PRIN 2022 Scorrimento - Prot. 2022YFYTY2

P-gp is an efflux protein belonging to the ATP Binding Cassette (ABC)-transporters family. A decreased P-gp activity and/or expression has been detected in neurodegenerative disorders as AD and PD and thus, the measure of this dysfunction or down-expression of the pump may be an useful strategy to early diagnose neurodegeneration. P-gp detection in humans has been investigated through the positron emission tomography (PET), able to label specific biomarkers. Increased or decreased brain distribution and uptake of such radiotracers, i.e. indirect parameters of P-gp hypo- or hyperactivity, have been demonstrated in central nervous system pathologies such as Alzheimer disease, Parkinson’s disease, schizophrenia, resistant epilepsy and treatment-resistant depression. However, the low brain uptake of radiotracers used in these studies, raised concerns on their capability of detecting P-gp activity variation, especially P-gp hyperactivity. Recently, our group has developed a new ligand bearing a 6,7-dimethoxytetrahydroisoquinoline moiety, named MC225, as 18F-radiotracer. A clinical trial in Tokyo has been carried out with this radiotracer (https://rctportal.niph.go.jp/en/detail?trial_id=jRCTs031190136, JRCT ID: jRCTs031190136 Registered date:20/11/2019, Title: First in human study of [18F]MC225 and additional studies are in progress in Groningen (NL)). [18F]MC225 demonstrated higher brain uptake at baseline conditions as compared to other P-gp radiotracers thus surging as a reliable and sensitive marker of P-gp hyperactivity. Starting from these promising results, the aim of the present project is to design P-gp inhibitors, since [18F]MC225 is a P-gp substrate, in order to deepen the P-gp role at BBB in CNS diseases. To date, potent and selective P-gp inhibitors are not available because tariquidar, the most studied P-gp radiotracer, is a dual P-gp/BCRP ligand. As known, PET technique is used as proof of concept, proof of mechanism and also proof of efficacy, and therefore, the design of 18F-radiolabelled P-gp inhibitors may allow additional information on P-gp dysfunction that triggers diseases in CNS. The results from substrate permit to evaluate P-gp activity whereas the finding from inhibitor gives information on P-gp expression. We have preliminarly designed and tested two ligand, MC18, the first potent and selective P-gp inhibitor, that has been 11C radiolabeled, and MC70, the most potent P-gp inhibitor, that is used as tool as commercially available, bearing an useful group to develop 18F radiolabeleled derivative. Aim of the present proposal is to design and validate the radiosynthesis of MC18 and MC70 as 18F-radioligands, in order to investigate the role of P-gp expression at BBB level and deepen the potential of the two fluoroethoxy-derivatives as theranostics for neurodegeneration.

Working group:

• Maria Lucia Calcagni - Responsabile scientifico UCSC
• Daniela Di Giuda

Partners:

• Università degli Studi di Bari Aldo Moro