Characterization of (R)- and (S)-[18F]OF-NB1 in Rodents as Positron Emission Tomography Probes for Imaging GluN2B Subunit-Containing N-Methyl-d-Aspartate Receptors.

The N-methyl-d-aspartate receptor (NMDAR) subtype 2B (GluN1/2B) is implicated in various neuropathologies. Given the lack of a validated radiofluorinated positron emission tomography (PET) probe for the imaging of GluN1/2B receptors, we comprehensively investigated the enantiomers of [18F]OF-NB1 in rodents. Particularly, the (R)- and (S)- enantiomers were evaluated using in silico docking, in vitro autoradiography, in vivo PET imaging, and ex vivo biodistribution studies. A select panel of GluN1/2B antagonists (CP-101,606, CERC-301, and eliprodil) and the off-target sigma-1 receptor ligands (fluspidine and SA4503) were used to determine the specificity and selectivity of the tested enantiomers. Additionally, a nonmetal-mediated radiofluorination strategy was devised that harnesses the potential of diaryliodoniums in the nucleophilic radiofluorination of nonactivated aromatic compounds. Both enantiomers exhibited known GluN1/2B binding patterns; however, the R-enantiomer showed higher GluN1/2B-specific accumulation in rodent autoradiography and higher brain uptake in PET imaging experiments compared to the S-enantiomer. Molecular simulation studies provided further insights with respect to the difference in binding, whereby a reduced ligand-receptor interaction was observed for the S-enantiomer. Nonetheless, both enantiomers showed dose dependency when two different doses (1 and 5 mg/kg) of the GluN1/2B antagonist, CP-101,606, were used in the PET imaging study. Taken together, (R)-[18F]OF-NB1 appears to exhibit the characteristics of a suitable PET probe for imaging of GluN2B-containing NMDARs in clinical studies.

Importance of Mid-Infrared Spectra Regions for the Prediction of Mastitis and Ketosis in Dairy Cows.

Mid-infrared (MIR) spectroscopy is routinely applied to determine major milk components, such as fat and protein. Moreover, it is used to predict fine milk composition and various traits pertinent to animal health. MIR spectra indicate an absorbance value of infrared light at 1060 specific wavenumbers from 926 to 5010 cm-1. According to research, certain parts of the spectrum do not contain sufficient information on traits of dairy cows. Hence, the objective of the present study was to identify specific regions of the MIR spectra of particular importance for the prediction of mastitis and ketosis, performing variable selection analysis. Partial least squares discriminant analysis (PLS-DA) along with three other statistical methods, support vector machine (SVM), least absolute shrinkage and selection operator (LASSO), and random forest (RF), were compared. Data originated from the Austrian milk recording and associated health monitoring system (GMON). Test-day data and corresponding MIR spectra were linked to respective clinical mastitis and ketosis diagnoses. Certain wavenumbers were identified as particularly relevant for the prediction models of clinical mastitis (23) and ketosis (61). Wavenumbers varied across four distinct statistical methods as well as concerning different traits. The results indicate that variable selection analysis could potentially be beneficial in the process of modeling.

Depression and loneliness of older adults in Europe and Israel after the first wave of covid-19.

Epidemic control measures that aim to introduce social distancing help to decelerate the spread of the COVID-19 pandemic. However, their consequences in terms of mental well-being might be negative, especially for older adults. While existing studies mainly focus on the time during the first lockdown, we look at the weeks afterward in order to measure the medium-term consequences of the first wave of the pandemic. Using data from the SHARE Corona Survey, we include retired respondents aged 60 and above from 25 European countries plus Israel. Combining SHARE data with macro-data from the Oxford COVID-19 Government Response Tracker allows us to include macro-indicators at the country level, namely the number of deaths per 100,000 and the number of days with stringent epidemic control measures, in addition to individual characteristics. The findings show that both macro-indicators are influential for increased feelings of sadness/depression, but that individual factors are crucial for explaining increased feelings of loneliness in the time after the first lockdown. Models with interaction terms reveal that the included macro-indicators have negative well-being consequences, particularly for the oldest survey participants. Additionally, the results reveal that especially those living alone had a higher risk for increased loneliness in the time after the first COVID-19 wave. Supplementary Information: The online version contains supplementary material available at 10.1007/s10433-021-00640-8.

Prodrug Approach toward the Development of a PET Radioligand for Imaging the GluN2A Subunits of the NMDA Receptor.

A straightforward synthesis of a fluorine-18-labeled prodrug of AFA233 is reported. The key step in the preparation of [18F]AFA233-prodrug is the selective deprotection of the tert-butyl protection groups of the quinoxalinedione moiety without cleavage of the tert-butyl-S-acyl-2-thioethyl protection groups on the phosphate esters. In addition, the preparation of the nonradioactive prodrug reference compound of AFA233 is reported.

Preclinical Development of 18F-OF-NB1 for Imaging GluN2B-Containing N-Methyl-d-Aspartate Receptors and Its Utility as a Biomarker for Amyotrophic Lateral Sclerosis.

As part of our continuous efforts to develop a suitable 18F-labeled PET radioligand with improved characteristics for imaging the N-methyl-d-aspartate receptors (NMDARs) subtype 2B (GluN1/2B), we investigated in the current work ortho-fluorinated (OF) and meta-fluorinated (MF) analogs of 18F-para-fluorinated (PF)-NB1, a 3-benzazepine-based radiofluorinated probe. Methods: OF-NB1 and MF-NB1 were prepared using a multistep synthesis, and their binding affinities toward GluN2B subunits and selectivity over σ1 receptors (σ1Rs) were determined via competitive binding assays. 18F-OF-NB1 was synthesized via copper-mediated radiofluorination and was evaluated in Wistar rats by in vitro autoradiography, PET imaging, ex vivo biodistribution, metabolite experiments, and receptor occupancy studies using CP-101,606, an established GluN2B antagonist. To determine in vivo selectivity, 18F-OF-NB1 was validated in wild-type and σ1R knock-out mice. Translational relevance was assessed in autoradiographic studies using postmortem human brain tissues from healthy individuals and ALS patients, the results of which were corroborated by immunohistochemistry. Results: The binding affinity values for OF-NB1 and MF-NB1 toward the GluN2B subunits were 10.4 ± 4.7 and 590 ± 36 nM, respectively. For σ1R binding, OF-NB1 and MF-NB1 exhibited inhibition constants of 410 and 2,700 nM, respectively. OF-NB1, which outperformed MF-NB1, was radiolabeled with 18F to afford 18F-OF-NB1 in more than 95% radiochemical purity and molar activities of 192 ± 33 GBq/µmol. In autoradiography experiments, 18F-OF-NB1 displayed a heterogeneous and specific binding in GluN2B subunit-rich brain regions such as the cortex, striatum, hypothalamus, and hippocampus. PET imaging studies in Wistar rats showed a similar heterogeneous uptake, and no brain radiometabolites were detected. A dose-dependent blocking effect was observed with CP-101,606 (0.5-15 mg/kg) and resulted in a 50% receptor occupancy of 8.1 µmol/kg. Postmortem autoradiography results revealed lower expression of the GluN2B subunits in ALS brain tissue sections than in healthy controls, in line with immunohistochemistry results. Conclusion:18F-OF-NB1 is a highly promising PET probe for imaging the GluN2B subunits of the N-methyl-d-aspartate receptor. It possesses utility for receptor occupancy studies and has potential for PET imaging studies in ALS patients and possibly other brain disorders.

Neuroimaging with Radiopharmaceuticals Targeting the Glutamatergic System.

Radiopharmacy at ETH has worked on the development of novel PET tracers for neuro-, cardiac- and tumor imaging for many years. In this paper, our efforts on targeting the glutamatergic system of the metabotropic glutamate receptor subtype 5 (mGluR5) and the ionotropic N-methyl-D-aspartate (NMDA) receptor are summarized. We briefly described the principles of positron emission tomography (PET) tracer development for the central nervous system (CNS) and the radiolabeling methods used in our laboratory. To assess the radioligands, results of in vitro autoradiography, biodistribution, and metabolite studies as well as PET imaging data are discussed. Furthermore, key PET parameters for kinetic modeling and quantification methods are provided. Two mGluR5 PET tracers, [11C]ABP688 and [18F]PSS232, were translated in our GMP labs and evaluated in human subjects. The newly developed GluN2B PET tracer [11C]Me-NB1 is currently being investigated in a first-in-human PET study and several F-18 labeled tracers are being evaluated in non-human primates in which the first-in-class will be translated for human studies.

The long-term effect of intra-European migration on cognitive abilities in later life.

The study raises the question about the long-term effect of intra-European migration on cognitive abilities in later life. In contrast to previous research that compares migrants to natives of the destination country, this study uses stayers in the European origin countries as reference group for migrants who moved to another European country earlier in life and are now growing old abroad. Selection into migration is addressed methodologically by applying an instrumental variable approach. Using the Global Bilateral Migration Database to generate the country- and time-specific share of emigrants as instrument for migration, the results indicate that intra-European migration turns out to have a negative long-term effect on the level of cognitive abilities.

Structure-Affinity Relationships of 2,3,4,5-Tetrahydro-1H-3-benzazepine and 6,7,8,9-Tetrahydro-5H-benzo[7]annulen-7-amine Analogues and the Discovery of a Radiofluorinated 2,3,4,5-Tetrahydro-1H-3-benzazepine Congener for Imaging GluN2B Subunit-Containing N-Methyl-d-aspartate Receptors.

Aspiring to develop a positron emission tomography (PET) imaging agent for the GluN2B subunits of the N-methyl-d-aspartate receptor (NMDAR), a key therapeutic target for drug development toward several neurological disorders, we synthesized a series of 2,3,4,5-tetrahydro-1H-3-benzazepine and 6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-amine analogues. After in vitro testing via competition binding assay and autoradiography, [18F]PF-NB1 emerged as the best performing tracer with respect to specificity and selectivity over σ1 and σ2 receptors and was thus selected for further in vivo evaluation. Copper-mediated radiofluorination was accomplished in good radiochemical yields and high molar activities. Extensive in vivo characterization was performed in Wistar rats comprising PET imaging, biodistribution, receptor occupancy, and metabolites studies. [18F]PF-NB1 binding was selective to GluN2B-rich forebrain regions and was specifically blocked by the GluN2B antagonist, CP-101,606, in a dose-dependent manner with no brain radiometabolites. [18F]PF-NB1 is a promising fluorine-18 PET tracer for imaging the GluN2B subunits of the NMDAR and has utility for receptor occupancy studies.

Unexpected reactivity of cyclic perfluorinated iodanes with electrophiles.

We have found that cyclic perfluorinated iodanes react with electrophiles (E+ = Br, Cl, F, I) to afford perfluorinated E-RF compounds. This reactivity is unexpected since cyclic perfluorinated iodanes are considered as electrophilic reagents that normally react with nucleophiles (e.g. Nu- = SR, OR) to afford Nu-RF products. The utility of this new transformation is demonstrated for a [18F]CF3CF2-containing compound which was prepared from [18F]XeF2 obtained from cyclotron produced [18F]fluoride.

Identification and Preclinical Evaluation of a Radiofluorinated Benzazepine Derivative for Imaging the GluN2B Subunit of the Ionotropic NMDA Receptor.

The previously reported carbon-11 labeled GluN2B PET radioligand 11C-Me-NB1 served as a starting point for derivatization and led to the successful development of a radiofluorinated analogue designated (R)-18F-OF-Me-NB1. Given the short physical half-life of 20.3 min for carbon-11, (R)-18F-OF-Me-NB1 with a physical half-life of 109.8 min would allow satellite distribution to nuclear medicine facilities without an on-site cyclotron. Methods: Two fluorinated Me-NB1 derivatives, OF-Me-NB1 and PF-Me-NB1, were synthesized. Upon chiral resolution, the respective enantiomers were radiolabeled with carbon-11 and assessed in a proof-of-concept study by applying in vitro autoradiography on rodent brain sections. Based on the autoradiograms, (R)-OF-Me-NB1 was selected for radiofluorination and preclinical evaluation by ex vivo autoradiography, PET imaging, biodistribution and metabolite studies in Wistar rats. To rule out off-target binding to the σ1 receptor, the brain uptake of (R)-18F-OF-Me-NB1 in wild-type mice was compared with σ1 receptor knock-out mice. Results: Autoradiographic assessment revealed that both enantiomers of 11C-PF-Me-NB1 distributed homogenously across all brain regions on rodent brain sections. In contrast, the two enantiomers of 11C-OF-Me-NB1 exhibited an entirely different behaviour. While (S)-11C-OF-Me-NB1 bound virtually to all brain regions with considerable σ1 receptor binding, (R)-11C-OF-Me-NB1 exhibited high selectivity and specificity for the GluN2B-rich rat forebrain. These findings were confirmed for the radiofluorinated analogue (R)-11C-OF-Me-NB1, which was obtained via copper-mediated radiofluorination in radiochemical yields of 13-25% and molar activities ranging from 61-168 GBq/µmol. PET imaging and biodistribution studies in Wistar rats indicated appropriate pharmacokinetic profile and high in vivo specific binding of (R)-18F-OF-Me-NB1 as revealed by blocking studies with GluN2B-antagonist CP101,606. Off-target binding to the σ1 receptor was excluded by PET imaging with σ1 receptor knock-out mice. Receptor occupancy experiments with CP101,606 revealed a D50-value of 8.3 µmol/kg (intravenous). Conclusion: (R)-18F-OF-Me-NB1 is a promising radiofluorinated probe that exhibits specificity and selectivity for the GluN2B-containing N-methyl-D-aspartate (NMDA) complex and enables in vivo target occupancy studies in rodents.

Differences in Subjective Well-being Between Older Migrants and Natives in Europe.

This study examines disparities in subjective well-being (SWB) among older migrants and natives across several European countries using data from the Survey of Health, Aging and Retirement in Europe (SHARE). Our results show a significant SWB gap between migrants and non-migrants that diminishes with increasing age. While migrants from Northern and Central Europe have similar SWB levels as natives, Southern European, Eastern European, and Non-European migrants have significantly lower levels of SWB than the native population. The immigrant-native gap becomes smaller but remains significant after controlling for sociodemographic characteristics and health, the financial situation, citizenship, age at migration, and length of residence. Additionally, we find that the size of the SWB gap varies largely across countries. Current family reunion policies as measured by the Migrant Integration Policy Index (MIPEX) correlate with these country differences. The immigrant-native gap is bigger in countries with restrictive and smaller in countries with open policies.

Imaging the glutamate receptor subtypes-Much achieved, and still much to do.

Functional imaging of glutamate receptors using PET imaging modality can be used to study numerous CNS disorders and also to select appropriate doses of clinically relevant glutamate-receptor-targeting candidate drugs. Great strides have been made in developing PET imaging probes for the non-invasive detection of glutamate receptors in the brain. This review highlights recent progress made towards the development of glutamatergic PET imaging agents. Focus is placed on PET imaging probes that have been labelled with either carbon-11 or fluorine-18.

Enhanced copper-mediated (18)F-fluorination of aryl boronic esters provides eight radiotracers for PET applications.

[(18)F]FMTEB, [(18)F]FPEB, [(18)F]flumazenil, [(18)F]DAA1106, [(18)F]MFBG, [(18)F]FDOPA, [(18)F]FMT and [(18)F]FDA are prepared from the corresponding arylboronic esters and [(18)F]KF/K222 in the presence of Cu(OTf)2py4. The method was successfully applied using three radiosynthetic platforms, and up to 26 GBq of non-carrier added starting activity of (18)F-fluoride.

A general copper-mediated nucleophilic 18F†fluorination of arenes.

Molecules labeled with fluorine-18 are used as radiotracers for positron emission tomography. An important challenge is the labeling of arenes not amenable to aromatic nucleophilic substitution (SNAr) with [(18)F]F(-). In the ideal case, the (18)F fluorination of these substrates would be performed through reaction of [(18)F]KF with shelf-stable readily available precursors using a broadly applicable method suitable for automation. Herein, we describe the realization of these requirements with the production of (18)F arenes from pinacol-derived aryl boronic esters (arylBPin) upon treatment with [(18)F]KF/K222 and [Cu(OTf)2(py)4] (OTf = trifluoromethanesulfonate, py = pyridine). This method tolerates electron-poor and electron-rich arenes and various functional groups, and allows access to 6-[(18)F]fluoro-L-DOPA, 6-[(18)F]fluoro-m-tyrosine, and the translocator protein (TSPO) PET ligand [(18)F]DAA1106.

Asymmetric hydrogenation with iridium C,N and N,P ligand complexes: characterization of dihydride intermediates with a coordinated alkene.

Previously elusive iridium dihydride alkene complexes have been identified and characterized by NMR spectroscopy in solution. Reactivity studies demonstrated that these complexes are catalytically competent intermediates. Additional H2 is required to convert the catalyst-bound alkene into the hydrogenation product, supporting an Ir(III) /Ir(V) cycle via an [Ir(III) (H)2 (alkene)(H2 )(L)](+) intermediate, as originally proposed based on DFT calculations. NMR analyses indicate a reaction pathway proceeding through rapidly equilibrating isomeric dihydride alkene intermediates with a subsequent slow enantioselectivity-determining step. As in the classical example of asymmetric hydrogenation with rhodium diphosphine catalysts, it is a minor, less stable intermediate that is converted into the major product enantiomer.

Susceptibility of podocytes to palmitic acid is regulated by stearoyl-CoA desaturases 1 and 2.

Type 2 diabetes mellitus is characterized by dyslipidemia with elevated free fatty acids (FFAs). Loss of podocytes is a hallmark of diabetic nephropathy, and podocytes are highly susceptible to saturated FFAs but not to protective, monounsaturated FFAs. We report that patients with diabetic nephropathy develop alterations in glomerular gene expression of enzymes involved in fatty acid metabolism, including induction of stearoyl-CoA desaturase (SCD)-1, which converts saturated to monounsaturated FFAs. By IHC of human renal biopsy specimens, glomerular SCD-1 induction was observed in podocytes of patients with diabetic nephropathy. Functionally, the liver X receptor agonists TO901317 and GW3965, two known inducers of SCD, increased Scd-1 and Scd-2 expression in cultured podocytes and reduced palmitic acid-induced cell death. Similarly, overexpression of Scd-1 attenuated palmitic acid-induced cell death. The protective effect of TO901317 was associated with a reduction of endoplasmic reticulum stress. It was lost after gene silencing of Scd-1/-2, thereby confirming that the protective effect of TO901317 is mediated by Scd-1/-2. TO901317 also shifted palmitic acid-derived FFAs into biologically inactive triglycerides. In summary, SCD-1 up-regulation in diabetic nephropathy may be part of a protective mechanism against saturated FFA-derived toxic metabolites that drive endoplasmic reticulum stress and podocyte death.

Fast and highly regioselective allylation of indole and pyrrole compounds by allyl alcohols using Ru-sulfonate catalysts.

New Ru-sulfonate catalysts have been synthesized and shown to very rapidly allylate indole and pyrrole compounds using allyl alcohols as substrates. The observed regioselectivity is exceptionally high (up to 100% of the branched isomer). Density functional theory calculations explain these results.

Fast, efficient Ru(IV)-catalysed regioselective allylation of indoles using allyl alcohol (without additives) under mild conditions.

The new Ru(IV) salt, [Ru(eta(3)-C(3)H(5))(Cp*)(CH(3)CN)(2)](PF(6))(2), is an excellent catalyst for the regioselective allylation of a variety of indole compounds using allyl alcohol as substrate; there are no co-catalysts required in this chemistry and the yields and reaction conditions are very favorable.