Preclinical Validation of Novel High Affinity D2 Receptor Agonists for PET Neuroimaging

PROJECT SUMMARY
The goal of this project is to develop commercialF PET radiopharmaceuticals for evaluating the proportion of
Dreceptors in the high affinity state in human diseasesincluding Parkinson s disease and restless legs
syndromeThe D high receptor is the functional form of the Dreceptor to which endogenous dopamine bindsAn agonist radioligand should be more sensitive to endogenous DA levels than antagonist radioligands sinceunlike antagonistsagonist radioligands bind preferentially to the receptor in its high affinity stateThusagonist
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 wholeThe majority of known radioligands are based on Dantagonists andas suchdo not specifically target the D high stateAmong the known agonist ligandsnone
possess high selectivity for Dover Dand more importantlynone of the agonist ligands have been
successfully developed asF PET radioligandsIndeedthe development of an effectiveF labeled Dagonist radioligand has proven challengingand there are no commercially available agonist PET radioligands
for measuring Dfunction in the brainIn contrastfluoroaporphineswhich are the focus of this projectare
fluorinated Dreceptor agonists that specifically and selectively target D high receptors in vitro and in vivoThereforethe objective of this project is to carry out the necessary preclinical evaluations in order to file an
investigational new drug applicationINDand develop the fluoroaporphines as commercialF PET
radiopharmaceuticals to aid in the diagnosis of dopamine dependent disordersThe DagonistF PET
radioligands will be used forafor early diagnosis of PD LBD and RLS
bas a diagnostic biomarker in clinical trialsto measure the efficacy of medications being developed forPDRLSand other disorders involving the dysfunction of the dopaminergic system
Such radioligands will be a superior tool for in vivo evaluation of the human brainfor earlier diagnosis of
diseaseand will foster the development of more targeted and effective therapies for PDRLSschizophreniaaddictionand other neuropsychiatric disorders involving the D high receptorSuch radioligands will have a
widespread and positive impact on public health worldwideTheseF radiopharmaceuticals will have a positive
impact on patientslives by providing a way to get a correct diagnosis earlier and therefore obtain appropriate
treatment earlierand in turn by lowering the overall socio economical burden to the patients and their families