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Background: The molecular actions underlying the clinical effects of inhaled anaesthetics such as sevoflurane and isoflurane are not fully understood. Unexpected observations in positron emission tomography (PET) studies with [ 11 C]AZD9272, a metabotropic glutamate receptor 5 (mGluR5) radioligand with possible affinity for monoamine oxidase-B (MAO-B), suggest that its binding is sensitive to anaesthesia with sevoflurane. The objective of the present study was to assess the effects of sevoflurane anaesthesia on the binding of [ 11 C]AZD9272 and of [ 11 C]L-deprenyl-D 2 , a radioligand selective for MAO-B in non-human primates (NHPs)., Methods: Altogether, 12 PET measurements were conducted with a high-resolution research tomograph using the ligands [ 11 C]AZD9272 or [ 11 C]L-deprenyl-D 2 in six cynomolgus monkeys anaesthetised with sevoflurane or ketamine/xylazine., Results: The specific binding of [ 11 C]AZD9272 and [ 11 C]L-deprenyl-D 2 was markedly reduced during anaesthesia with sevoflurane compared with ketamine/xylazine. The reduction was 80-90% (n=3) for [ 11 C]AZD9272 and 77-80% (n=3) for [ 11 C]L-deprenyl-D 2 ., Conclusions: Sevoflurane anaesthesia inhibited radioligand binding to MAO-B in the primate brain. The observation of lower MAO-B binding at clinically relevant concentrations of sevoflurane warrants further exploration of the potential role of MAO-B related mechanisms in regulation of systemic blood pressure during anaesthesia., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: The myeloperoxidase inhibitor AZD3241 has been selected as a candidate drug currently being developed to delay progression in patients with neurodegenerative brain disorders. Part of the decision tree for translation of AZD3241 into clinical studies included the need for assessment of brain exposure in non-human primates by PET microdosing. For that purpose a rapid multistep method for (11)C-labeling of AZD3241 was developed., Methods: AZD3241 was labeled in the thio-carbonyl position starting from [(11)C]potassium cyanide in a 4-step procedure using microwave assisted heating. In the first step [(11)C]potassium cyanide was converted to [(11)C]potassium thiocyanate followed by reaction with benzoyl chloride to yield benzoyl [(11)C]isothiocyanate. The benzoyl [(11)C]isothiocyanate was subsequently reacted with the precursor ethyl 3-(2-isopropoxyethylamino)-1H-pyrrole-2-carboxylate and the formed intermediate underwent a base catalyzed cyclization to obtain [(11)C]AZD3241 in the final step. To assess [(11)C]AZD3241 brain exposure PET measurements were performed in three cynomolgus monkeys., Results: [(11)C]AZD3241 was produced in good and reproducible radiochemical yield 710 ± 294 MBq (mean ± SD, n = 7). Total time of synthesis was 60 min from end of bombardment. The specific radioactivity was 9 ± 4GBq/μmol and the radiochemical purity was >98%. Following iv administration of [(11)C]AZD3241 there was a rapid presence of radioactivity in brain in each of the three monkeys. The distribution of [(11)C]AZD3241 to brain was fast and a Cmax of 1.9 to 2.6% of the injected radioactivity was observed within 1.5 min. [(11)C]AZD3241 was homogeneously distributed in brain., Conclusion: The MPO inhibitor AZD3241 was successfully labeled with carbon-11 in a challenging 4-step procedure in good radiochemical yield allowing PET microdosing studies in cynomolgus monkey. [(11)C]AZD3241 rapidly entered brain and confirmed adequate brain exposure to support translation of AZD3241 to phase 2a studies in patients., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Introduction: Glucokinase (GK) is potentially a target for imaging of islets of Langerhans. Here we report the radiosynthesis and preclinical evaluation of the GK activator, [(11)C]AZ12504948, for in vivo imaging of GK., Methods: [(11)C]AZ12504948 was synthesized by O-methylation of the precursor, AZ125555620, using carbon-11 methyl iodide ([(11)C]CH₃I). Preclinical evaluation was performed by autoradiography (ARG) of human tissues and PET/CT studies in pig and non-human primate., Result: [(11)C]AZ12504948 was produced in reproducible good radiochemical yield in 28-30 min. Radiochemical purity of the formulated product was >98% for up to 2 h with specific radioactivities 855 ± 209 GBq/μmol (n=8). The preclinical evaluation showed some specificity for GK in liver, but not in pancreas., Conclusion: [(11)C]AZ12504948 images GK in liver, but the low specificity impedes the visualization of GK in pancreas. Improved target specificity is required for further progress using PET probes based on this class of GK activators., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Introduction: The positron emission tomography (PET) tracer 9-[(18)F]fluoroethyl-(+)-dihydrotetrabenazine ([(18)F]-FE-(+)-DTBZ) is a potential candidate for quantifying beta-cell mass in vivo. The purpose was to investigate in vitro and in vivo utility of this tracer for the assessment of beta-cell mass., Methods: Three pigs were intravenously administered [(18)F]-FE-(+)-DTBZ and examined by PET/computed tomography. Binding parameters were estimated by kinetic modeling. In vitro k(D) and B(max) were determined by saturation binding studies of endocrine and exocrine human tissue homogenates. In vitro pancreatic uptake was determined by tissue autoradiography with pancreases from patients with types 1 (T1DM) and 2 diabetes mellitus (T2DM) and healthy controls., Results: [(18)F]-FE-(+)-DTBZ had a k(D) of 3.5+/-1.0 nM, a B(max) of 382+/-108 fmol/mg protein and a specificity of 89+/-1.8% in islet homogenates. The total exocrine uptake was lower and 65% was nondisplaceable. No uptake difference was observed in pancreatic tissue slices from patients with T1DM, T2DM or healthy controls. The in vivo porcine pancreatic uptake reached a peak of standardized uptake value (SUV) of 2.8 with a low distribution volume ratio in all animals. Moderate to high tracer uptake was identified in the bile system and in bone., Conclusions: [(18)F]-FE-(+)-DTBZ binds to vesicular monoamine transporter 2 (VMAT2) with high specificity in pure islet tissue in vitro. However, there is high nondisplaceable binding to exocrine tissue. In addition, in vivo tracer metabolism and dehalogenation result in severe underestimation of porcine pancreatic VMAT2 expression and BCM. The results do not support [(18)F]-FE-(+)-DTBZ as a suitable tracer for in vivo beta-cell imaging., (Copyright 2010 Elsevier Inc. All rights reserved.)

Introduction: The objectives of this work were to develop an automated production of N-succinimidyl 4-[(18)F]fluorobenzoate ([(18)F]-SFB) and to test whether the vasoactive peptide urotensin-II (U-II) could be labelled by conjugation with [(18)F]-SFB., Methods: A TRACERlab MX(FDG) synthesizer including an HPLC unit was used. The MS Excel synthesis sequence and the standard disposable FDG cassette were modified to allow the synthesis of [(18)F]-SFB. U-II was subsequently conjugated with [(18)F]-SFB, and the resulting (18)F-labelled peptides were characterised using in vitro ligand binding assays., Results: [(18)F]-SFB was successfully synthesised in the TRACERlab MX(FDG) in 44.3+/-2.5% (n=25) radiochemical yield in 98 min. [(18)F]-SFB (8-12 GBq) has been produced with specific activities in the range of 250-350 GBq/mumol and a radiochemical purity >95%. [(18)F]-SFB was subsequently used to label U-II. Two radiolabelled products, [(18)F]-(Glu(1))-U-II and [(18)F]-(Lys(8))-U-II, were formed in an isolated radiochemical yield from [(18)F]-SFB of 5.2+/-0.3% and 29.0+/-3.7%, respectively (n=7). Radioligand binding assays revealed that [(18)F]-(Glu(1))-U-II had retained subnanomolar affinity. Binding to human skeletal muscle (n=3) was concentration dependent and saturable with K(d)=0.84+/-0.51 nM, B(max)=0.69+/-0.14 fmol/mg protein and Hill slope (nH)=1.03+/-0.12., Conclusions: [(18)F]-SFB has been synthesised using the TRACERlab MX(FDG) module, allowing production of up to 8-12 GBq of [(18)F]-SFB with specific activities of 250-350 GBq/mumol. [(18)F]-SFB was used for the labelling of U-II. In vitro characterisation demonstrated that [(18)F]-(Glu(1))-U-II had retained desirable binding properties and may be suitable as a positron emission tomography radioligand for the imaging of the U-II receptor.

The biodistribution of 11C-labeled 4-(3-bromoanilino)-6,7-dimethoxyquinazoline, an inhibitor of the epidermal growth factor (EGF) receptor tyrosine kinase, has been evaluated in vivo in rats using positron emission tomography (PET). Time-activity data obtained after i.v. administration in one rat revealed that the radiotracer rapidly cleared from plasma with subsequent uptake in major organs of the body (brain, heart, liver, gastrointestinal tract and bladder). Uptake in proliferating tissue in rats with human neuroblastoma xenografts indicate that [O-11C-methyl]PD153035 shows promise as a new agent for in vivo imaging of tumors with PET.