Biodistribution studies of two super(18)F-labeled pyridinylphenyl amides as subtype selective radioligands for the dopamine D3 receptor

Introduction: Dopamine D3 receptors are implicated in various neuropsychiatric diseases, drug abuse and alcoholism, but specific agents for D3 molecular imaging are lacking. We evaluated two in vitro selective fluorine-18-labeled radioligand candidates ([ super(18)F]5 and [ super(18)F]6) for positron emission tomography (PET) imaging of D3 receptor availability in the brain. Methods: Biodistribution was evaluated in Sprague-Dawley rats using ex vivo autoradiography and small-animal PET. Protein binding studies were conducted in human plasma and cerebrospinal fluid. Results: [ super(18)F]5 showed rapid blood-brain barrier penetration and fast washout after intravenous injection, whereas the rat brain penetration of [ super(18)F]6 was lower. The total distribution volume (V sub(T)) of [ super(18)F]5 was 20-26 mL g super(-1) throughout brain. Co-injection with the D3 antagonist BP897 resulted in globally increased cerebral washout of [ super(18)F]5 and [ super(18)F]6, but SUV analysis and parametric mapping of binding potential (BP sub(ND)) relative to the cerebellum did not reveal specific binding of either ligand in D3-rich brain regions, i.e. the ventral striatum. However, there was substantial displaceable binding of [ super(18)F]5, and to a lesser extent [ super(18)F]6, in the pituitary. Conclusion: These radioligands reveal dopamine D3 receptors in the pituitary, but are not suitable for PET imaging of in brain, possibly due to low specific signal relative to the globally high V sub(T).