Imaging Mitochondrial Dysfunction in Neurodegenerative and Cardiovascular Diseases by Targeting the Alpha Subunit of ATP Synthase (ATP5A)
Description: Background and rationale. There increasing evidence to support that mitochondrial dysfunction might be an early stage hallmark of various neurodegenerative and cardiovascular diseases. The alpha subunit of mitochondrial ATP synthase (ATP5A) was recently identified as a therapeutic target since the discovery of J147 – a phenyl hydrazide derivative. ATP5A has been reported to be decreased in the hippocampus and entorhinal cortex of AD patients, while an increased expression was found in hearts of patients with ischaemic cardiopmyopathy and patients after a severe acute myocardial infarction. J147 offers the opportunity to develop new therapeutic strategies for the treatment of age-related disorders and heart failure by targeting mitochondrial dysfunction via ATP5A.Overall objectives and specific aims. The aim of this project is to develop a novel positron emission tomography (PET) tracer targeting ATP5A for non-invasive imaging of mitochondrial dysfunction in neurodegenerative and cardiovascular diseasesMethods. (1) design and synthesis of novel ATP5A ligands which have the potential as PET probes; (2) studies on the interaction between the ligand and target (in collaboration with Prof. Riek/Dr. Orts from the Physical Chemical Laboratory at the ETHZ); (3) radiosynthesis of the most promising ligands and in vitro evaluation; (4) PET imaging of healthy rodents and diseased animal models with most promising PET probe(s). Ultimately, the PET tracer(s) is/are expected to enable monitoring of the progress of mitochondrial dysfunction in patients with neurodegenerative (AD and stroke) and cardiovascular diseases.Expected results. This proposal will lead to the identification, synthesis, and characterisation of a series of novel ATP5A ligands with improved physicochemical, pharmacological and pharmacokinetic properties compared to J147. Criteria for successful candidates include: (i) binding affinities below 10 nM to ATP5A; (ii) specificity and selectivity over mitochondrial complex I, Aß, tau and alpha-synuclein; (iii) efficient radiolabelling with either 11C or 18F; (iv) high stability in rodent and human serum; (v) ability to identify variable expression of ATP5A in healthy and diseased animal models in vivo PET imaging and in vitro autoradiography on post mortem human brain and heart samples.Impact. We are convinced that the development of an ATP5A-selective radiotracer constitutes a major step towards the understanding of mitochondrial function in aging process and its role under different pathological conditions. The information gained from a potent ATP5A PET tracer will help to elucidate pathophysiology of different diseases on a molecular basis and allow monitoring of disease progression and therapeutic effects (particularly for the current clinical studies with J147). Thus, the ultimate aim of this project is to clinically translate the most promising 11C or 18F-labelled radiotracers to assess disease progression and support the development of novel therapeutics against AD and heart failure. A clinically useful ATP5A PET tracer will be a valuable contribution to worldwide AD research and particularly for our current ongoing clinical AD project collaborated with Prof. Hock (UZH) and Prof. Frisoni (HUG).
Amount: CHF 382,500
Funding type: research
Funder scheme: Project funding
Start date: 2021-03-01
End date: 2026-02-28
Investigator: Mu, Linjing
Institution: ETH Zurich – ETHZ
Funded outputs count: 5
Funder award ID: 192409
OpenAlex ID: G8839557526