Dopamine D1 agonists have shown unique clinical potential for numerous disorders including cognitive deficits (e.g., from psychiatric or neurologic disorders or aging), attention deficit hyperactivity disorder, Parkinson?s disease, and cocaine abuse), and in the few reported clinical studies with experimental D1 agonists, the large effect sizes predicted from preclinical studies have been found. No brain available D1 agonist has yet been approved for clinical use largely because all high intrinsic activity D1 agonists were catechols, and had little oral bioavailability to justify clinical development. Pfizer Inc. has just reported non- catechol D1 agonists entering Phase III, and, although Phase II data are not public, their extensive studies in non-human primates (NHP) have confirmed the findings made with earlier, non-orally available compounds. This suggests that clinical use is on the horizon, raising numerous scientific questions, the most pressing of which is how the interactions of receptor occupancy and intrinsic activity translate into desired pharmacological effects. There are excellent D1 antagonist radioligands for in vivo imaging studies, but these ligands interact equivalently with active (high affinity G protein-coupled) and inactive (low affinity uncoupled) forms of the receptor. For this reason, they have been found to be insensitive to changes in dopamine signaling in vivo. We propose the discovery of a radiolabeled D1 selective agonist ligand that can be used in both laboratory and clinical imaging studies (e.g., SPECT) to quantify high affinity, functional receptors. We have selected a lead template based on excellent predicted pharmacodynamic properties and very accessible chemistry. We will make a precursor molecule that can be rapidly radioiodinated, and then deprotected to yield the candidate radioligand. We shall synthesize the intermediates and non-labeled predicted product, and validate the latter chemically and pharmacologically by its affinity and functional effects at dopamine receptors, and potential binding at off-target binding sites). Confirmation of its D1 agonist properties will be validated both behaviorally and physiologically, and we shall determine if it has metabolites that may affect its use. After the properties of the unlabeled probe have been confirmed, we shall develop and evaluate rapid and efficient radiosynthesis protocols for the candidate ligand. The proposed studies will use 125I, but are amendable to use of 123I (SPECT) or possibly PET (124I). We shall validate ligands by performing dose-response relationships, and compare the measured binding potential ex vivo with administered dose. We then shall select a tracer dose and perform competitive occupancy studies. Because we hypothesize that there are important in vivo differences between agonist and antagonist radioligands, we shall do parallel studies with the selective D1 antagonist [125I]- SCH28392, including autoradiography studies to compare the brain relative densities of high and low affinity sites. Finally, we shall validate the utility of the probe in vivo using functional assays for cognition and motor function.
Dopamine D1 agonists have shown unique clinical potential for numerous disorders including cognitive deficits (e.g., from psychiatric or neurologic disorders or aging), attention deficit hyperactivity disorder, Parkinson?s disease, and cocaine abuse. Study of the mechanisms of this target will require an in vivo radioligand suitable for SPECT and PET-type studies that has selectivity for the high affinity (active) state of the D1 receptor. We propose discovery and testing of such a molecule (a selective D1 radioagonist) to be used widely in basic and clinical studies.
