In the last 20 years, palladium-catalyzed C–H activation has emerged as a useful alternative to traditional cross-coupling methods and a powerful tool to access valuable intermediates for the synthesis of complex functional molecules. The biaryl fragment is one of the most frequent units present in bioactive molecules, functional organic materials and natural products. Despite major advances, significant limitations persist with regard to their preparation, in term of reactivity, selectivity and sustainability. Based on the recent achievements in the synthesis of ortho-iodobiaryls following a Catellani strategy, the overall objective of this proposal is the development of a general and sustainable method for the direct synthesis of ortho-iodobiaryls and selectively substituted haloarenes as valuable intermediates for the synthesis of a large number of high value-added compounds. The project aims also to develop protocols for the straightforward synthesis of new biaryl-containing phosphines, as a valuable application of this methodology. CAT4Arene will allow the selective construction of halogenated biaryls and arenes which can be further easily converted into a broad variety of high value-added compounds. In particular, thanks to the easily manipulation of the C-halogen bond, especially C-I and C-Br bonds, these new methodologies will unlock the direct construction of tricky molecular architectures, including biaryl-containing phosphines and bioactive nitrogen derivatives. Likewise, new classes of organic molecules would be also accessed, unlocking the opportunity to enlarge the range of compounds available for the medicinal chemistry and the agrochemical industry. The development of unconventional haloarenes formation protocols will be an outstanding breakthrough for the organic chemistry community.

The incidence of chronic vision-impairing retinal diseases is increasing due to population ageing. Monthly intraocular injections are the standard of care, despite the important risks (e.g., infection and haemorrhage) associated with this practice. A promising alternative is the periocular injection of nanocarriers, which are able to enhance the permeability across the ocular membranes. However, as periocular administration relies on the drug transport mechanisms in the tissues to reach the target, animal tests are generally needed for a prediction of drug distribution after the injection. The researcher aims at the development of an ex vivo model of a whole porcine eye which will constitute an evaluation tool for periocular nanoformulations targeting the retina and will allow for a deep understanding of the ocular penetration paths. The project will (i) provide a safer alternative to intraocular injections, (ii) reduce the need for animal testing in the pre-clinical phase of product development and (iii) overcome the current limitations of mathematical models, which are generally unable to predict the complexity of nanoformulations transport. This MSCA will be implemented throughout 24 months at the University of Parma, and it will include two 3-months secondments: the researcher will be trained on pharmacokinetics mathematical models at the University of Navarra and on Organs-on-a-Chip models at Tel Aviv University. The selected methodology allows for a cutting-edge approach to nanoparticles design, promoting the synergistic use of chemistry tools (spectroscopy) with medicine and biology (ex vivo models, 3D imaging, cellular assays) and engineering tools (mathematical models, Organs-on-a-Chip). The competencies acquired during the project will complement the researcher’s background towards the ultimate goal of becoming an expert in the development of innovative and effective ophthalmic therapeutics, with a focus on alternative methods to animal testing.

Depressed mood, agitation, false beliefs, lack of motivation and other alterations in behaviour, usually named with the umbrella term of neuropsychiatric symptoms (NPS), are commonly observed in people with Alzheimer’s disease (AD). NPS are highly prevalent in people with AD (35-85%) and increase the risk of dementia by up to 10 times. The onset of NPS may even precede that of cognitive deficits and predict subsequent cognitive decline. Although not all patients experience NPS and some experience only very mild symptoms, clarifying AD aetiology is of primary importance to improve early diagnosis, provide better care and mitigate the economic burden of dementia. The neural changes associated with NPS in AD are still unclear and, consequently, wide consensus on the best treatment strategies is lacking. Since the earliest accumulation of AD pathology is observed in the nuclei involved in the production of neurotransmitters, the NINFA-AD project aims to investigate whether alterations in brain functioning influenced by abnormalities in different neurotransmitter pathways may be associated with NPS in people either with or at risk for AD. This aim will be pursued by applying an innovative interdisciplinary approach combining functional magnetic resonance with positron emission tomography imaging, fluid AD biomarkers and cognitive data. The NINFA-AD project will provide novel hypothesis-based insights on the cause of these symptoms that will lead to more efficient treatments and improvements in patients' prognosis. Moreover, the findings could be exploited to develop more informative biomarkers to be used in trials to test the mechanisms of action and effectiveness of novel interventions targeting behavioural problems in AD.