Synthesis and in vivo evaluation of [11C]tucatinib for HER2-targeted PET imaging.

Tucatinib is a selective human epidermal growth factor receptor 2 (HER2) tyrosine kinase inhibitor approved by the U.S. Food and Drug Administration (FDA) in April 2020 for HER2-positive lesions in metastatic breast cancer patients, including CNS metastases. In this article, we attempted to develop the first small molecule, blood-brain-barrier (BBB) penetrant HER2 PET imaging probe based on tucatinib. [11C]tucatinib was synthesized via a Stille-coupling from the respective trimethylstannyl precursor and its biodistribution was evaluated in NMRI nude mice bearing HER2-overexpressing human ovarian cancer cells (SKOV-3). No significant tumor accumulation was observed despite its high affinity for HER-2 receptors (IC50 = 6.9 nM). High liver and intestinal uptake indicate that [11C]tucatinib is too lipophilic to be used as a tumor targeting PET tracer. Therefore, chemical modifications of [11C]tucatinib are needed to increase the polarity for tumor imaging. Tucatinib as an FDA approved drug is still an interesting platform to develop the first small molecule HER2-selective PET tracer. The study highlights the differences between a drug, which needs to be effective, and an imaging agent, which is dependent on contrast.

Development of 11 C-labeled CRANAD-102 for positron emission tomography imaging of soluble Aß-species.

CRANAD-102, a selective near-infrared fluorescent tracer targeting soluble amyloid-ß (Aß) species, has recently attracted attention due to its potential to be used as a diagnostic tool for early stages of Alzheimer's disease (AD). Development of a positron emission tomography (PET) tracer based on CRANAD-102 could as such allow to noninvasively study soluble and protofibrillar species of Aß in humans. These soluble and protofibrillar species are thought to be responsible to cause AD. Within this work, we successfully 11 C-labeled CRANAD-102 via a Suzuki-Miyaura reaction in a RCС of 48 ± 9%, with a RCP of >96% and a molar activity (Am ) of 25 ± 7 GBq/µmol. Future studies have to be conducted to evaluate if [11 C]CRANAD-102 can be used to detect soluble protofibrils in vivo and if [11 C]CRANAD-102 can be used to detect AD earlier as possible with current diagnostics.

Transition Metal-Free Synthesis of meta-Bromo- and meta-Trifluoromethylanilines from Cyclopentanones by a Cascade Reaction.

Anilines are key constituents in biologically active compounds and often obtained from transition metal-catalyzed coupling of an aryl halide with an amine. In this work, we report a transition metal-free method for the synthesis of meta-bromo- and meta-trifluoromethylanilines starting from 3-tribromomethylcyclopentanone or 3-(2-bromo-2-chloro-1,1,1-trifluoroethyl)cyclopentanone, respectively. The scope of the transformation is shown by application of primary, secondary and aromatic amines. The reaction proceeds in acceptable to high yields (20-81 %), and allows for the synthesis of anilines with substitution patterns otherwise difficult to access.

Synthesis of Polysubstituted Meta-Halophenols by Anion-Accelerated 2π-Electrocyclic Ring Opening.

Disrotatory - thermally allowed - 2π-electrocyclic ring-opening reactions require high temperatures to proceed. Herein, we report the first anion-accelerated 2π-electrocyclic ring opening of 6,6-dihalobicyclo[3.1.0]hexan-2-ones at low temperature to give the corresponding meta-halophenols in good to high yields (18 examples, 29-92 % yield, average: 65 %). Many of the phenols have unconventional substitution patterns and are reported here for the first time. Furthermore, the strength of the methodology was shown by the total synthesis of the densely functionalized phenolic natural product caramboxin (isolated as the lactam dehydrate). The reaction mechanism underlying the anion-acceleration was investigated in an ab initio study, which concluded that base-mediated proton abstraction anti to the concurrently departing endo-bromine was the initiating step in an overall concerted reaction mechanism leading directly to the meta-halophenol.

Synthesis and pharmacological characterization of conformationally restricted 2-amino-Adipic acid analogs and carboxycyclopropyl glycines as selective metabotropic glutamate 2 receptor agonists.

The metabotropic glutamate (Glu) receptors (mGluRs) are G-protein coupled receptors, which play a central role in modulating excitatory neurotransmission in the central nervous system (CNS). Thus, the development of tool compounds thereto, continues to interest the scientific community. In this study, we report the design and synthesis of new conformationally restricted 2-aminoadipic acid (2AA) 2-4, and glutamic acid 5, 6 analogs, which share the cyclopropane ring as the restrictor. The analogs were characterized at rat mGlu1-8 in an IP-One functional assay. While the 2AA analogs 3a, 4a and CCG-I analog 5a were shown to be selective mGlu2 agonists with low micromolar potencies, CCG-II analog 5b was shown to be a potent full agonist at mGlu2 (EC50 = 82 nM) with ∼15-fold selectivity over mGlu3, >25-fold selectivity over group III, and >60-fold selectivity over group I subtypes. An in silico study was performed to address this significant change (>3500 fold) in potency upon introduction of this methyl group (L-CCG-II vs 5b).

Design, Synthesis, Pharmacology, and In Silico Studies of (1S,2S,3S)-2-((S)-Amino(carboxy)methyl)-3-(carboxymethyl)cyclopropane-1-carboxylic Acid (LBG30300): A Picomolar Potency Subtype-Selective mGlu2 Receptor Agonist.

Metabotropic glutamate (Glu) receptors (mGlu receptors) play a key role in modulating excitatory neurotransmission in the central nervous system (CNS). In this study, we report the structure-based design and pharmacological evaluation of densely functionalized, conformationally restricted glutamate analogue (1S,2S,3S)-2-((S)-amino(carboxy)methyl)-3-(carboxymethyl)cyclopropane-1-carboxylic acid (LBG30300). LBG30300 was synthesized in a stereocontrolled fashion in nine steps from a commercially available optically active epoxide. Functional characterization of all eight mGlu receptor subtypes showed that LBG30300 is a picomolar agonist at mGlu2 with excellent selectivity over mGlu3 and the other six mGlu receptor subtypes. Bioavailability studies on mice (IV administration) confirm CNS exposure, and an in silico study predicts a binding mode of LBG30300 which induces a flipping of Tyr144 to allow for a salt bridge interaction of the acetate group with Arg271. The Tyr144 residue now prevents Arg271 from interacting with Asp146, which is a residue of differentiation between mGlu2 and mGlu3 and thus could explain the observed subtype selectivity.

Clearing and Masking Agents in Pretargeting Strategies.

'Pretargeting' led to increased target-to-background ratios of nanomedicines in short timeframes. However, clearing or masking agents are needed to reach the full potential of pretargeted approaches. This review gives an overview of clearing and masking agents employed in pretargeting strategies in both preclinical and clinical settings and discusses how these agents work.

Analgesic Use in Sports.

BACKGROUND: Consumption of medication to alleviate pain is widespread in Germany. Around 1.9 million men and women take analgesics every day; some 1.6 million persons are addicted to painkillers. Analgesic use is thought also to be common in sports, even in the absence of pain. The aim of this study was to assess the extent of painkiller use among athletes. METHODS: In line with the PRISMA criteria and the modified PICO(S) criteria, a systematic literature review was registered (Openscienceframework, https://doi. org/10.17605/OSF.IO/VQ94D) and carried out in PubMed and SURF. The publications identified (25 survey studies, 12 analyses of doping control forms, 18 reviews) were evaluated in standardized manner using the Newcastle Ottawa Scale (NOS) and AMSTAR (A MeaSurement Tool to Assess systematic Reviews). RESULTS: Analgesic use is widespread in elite sports. The prevalence varies between 2.8% (professional tennis) and 54.2% (professional soccer). Pain medication is also taken prophylactically in the absence of symptoms in some non-elite competitive sports. In the heterogeneous field of amateur sports the data are sparse and there is no reliable evidence of wide-reaching consumption of painkillers. Among endurance athletes, 2.1% of over 50 000 persons stated that they used analgesics at least once each month in connection with sports. CONCLUSION: Analgesic use has become a problem in many areas of professional/ competitive sports, while the consumption of pain medication apparently remains rare in amateur sports. In view of the increasing harmful use of or even addiction to painkillers in society as a whole, there is a need for better education and, above all, restrictions on advertising.

Site-specific one-pot dual labeling of DNA by orthogonal cycloaddition chemistry.

Bioorthogonal reactions are of high interest in biosciences as they allow the introduction of fluorescent dyes, affinity tags, or other unnatural moieties into biomolecules. The site-specific attachment of two or more different labels is particularly demanding and typically requires laborious multistep syntheses. Here, we report that the most popular cycloaddition in bioconjugation, the copper-catalyzed azide-alkyne click reaction (CuAAC), is fully orthogonal to the inverse electron-demand Diels-Alder reaction (DAinv). We demonstrate that both bioorthogonal reactions can be conducted concurrently in a one-pot reaction by just mixing all components. Orthogonality has been established even for highly reactive trans-cyclooctene-based dienophiles (with rate constants up to 380 000 M(-1) s(-1)). These properties allow for the convenient site-specific one-step preparation of oligonucleotide FRET probes and related reporters needed in cellular biology and biophysical chemistry.

FAIR data for prehistoric mining archaeology.

This paper presents an approach how to create FAIR data for prehistoric mining archaeology, based on the CIDOC CRM ontology and semantic web standards. The interdisciplinary Research Centre HiMAT (History of mining activities in the Tyrol and adjacent areas, University of Innsbruck) investigates mining history from prehistoric to modern times with an interdisciplinary approach. One of the projects carried out at the research centre is the multinational DACH project "Prehistoric copper production in the eastern and central Alps". For a specific geographical region of the project, the data transformation to open and re-usable data is investigated in a separate Open Research Data pilot project. The methodological approach will use the FAIR principles to make data Findable, Accessible, Interoperable and Re-usable. Every archaeological investigation in Austria has to be documented according to the requirements of the Austrian Federal Monuments Office. This documentation is deposited in the CERN-based EU supported research data repository ZENODO. For each deposited file, metadata are created through the application of the conceptual metadata schema CIDOC CRM, an ISO standard for Cultural Heritage Information, which was adopted by ARIADNE, the European Union Research Infrastructure for archaeological resources. Concepts specific to mining archaeology research are organized with the DARIAH Back Bone Thesaurus, a model for sustainable interoperable thesauri maintenance, developed in the European Union Digital Research Infrastructure for the Arts and Humanities. Metadata are created through the extraction of information from the documentation and the transformation to a knowledge graph using semantic web standards. To facilitate usage, graph data are exported to hierarchical and tabular formats representing sites and objects with their geographic locations, temporal and typological assignments and links to the research activities and documents. Metadata are deposited together with the documentation into the repository.

A Diversity Oriented Synthesis Approach to New 2,3-trans-Substituted l-Proline Analogs as Potential Ligands for the Ionotropic Glutamate Receptors.

Discovery of chemical tools for the ionotropic glutamate receptors continues to be a challenging task. Herein we report a diversity-oriented approach to new 2,3-trans-l-proline analogs whereby we study how the spatial orientation of the distal carboxylate group influences the binding affinity and receptor class and subtype selectivity. In total, 10 new analogs were synthesized and 14 stereoisomers characterized in binding assays at native rat ionotropic glutamate receptors, and at cloned human homomeric kainic acid (KA) receptor subtypes GluK1-3. The study identified isoxazole analogs 3d,e, which displayed selectivity in binding at native N-methyl-d-aspartate (NMDA) receptors over native α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and KA receptors, in the high nanomolar to low micromolar range. Furthermore, analogs 3i-A/B showed a preference in binding affinity for GluK3 over GluK1,2. Finally, analog 3j displayed high nanomolar affinity for native NMDA receptors as well as for homomeric GluK3 receptors.

Stereoselective Synthesis of New (2S,3R)-3-Carboxyphenyl)pyrrolidine-2-carboxylic Acid Analogues Utilizing a C(sp3)-H Activation Strategy and Structure-Activity Relationship Studies at the Ionotropic Glutamate Receptors.

Competitive antagonists for ionotropic glutamate receptors (iGluRs) are highly valuable tool compounds for studying health and disease states in the central nervous system. However, only few subtype selective tool compounds are available and the discovery of antagonists with novel iGluR subtype selectivity profiles remains a profound challenge. In this paper, we report an elaborate structure-activity relationship (SAR) study of the parental scaffold 2,3-trans-3-carboxy-3-phenyl-proline by the synthesis of 40 new analogues. Three synthetic strategies were employed with two new strategies of which one being a highly efficient and fully enantioselective strategy based on C(sp3)-H activation methodology. The SAR study led to the conclusion that selectivity for the NMDA receptors was a general trend when adding substituents in the 5'-position. Selective NMDA receptor antagonists were obtained with high potency (IC50 values as low as 200 nM) and 3-34-fold preference for GluN1/GluN2A over GluN1/GluN2B-D NMDA receptors.

Identification and Structure-Activity Relationship Study of Imidazo[1,2-a]pyridine-3-amines as First Selective Inhibitors of Excitatory Amino Acid Transporter Subtype 3 (EAAT3).

In the present study, screening of a library of 49,087 compounds at the excitatory amino acid transporter subtype 3 (EAAT3) led to the identification of 2-(furan-2-yl)-8-methyl-N-(o-tolyl)imidazo[1,2-a]pyridin-3-amine (3a) which showed a >20-fold preference for inhibition of EAAT3 (IC50 = 13 µM) over EAAT1,2,4 (EAAT1: IC50 ∼ 250 µM; EAAT2,4: IC50 > 250 µM). It was shown that a small lipophilic substituent (methyl or bromine) at the 7- and/or 8-position was essential for activity. Furthermore, the substitution pattern of the o-tolyl group (compound 5b) and the chemical nature of the substituent in the 2-position (compound 7b) were shown to be essential for the selectivity toward EAAT3 over EAAT1,2. The most prominent analogues to come out of this study are 3a and 3e that display ∼35-fold selectivity for EAAT3 (IC50 = 7.2 µM) over EAAT1,2,4 (IC50 ∼ 250 µM).

Contribution of lateral substituents in symmetrical and non-symmetrical heptane-bisammonio compounds to the allosteric stabilization of N-methylscopolamine binding to muscarinic M2 receptors.

Allosteric modulators are able to enhance or decrease the equilibrium binding of orthosteric agonists or antagonists. The treatment of Alzheimer's disease and the organophosphorus poisoning can take advantage of the enhancement of the ligand binding. Prerequisite is the formation of ternary complexes consisting of the receptor protein, the orthosteric ligand, e. g. N-methylscopolamine (NMS), and the alloster optimized for the corresponding orthoster. In this study, heptane-bisammonio compounds were optimized with regard to the orthosteric antagonist NMS. Comparing pairs of compounds characterized by phthalimides, cyclohexanedicarbonic acid imide and succinimides at both ends or a phthalimide at one end and either of the three imides at the other end stressed the importance of an aromatic moiety at both ends of the heptane-bisammonio chain.