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Background: In Parkinson's disease (PD), postural instability and gait disorder (PIGD) symptoms are associated with a worse prognosis for an unknown reason., Objective: The objective was to explore the relationship between cannabinoid receptor type 1 (CB1R) availability and motor symptoms in PD with [ 18 F]FMPEP-d 2 positron emission tomography (PET)., Methods: Fifteen individuals with PD underwent [ 18 F]FMPEP-d 2 PET to measure cerebral CB1R availability. The Unified Parkinson's Disease Rating Scale motor part (UPDRS-III) was used to evaluate the motor symptoms., Results: A negative correlation was observed between [ 18 F]FMPEP-d 2 V T and PIGD score (P = 0.002) as well as rigidity subscore (P < 0.001). Both clusters covered widespread areas of both hemispheres. In contrast, tremor or bradykinesia did not correlate to [ 18 F]FMPEP-d 2 V T ., Conclusions: Gait, postural instability, and rigidity in PD are associated with decreased CB1R availability, unlike tremor or bradykinesia, suggesting that the endocannabinoid system has a role in the pathophysiology of different motor symptoms in PD. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Aims/hypothesis: Stem cell-derived islets (SC-islets) are being used as cell replacement therapy for insulin-dependent diabetes. Non-invasive long-term monitoring methods for SC-islet grafts, which are needed to detect misguided differentiation in vivo and to optimise their therapeutic effectiveness, are lacking. Positron emission tomography (PET) has been used to monitor transplanted primary islets. We therefore aimed to apply PET as a non-invasive monitoring method for SC-islet grafts., Methods: We implanted different doses of human SC-islets, SC-islets derived using an older protocol or a state-of-the-art protocol and SC-islets genetically rendered hyper- or hypoactive into mouse calf muscle to yield different kinds of grafts. We followed the grafts with PET using two tracers, glucagon-like peptide 1 receptor-binding [ 18 F]F-dibenzocyclooctyne-exendin-4 ([ 18 F]exendin) and the dopamine precursor 6-[ 18 F]fluoro-L-3,4-dihydroxyphenylalanine ([ 18 F]FDOPA), for 5 months, followed by histological assessment of graft size and composition. Additionally, we implanted a kidney subcapsular cohort with different SC-islet doses to assess the connection between C-peptide and stem cell-derived beta cell (SC-beta cell) mass., Results: Small but pure and large but impure grafts were derived from SC-islets. PET imaging allowed detection of SC-islet grafts even <1 mm 3 in size, [ 18 F]exendin having a better detection rate than [ 18 F]FDOPA (69% vs 44%, <1 mm 3 ; 96% vs 85%, >1 mm 3 ). Graft volume quantified with [ 18 F]exendin (r 2 =0.91) and [ 18 F]FDOPA (r 2 =0.86) strongly correlated with actual graft volume. [ 18 F]exendin PET delineated large cystic structures and its uptake correlated with graft SC-beta cell proportion (r 2 =0.68). The performance of neither tracer was affected by SC-islet graft hyper- or hypoactivity. C-peptide measurements under fasted or glucose-stimulated conditions did not correlate with SC-islet graft volume or SC-beta cell mass, with C-peptide under hypoglycaemia having a weak correlation with SC-beta cell mass (r 2 =0.52)., Conclusions/interpretation: [ 18 F]exendin and [ 18 F]FDOPA PET enable non-invasive assessment of SC-islet graft size and aspects of graft composition. These methods could be leveraged for optimising SC-islet cell replacement therapy in diabetes., (© 2024. The Author(s).)

18 F-labelled radiopharmaceuticals are indispensable in positron emission tomography. The critical step in the preparation of 18 F-labelled tracers is the anhydrous F-18 nucleophilic substitution reaction, which involves [ 18 F]F - anions generated in aqueous media by the cyclotron. For this, azeotropic drying by distillation is widely used in standard synthesisers, but microfluidic systems are often not compatible with such a process. To avoid this step, several methods compatible with aqueous media have been developed. We summarised the existing approaches and two of them have been studied in detail. [ 18 F]fluoride elution efficiencies have been investigated under different conditions showing high 18 F-recovery. Finally, a large scope of precursors has been assessed for radiochemical conversion, and these hydrous labelling techniques have shown their potential for tracer production using a microfluidic approach, more particularly compatible with iMiDEV™ cassette volumes.

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 [ 18 F]FMPEP-d 2 positron emission tomography (PET) and the effect of dopaminergic medication on the [ 18 F]FMPEP-d 2 binding., Methods: The data consisted of 16 subjects with PD and 10 healthy control subjects (HCs). All participants underwent a [ 18 F]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 [ 18 F]FMPEP-d 2 binding, 15 subjects with PD underwent [ 18 F]FMPEP-d 2 PET twice, both on and off antiparkinsonian medication., Results: [ 18 F]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. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

This first-in-humans study investigated the safety, biodistribution, and radiation dosimetry of a novel 18 F-labeled radiohybrid prostate-specific membrane antigen (rhPSMA) PET imaging agent, 18 F-rhPSMA-7.3. Methods: Six healthy volunteers (3 men, 3 women) underwent multiple whole-body PET acquisitions at scheduled time points up to 248 min after the administration of 18 F-rhPSMA-7.3 (mean activity, 220; range, 210-228 MBq). PET scans were conducted in 3 separate sessions, and subjects were encouraged to void between sessions. Blood and urine samples were collected for up to 4 h after injection to assess metabolite-corrected radioactivity in whole blood, plasma, and urine. Quantitative measurements of 18 F radioactivity in volumes of interest over target organs were determined directly from the PET images at 8 time points, and normalized time-activity concentration curves were generated. These normalized cumulated activities were then inputted into the OLINDA/EXM package to calculate the internal radiation dosimetry and the subjects' effective dose. Results: 18 F-rhPSMA-7.3 was well tolerated. One adverse event (mild headache, not requiring medication) was considered possibly related to 18 F-rhPSMA-7.3. The calculated effective dose was 0.0141 mSv/MBq when using a 3.5-h voiding interval. The organs with the highest mean absorbed dose per unit of administered radioactivity were the adrenals (0.1835 mSv/MBq), the kidneys (0.1722 mSv/MBq), the submandibular glands (0.1479 mSv), and the parotid glands (0.1137 mSv/MBq). At the end of the first scanning session (mean time, 111 min after injection), an average of 7.2% (range, 4.4%-9.0%) of the injected radioactivity of 18 F-rhPSMA-7.3 was excreted into urine. Conclusion: The safety, biodistribution, and internal radiation dosimetry of 18 F-rhPSMA-7.3 are considered favorable for PET imaging., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

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, [ 18 F]FPATPP. [ 18 F]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.

Here, we describe the development of an in-house-built device for the fully automated multistep synthesis of the cannabinoid CB 1 receptor imaging tracer (3R,5R)-5-(3-([ 18 F]fluoromethoxy-d 2 )phenyl)-3-(((R)-1-phenylethyl)amino)-1-(4-(trifluoromethyl)phenyl)pyrrolidin-2-one ([ 18 F]FMPEP-d 2 ), following good manufacturing practices. The device is interfaced to a HPLC and a sterile filtration unit in a clean room hot cell. The synthesis involves the nucleophilic 18 F-fluorination of an alkylating agent and its GC purification, the subsequent 18 F-fluoroalkylation of a precursor molecule, the semipreparative HPLC purification of the 18 F-fluoroalkylated product, and its formulation for injection. We have optimized the duration and temperature of the 18 F-fluoroalkylation reaction and addressed the radiochemical stability of the formulated product. During the past 5 years (2013-2018), we have performed a total of 149 syntheses for clinical use with a 90% success rate. The activity yield of the formulated product has been 1.0 ± 0.4 GBq starting from 11 ± 2 GBq and the molar activity 600 ± 300 GBq/μmol at the end of synthesis., (© 2020 The Authors. Journal of Labelled Compounds and Radiopharmaceuticals published by John Wiley & Sons Ltd.)

[ 18 F]NS12137 (exo-3-[(6-[ 18 F]fluoro-2-pyridyl)oxy]8-azabicyclo[3.2.1]octane) is a highly selective norepinephrine transporter (NET) tracer. NETs are responsible for the reuptake of norepinephrine and dopamine and are linked to several neurodegenerative and neuropsychiatric disorders. The aim of this study was to develop a copper-mediated 18 F-fluorination method for the production of [ 18 F]NS12137 with straightforward synthesis conditions and high radiochemical yield and molar activity. [ 18 F]NS12137 was produced in two steps. Radiofluorination of [ 18 F]NS12137 was performed via a copper-mediated pathway starting with a stannane precursor and using [ 18 F]F - as the source of the fluorine-18 isotope. Deprotection was performed via acid hydrolysis. The radiofluorination reaction was nearly quantitative as was the deprotection based on HPLC analysis. The radiochemical yield of the synthesis was 15.1 ± 0.5%. Molar activity of [ 18 F]NS12137 was up to 300 GBq/μmol. The synthesis procedure is straightforward and can easily be automated and adapted for clinical production., (© 2019 The Authors. Journal of Labelled Compounds and Radiopharmaceuticals Published by John Wiley & Sons Ltd.)

Activating brown adipose tissue (BAT) could provide a potential approach for the treatment of obesity and metabolic disease in humans. Obesity is associated with upregulation of the endocannabinoid system, and blocking the cannabinoid type 1 receptor (CB1R) has been shown to cause weight loss and to decrease cardiometabolic risk factors. These effects may be mediated partly via increased BAT metabolism, since there is evidence that CB1R antagonism activates BAT in rodents. To investigate the significance of CB1R in BAT function, we quantified the density of CB1R in human and rodent BAT using the positron emission tomography radioligand [ 18 F]FMPEP- d 2 and measured BAT activation in parallel with the glucose analog [ 18 F]fluorodeoxyglucose. Activation by cold exposure markedly increased CB1R density and glucose uptake in the BAT of lean men. Similarly, β3-receptor agonism increased CB1R density in the BAT of rats. In contrast, overweight men with reduced BAT activity exhibited decreased CB1R in BAT, reflecting impaired endocannabinoid regulation. Image-guided biopsies confirmed CB1R mRNA expression in human BAT. Furthermore, CB1R blockade increased glucose uptake and lipolysis of brown adipocytes. Our results highlight that CB1Rs are significant for human BAT activity, and the CB1Rs provide a novel therapeutic target for BAT activation in humans., (© 2018 by the American Diabetes Association.)

2,6-Bis(1,4,7,10-tetraazacyclododecan-1-ylmethyl)pyridine (11a) and 1,3-bis(1,4,7,10-tetraazacyclododecan-1-ylmethyl)benzene (11b) have been shown to accelerate at 50 mmol·L-1 concentration both the cleavage and mutual isomerization of uridylyl-3',5'-uridine and uridylyl-2',5'-uridine by up to two orders of magnitude. The catalytically active ionic forms are the tri- (in the case of 11b) tetra- and pentacations. The pyridine nitrogen is not critical for efficient catalysis, since the activity of 11b is even slightly higher than that of 11a. On the other hand, protonation of the pyridine nitrogen still makes 11a approximately four times more efficient as a catalyst, but only for the cleavage reaction. Interestingly, the respective reactions of adenylyl-3',5'-adenosine were not accelerated, suggesting that the catalysis is base moiety selective.