Depression, Volition, and Death: The Effect of Depressive Disorders on the Autonomous Choice to Forgo Medical Treatment

Many contemporary models of medical ethics champion patient autonomy to counterbalance historically paternalistic decision-making processes. These models tend to suggest an autonomous agent free from cognitive bias and systematic distortion (e.g., Kantian or Cartesian rational agents). Evidence is emerging from the fields of cognitive psychology, cognitive science, and neuroscience that fundamentally challenge this cognitive model, demonstrating the dependence of cognition on deeper, avolitional structures (e.g., backstage cognition, cognitive heuristics and biases, automaticity, emotionally-valenced memory, etc.), and hence, shifting the cognitive model towards reductionistic and deterministic philosophies and psychologies. Medical ethics models must adapt their sense of autonomy in light of these findings if the term is to have any meaning - absent this necessary adaptation, medical ethics centers around a cognitive agent that does not actually exist. In contrast to the homuncular models championed (i.e., overly rationalistic and lacking an account of empirically-validated cognitive phenomena), a cognitive model of autonomy is proposed, along with useful psychometrics and a case metric to assist clinicians in assessing the possibility of compromised autonomy in patients electing to forgo medical treatment

[¹⁸F]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)