Preclinical evaluation of the D2 receptor agonist MCL-524 as diagnostic marker for presymptomatic Parkinson's Disease

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Summary Parkinson`s disease (PD) is characterized by a progressive loss of dopaminergic (DA) neurons in the nigrostriatal region which starts 4-7 years before symptoms such as movement disturbances become manifest. Diagnosis of the disease in the asymptomatic phase is ideal, as it would enable earlier treatment and provide new targets for therapeutic intervention. We have developed a highly specific agonist, MCL-524, for the active form of the dopamine receptor, D2high, which is up-regulated in early PD. This early, transient upregulation is an opportunity to use it as a biomarker. We aim to characterize MCL-524 in a moderate animal model of pre-symptomatic PD. In this model, by injection of 6-OHDA into three discrete sites in the striatum, a progressive but incomplete loss of DA neurons in the nigrostriatal pathway is induced, which resembles early stages of PD. In our first specific aim, we will use [3H]MCL-524 to detect the up-regulation of the D2high receptor in 6-OHDA rats compared with sham operated controls. D2 receptor binding will be evaluated through quantitative autoradiography. In the second aim, we will confirm specificity of MCL-524 by intravenous pre-treatment with a specific D2 receptor antagonist, N-(methyl) benperidol, which should abolish all binding of [3H]MCL-524 to D2; or a specific D3 receptor antagonist, SB277011A, which should not interfere with binding of MCL-524 to D2high. Completion of these aims will: a) validate MCL-524 as a highly selective and specific agonist ligand which can unambiguously detect early, key changes to D2 receptor expression and function; and b) allow for development of a robust protocol for diagnosing Parkinson’s disease in the prodromal stage. The overarching goal is to develop MCL-524 as a positron emission tomography (PET) radiotracer for early clinical diagnosis of PD. Early detection of this neurodegenerative disease will allow for earlier and better treatment opportunities for the patient, and will help alleviate the socio-economic burden for PD patients and their families.