKR-deficient U937 cells confers the susceptibility of these cells to TNF-α-induced apoptosis. This latter result indicates that p53 induction is an event downstream of TNF-α-induced up- regulation of PKR, thereby further establishing the critical role of p53 in TNF-α-induced apoptosis in U937 cells. PKR-overexpressing U937 cells were found to possess a constitutively higher level of p53, which partly explains why these cells spontaneously undergo apoptosis even without TNF-α treatment. Finally, a model is presented on the interplay between PKR and p53 in effecting TNF-α-induced apoptosis in U937 cells.link_to_subscribed_fulltex