Each year in the UK, around 80,000 individuals are diagnosed with Alzheimer’s disease, and there are 20,000 new cases of dementia with Lewy bodies (DLB), and 20,000 de novo Parkinson’s disease (PD) cases. Although we are critically aware of these disorders, treatments are only symptomatic and for dementia, only delay progression. Diagnosis is also hampered by the lack of any suitable fluid disease markers that can specifically identify what disorder a person may have. This lack of a disease marker can lead to delays in treatment and the poor success of clinical trial.

DLB and PD are “synucleinopathies”, characterised by the presence of neuronal protein aggregates - Lewy bodies and Lewy neurites - consisting of alpha-synuclein (ASYN) protein. Diagnosis of synucleinopathies consists of extensive clinical examination and early diagnosis is difficult with no clinically validated laboratory tests able to identify the presence of disease. Early disease detection of synucleinopathy would significantly advance clinical management and allow early treatment.
 
We are interested in developing new ways to diagnose neurodegenerative disorders and synucleinopathies and similar disorders including Alzheimer’s disease. These disorders are all characterised by the presence of disease-related protein aggregates with nerve cells in the brain, with these protein aggregates leading to nerve cell death and the development of clinical symptoms. A specific feature of these protein inclusions is the formation of parallel beta-pleated sheet structures or “amyloid” protein folding leading to protein insolubility.
 
Whilst ASYN protein folds abnormally and deposits in synucleinopathies, different proteins fold abnormally in Alzheimer’s including tau protein and amyloid beta peptide. When aggregated, these misfolded proteins can be detected with specific chemicals that bind to common motifs within the beta-pleated sheet structures, with the chemicals often showing enhanced fluorescence and allowing detection. This ability of specific chemicals to bind to amyloids can be exploited to detect amyloid proteins using a variety of detection including protein aggregation assays, histological tissue analysis, cellular assays, or nuclear imaging in vivo using positron or single photon emission tomography. These chemicals, unfortunately, often show very low specificity for specific proteins and can cross-react with many different amyloids. The design and synthesis of novel compounds able to bind to specific proteins would permit detection of specific disease states, improving rates of detection and facilitating treatment.
 
This study will therefore aim to develop novel chemicals able to specifically bind to the insoluble amyloid proteins found in the key neurodegenerative disorders of ageing with a specific focus on synucleinopathies.

Parkinson’s disease (PD) is a chronic and progressive movement disorder with an urgent unmet need for efficient symptomatic therapies with fewer side effects. GPR6 is an orphan G-protein coupled receptor (GPCR) with highly restricted expression in dopamine receptor D2-type medium spiny neurons (MSNs) of the indirect pathway, a striatal brain circuit which shows aberrant hyperactivity in PD patients.

CVN424 is a potent and selective GPR6 inverse agonist (IAG) that was developed from a low potency screening hit (EC50 = 43 μM). And was subsequently developed into a potent compound and is subsequently in clinical development to treat motor symptoms in Parkinson’s disease.

Preparation of [18F]-CVN424 would allow visualisation of the GPR6 in a variety of disease states, this is the main aim of this project.