Blockade of [11C](+)-PHNO binding in human subjects by the dopamine D3 receptor antagonist ABT-925.

Dopamine D₃ receptors are preferentially localized in the limbic system and midbrain, and thus may be involved in the pathophysiology of neuropsychiatry disorders. [¹¹C](+)-PHNO is the first preferential D₃ receptor radioligand in humans, yet there are no blockade studies with a D₃ receptor antagonist in humans. This study characterized the blockade of ^[11C](+)-PHNO binding by ABT-925, a D₃ receptor antagonist, in healthy male subjects. Sixteen subjects underwent 2-3 positron emission tomography (PET) scans, at baseline and following one or two doses of ABT-925 ranging from 50 mg to 600 mg. Receptor occupancies were estimated for globus pallidus, substantia nigra, caudate, putamen, and ventral striatum. At the 600-mg dose (n=9), ABT-925 receptor occupancy (meanμS.D.) was higher in substantia nigra (75±10%) and globus pallidus (64±22%) than in ventral striatum (44±17%), caudate (40±18%) and putamen (38±17%) (ANOVA: F_4,140=15.02, p<0.001). The fractions of [¹¹C](+)-PHNO binding attributable to D₃ receptors in D₃ receptor-rich regions were 100% (substantia nigra) and 90% (globus pallidus), and in D₂ receptor-rich regions were 55% (caudate) and 53% (putamen). The ED₅₀ of ABT-925 was 4.37 μg/ml across regions. Our results demonstrate that [¹¹C](+)-PHNO binding can be blocked by a D₃ receptor antagonist and confirm preclinical findings that [¹¹C](+)-PHNO signal in the substantia nigra and globus pallidus is mainly reflective of its binding to D₃ receptors. Thus, [¹¹C](+)-PHNO seems a suitable PET radiotracer to estimate D₃ receptor occupancy in humans. [ABSTRACT FROM AUTHOR]