Phase II year
2017
(last award dollars: 2018)
The goal of this project is to develop commercial 18F PET radiopharmaceuticals for evaluating the proportion of D2 receptors in the high affinity state in human diseases, including Parkinsons disease and restless legs syndrome. The D2high receptor is the functional form of the D2 receptor to which endogenous dopamine binds. An agonist radioligand should be more sensitive to endogenous DA levels than antagonist radioligands since, unlike antagonists, agonist radioligands bind preferentially to the receptor in its high affinity state. Thus, agonist radioligands have the potential to elucidate more detailed information on receptor subtype activity as a function of disease as well as DA system activity as a whole. The majority of known radioligands are based on D2 antagonists and, as such, do not specifically target the D2high state. Among the known agonist ligands, none possess high selectivity for D2 over D3, and more importantly, none of the agonist ligands have been successfully developed as 18F PET radioligands. Indeed, the development of an effective 18F-labeled D2 agonist radioligand has proven challenging, and there are no commercially available agonist PET radioligands for measuring D2 function in the brain. In contrast, fluoroaporphines, which are the focus of this project, are fluorinated D2 receptor agonists that specifically and selectively target D2high receptors in vitro and in vivo. Therefore, the objective of this project is to carry out the necessary preclinical evaluations in order to file an investigational new drug application (IND) and develop the fluoroaporphines as commercial 18F PET radiopharmaceuticals to aid in the diagnosis of dopamine-dependent disorders. The D2 agonist 18F PET radioligands will be used for: a) for early diagnosis of PD/LBD and RLS b) as a diagnostic biomarker in clinical trials, to measure the efficacy of medications being developed for PD, RLS, and other disorders involving the dysfunction of the dopaminergic system Such radioligands will be a superior tool for in vivo evaluation of the human brain, for earlier diagnosis of disease, and will foster the development of more targeted and effective therapies for PD, RLS, schizophrenia, addiction, and other neuropsychiatric disorders involving the D2high receptor. Such radioligands will have a widespread and positive impact on public health worldwide. These18F radiopharmaceuticals will have a positive impact on patients lives by providing a way to get a correct diagnosis earlier and therefore obtain appropriate treatment earlier, and in turn by lowering the overall socio-economical burden to the patients and their families.
Public Health Relevance Statement: PROJECT NARRATIVE The goal of this project is to develop commercial 18F PET radiopharmaceuticals for evaluating the proportion of D2 receptors in the high affinity state in human diseases, including Parkinsons disease and restless legs syndrome. The development of an effective 18F-labeled D2 agonist radioligand has proven challenging and there are no commercially available agonist PET radioligands for measuring D2 function in the brain; in contrast, fluoroaporphines, which are the focus of this project, are fluorinated D2 receptor agonists that specifically and selectively target D2high receptors in vitro and in vivo. The objective of this project is to carry out the necessary preclinical evaluations in order to file an investigational new drug application (IND) and develop the fluoroaporphines as commercial 18F PET radiopharmaceuticals: first, for early diagnosis of PD/LBD and RLS, and second, as a diagnostic biomarker in clinical trials, to measure the efficacy of medications being developed for PD, RLS, and other disorders involving the dysfunction of the dopaminergic system; such 18F radiopharmaceuticals will have a positive impact on patients lives by providing a way to get a correct diagnosis earlier and therefore obtain appropriate treatment earlier, and by lowering the overall socio-economical burden to the patients and their families.
Project Terms: addiction; Address; Affinity; Agonist; Amphetamines; Autoradiography; base; Binding; Biodistribution; Brain; Brain region; burden of illness; Cerebellum; Clinical; Clinical Trials; Corpus striatum structure; Data; Development; Diagnosis; Diagnostic; diagnostic biomarker; Disease; disease diagnosis; Disease Progression; Dopamine; Dopamine D2 Receptor; Early Diagnosis; Early treatment; Economic Burden; effective therapy; Ensure; Evaluation; experience; Family; Female; Fostering; Functional disorder; Goals; High Pressure Liquid Chromatography; Human; human disease; In Vitro; in vivo; Injectable; interest; Investigational New Drug Application; Label; Ligands; male; Measures; Monitor; N-n-propylnorapomorphine; neuroimaging; neuropsychiatric disorder; novel; Nucleus Accumbens; Olfactory tubercle; Organ; Parkinson Disease; pars compacta; Patients; Pharmaceutical Preparations; Phase; Positron-Emission Tomography; pre-clinical; preclinical evaluation; product development; Public Health; Raclopride; Radioactivity; Radiolabeled; radioligand; Radiopharmaceuticals; Rattus; receptor; receptor function; Reproducibility; Restless Legs Syndrome; Running; Schizophrenia; Slice; Societies; Specificity; Sprague-Dawley Rats; Substantia nigra structure; Symptoms; System; targeted treatment; Time; tool; Treatment Efficacy; uptake; Validation
