4 research outputs found
[<sup>18</sup>F]fluorination of biorelevant arylboronic acid pinacol ester scaffolds synthesized by convergence techniques
Aim: The development of small molecules through convergent multicomponent reactions (MCR) has been boosted during the last decade due to the ability to synthesize, virtually without any side-products, numerous small drug-like molecules with several degrees of structural diversity.(1) The association of positron emission tomography (PET) labeling techniques in line with the “one-pot” development of biologically active compounds has the potential to become relevant not only for the evaluation and characterization of those MCR products through molecular imaging, but also to increase the library of radiotracers available. Therefore, since the [18F]fluorination of arylboronic acid pinacol ester derivatives tolerates electron-poor and electro-rich arenes and various functional groups,(2) the main goal of this research work was to achieve the 18F-radiolabeling of several different molecules synthesized through MCR. Materials and Methods: [18F]Fluorination of boronic acid pinacol esters was first extensively optimized using a benzaldehyde derivative in relation to the ideal amount of Cu(II) catalyst and precursor to be used, as well as the reaction solvent. Radiochemical conversion (RCC) yields were assessed by TLC-SG. The optimized radiolabeling conditions were subsequently applied to several structurally different MCR scaffolds comprising biologically relevant pharmacophores (e.g. β-lactam, morpholine, tetrazole, oxazole) that were synthesized to specifically contain a boronic acid pinacol ester group. Results: Radiolabeling with fluorine-18 was achieved with volumes (800 μl) and activities (≤ 2 GBq) compatible with most radiochemistry techniques and modules. In summary, an increase in the quantities of precursor or Cu(II) catalyst lead to higher conversion yields. An optimal amount of precursor (0.06 mmol) and Cu(OTf)2(py)4 (0.04 mmol) was defined for further reactions, with DMA being a preferential solvent over DMF. RCC yields from 15% to 76%, depending on the scaffold, were reproducibly achieved. Interestingly, it was noticed that the structure of the scaffolds, beyond the arylboronic acid, exerts some influence in the final RCC, with electron-withdrawing groups in the para position apparently enhancing the radiolabeling yield. Conclusion: The developed method with high RCC and reproducibility has the potential to be applied in line with MCR and also has a possibility to be incorporated in a later stage of this convergent “one-pot” synthesis strategy. Further studies are currently ongoing to apply this radiolabeling concept to fluorine-containing approved drugs whose boronic acid pinacol ester precursors can be synthesized through MCR (e.g. atorvastatin)
Improving somatic health for outpatients with severe mental illness: the development of an intervention
Objective: Patients with severe mental illness (SMI) suffer from more somatic illness than the general population. Possible causes are side effects of neuropsychiatric medication, genetic vulnerability, insufficient health care and lifestyle. This co-morbidity is potentially reversible and augments the costs for health care and diminishes quality of life. Screening on symptoms and risks of somatic diseases and coordination of care are proposed to improve SMI-patients' somatic health status. Methods: A clinical facility was started to improve the somatic health status of patients in an outpatient centre in southern Netherlands. This outpatient centre was added to the specialized care for severe and enduring SMI. The intervention consisted of the inventarisation of side-effects and the detection of gaps in health care provision for 72 patients. This was based on interviewing the patients, laboratory screening, collecting information from their general practitioner and pharmacy. A list was compiled of possible diagnosis and health risks, and a plan of action was made for the treatment. Healthcare consumption, quality of life and general functioning were assessed to analyze cost-effectiveness. Evaluations were performed with the psychiatric care team on the process. Results: Mean annual cost of GP's and medical specialist's consultations were E492. There existed a negative relation between EQ5D VAS and the number of self reported chronic diseases. Conclusion: The authors conclude that the procedure is well feasible, but should be set up in close collaboration with all health care professionals of these patients to make tailor made solutions possible
Fuelling the zero-emissions road freight of the future: routing of mobile fuellers
The future of zero-emissions road freight is closely tied to the sufficient availability of new and clean fuel options such as electricity and Hydrogen. In goods distribution using Electric Commercial Vehicles (ECVs) and Hydrogen Fuel Cell Vehicles (HFCVs) a major challenge in the transition period would pertain to their limited autonomy and scarce and unevenly distributed refuelling stations. One viable solution to facilitate and speed up the adoption of ECVs/HFCVs by logistics, however, is to get the fuel to the point where it is needed (instead of diverting the route of delivery vehicles to refuelling stations) using "Mobile Fuellers (MFs)". These are mobile battery swapping/recharging vans or mobile Hydrogen fuellers that can travel to a running ECV/HFCV to provide the fuel they require to complete their delivery routes at a rendezvous time and space. In this presentation, new vehicle routing models will be presented for a third party company that provides MF services. In the proposed problem variant, the MF provider company receives routing plans of multiple customer companies and has to design routes for a fleet of capacitated MFs that have to synchronise their routes with the running vehicles to deliver the required amount of fuel on-the-fly. This presentation will discuss and compare several mathematical models based on different business models and collaborative logistics scenarios