LC-MS Supported Studies on the in Vitro Metabolism of both Enantiomers of Flubatine and the in Vivo Metabolism of (+)-[(18)F]Flubatine-A Positron Emission Tomography Radioligand for Imaging alpha4beta2 Nicotinic Acetylcholine Receptors

Both enantiomers of [18F]flubatine are promising radioligands for neuroimaging of α4β2 nicotinic acetylcholine receptors (nAChRs) by positron emission tomography (PET). To support clinical studies in patients with early Alzheimer’s disease, a detailed examination of the metabolism in vitro and in vivo has been performed. (+)- and (−)-flubatine, respectively, were incubated with liver microsomes from mouse and human in the presence of NADPH (β-nicotinamide adenine dinucleotide 2′-phosphate reduced tetrasodium salt). Phase I in vitro metabolites were detected and their structures elucidated by LC-MS/MS (liquid chromatography-tandem mass spectrometry). Selected metabolite candidates were synthesized and investigated for structural confirmation. Besides a high level of in vitro stability, the microsomal incubations revealed some species differences as well as enantiomer discrimination with regard to the formation of monohydroxylated products, which was identified as the main metabolic pathway in this assay. Furthermore, after injection of 250 MBq (+)-[18F]flubatine (specific activity > 350 GBq/μmol) into mouse, samples were prepared from brain, liver, plasma, and urine after 30 min and investigated by radio-HPLC (high performance liquid chromatography with radioactivity detection). For structure elucidation of the radiometabolites of (+)-[18F]flubatine formed in vivo, identical chromatographic conditions were applied to LC-MS/MS and radio-HPLC to compare samples obtained in vitro and in vivo. By this correlation approach, we assigned three of four main in vivo radiometabolites to products that are exclusively C- or N-hydroxylated at the azabicyclic ring system of the parent molecule

Torque vectoring for electric vehicles with individually controlled motors: State-of-the-art and future developments

© 2012 WEVA.This paper deals with the description of current and future vehicle technology related to yaw moment control, anti-lock braking and traction control through the employment of effective torque vectoring strategies for electric vehicles. In particular, the adoption of individually controlled electric powertrains with the aim of tuning the vehicle dynamic characteristics in steady-state and transient conditions is discussed. This subject is currently investigated within the European Union (EU) funded Seventh Framework Programme (FP7) consortium E-VECTOORC, focused on the development and experimental testing of novel control strategies. Through a comprehensive literature review, the article outlines the stateof- the-art of torque vectoring control for fully electric vehicles and presents the philosophy and the potential impact of the E-VECTOORC control structure from the viewpoint of torque vectoring for vehicle dynamics enhancement

Torque vectoring for electric vehicles with individually controlled motors: State-of-the-art and future developments

© 2012 WEVA.This paper deals with the description of current and future vehicle technology related to yaw moment control, anti-lock braking and traction control through the employment of effective torque vectoring strategies for electric vehicles. In particular, the adoption of individually controlled electric powertrains with the aim of tuning the vehicle dynamic characteristics in steady-state and transient conditions is discussed. This subject is currently investigated within the European Union (EU) funded Seventh Framework Programme (FP7) consortium E-VECTOORC, focused on the development and experimental testing of novel control strategies. Through a comprehensive literature review, the article outlines the stateof- the-art of torque vectoring control for fully electric vehicles and presents the philosophy and the potential impact of the E-VECTOORC control structure from the viewpoint of torque vectoring for vehicle dynamics enhancement

A new precursor for the preparation of 6-[18F]-fluoro-L-m-tyrosine (FMT): Efficient synthesis and comparison of radiolabeling

For the electrophilic preparation of 6-[18F]-Fluoro-L-m-tyrosine (FMT), a PET tracer for measuring changes in dopaminergic function in movement disorders, a novel precursor, N-(tert-butoxycarbonyl)-3-(tert-butoxycarbonyloxy)-6-trimethylstannnyl-L-phenylalanine ethyl ester, was synthesized in four steps and 26 percent yield starting from L-m-tyrosine. FMT produced by two methods at two institutions was comparable in decay corrected yield, 25-26 percent, and quality (chemical, enantiomeric, and radiochemical purity and specific activity) as that obtained with the original N-trifluoroacetyl-3-acetyl-6-trimethylstannyl-L-m-tyrosine ethyl ester FMT precursor

An Explorative Study of the Incidental High Renal Excretion of [F-18]PSMA-1007 for Prostate Cancer PET/CT Imaging

Positron emission tomography (PET) of prostate-specific membrane antigen (PSMA) allows for accurate diagnosis and staging of prostate cancer (PCa). Compared to other PSMA PET tracers available, [(18)F]PSMA-1007 is predominantly excreted via the hepatobiliary tract resulting in low renal excretion which improves evaluation of the pelvic area. However, some patients do show high urinary uptake of [(18)F]PSMA-1007. The present study aimed to investigate this sudden high urinary uptake of [(18)F]PSMA-1007 by evaluating [(18)F]PSMA-1007 PET scans from PCa patients. In this single-center retrospective study, patients that underwent [(18)F]PSMA-1007 PET imaging between July 2018 and January 2021 were included. Data regarding the individual patient characteristics, scan acquisition and batch production were analyzed. To determine the urinary excretion of [(18)F]PSMA-1007, a region of interest was drawn in the bladder, and standardized uptake values (SUVs) were calculated and compared to SUVs in the prostate. An SUVmax of >10 was considered high urinary excretion, an SUVmax 7.5-10 intermediate and an SUVmax < 7.5 low urinary excretion. A total of 344 patients underwent [(18)F]PSMA-1007 PET/CT imaging, with 37 patients receiving three or more [(18)F]PSMA-1007 PET/CT scans. The mean SUVmean and SUVmax of the bladder were 3.9 (SD 2.9) and 5.9 (SD 4.2), respectively. Fourteen percent of patients showed high urinary uptake of [(18)F]PSMA-1007. Twelve of the thirty-seven patients (32.4%) that had multiple scans showed a varying urinary uptake of [(18)F]PSMA-1007 per PSMA PET/CT scan. In terms of patient characteristics, risk factors, medication and blood laboratory results, no significant influencing variables were found. Nor was there a difference observed in the batch size and the mean radiochemical purity of PSMA-1007 for high- and low-excreting patients. However, the bladder volume affected the mean SUVmax in the bladder significantly, with higher SUVs in lower bladder volumes. In this study, we observed that a higher SUV in the urinary tract seemed to occur in patients with low bladder volume. A prospective study is needed to corroborate this hypothesis

Erythroidine alkaloids: A novel class of phytoestrogens

Erythrina poeppigiana is a medicinal plant which is widely used in Asia, Latin America, and Africa in traditional remedies for gynecological complications and maladies. In continuation of studies for the discovery of novel phytoestrogens, four erythroidine alkaloids, namely α-erythroidine, β-erythroidine, and their oxo-derivatives 8-oxo-α-erythroidine and 8-oxo-β-erythroidine, were isolated and structurally characterized from the methanolic extract of the stem bark of E. poeppigiana. Due to the high amounts of erythroidines in the extract and considering the widespread utilization of Erythrina preparations in traditional medicine, the exploration of their estrogenic properties was performed. The estrogenicity of the isolated erythroidines was assayed in various estrogen receptor-(ER)-dependent test systems, including receptor binding affinity, cell culture based ER-dependent reporter gene assays, and gene expression studies in cultured cells using reverse transcription polymerase chain reaction techniques. α-Erythroidine and β-erythroidine showed binding affinity values for ERα of 0.015 ± 0.010% and 0.005 ± 0.010%, respectively, whereas only β-erythroidine bound to ERβ (0.006 ± 0.010%). In reporter gene assays, both erythroidines exhibited a significant dose-dependent estrogenic stimulation of ER-dependent reporter gene activity in osteosarcoma cells detectable already at 10 nM. Results were confirmed in the MVLN cells, a bioluminescent variant of MCF-7 breast cancer cells. Further, α-erythroidine and β-erythroidine both induced the enhanced expression of the specific ERα-dependent genes trefoil factor-1 and serum/glucocorticoid regulated kinase 3 in MCF-7 cells, confirming estrogenicity. Additionally, using molecular docking simulations, a potential mode of binding on ERα, is proposed, supporting the experimental evidences. This is the first time that an estrogenic profile is reported for erythroidine alkaloids, potentially a new class of phytoestrogens. © Georg Thieme Verlag KG Stuttgart New York