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

Dopamine D-3 receptors are preferentially localized in the limbic system and midbrain, and thus may be involved in the pathophysiology of neuropsychiatry disorders. [C-11](+)-PHNO is the first preferential D-3 receptor radioligand in humans, yet there are no blockade studies with a D-3 receptor antagonist in humans. This study characterized the blockade of [C-11](+))-PHNO binding by ABT-925, a D-3 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 (mean +/- S.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,F-140 = 15.02, p<0.001). The fractions of [C-11](+)-PHNO binding attributable to D-3 receptors in D-3 receptor-rich regions were 100% (substantia nigra) and 90% (globus pallidus), and in D-2 receptor-rich regions were 55% (caudate) and 53% (putamen). The ED50 of ABT-925 was 4.37 mu g/ml across regions. Our results demonstrate that [C-11](+)-PHNO binding can be blocked by a D-3 receptor antagonist and confirm preclinical findings that [C-11](+)-PHNO signal in the substantia nigra and globus pallidus is mainly reflective of its binding to D-3 receptors. Thus, [C-11](+)-PHNO seems a suitable PET radiotracer to estimate D-3 receptor occupancy in humans.