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

2009, The International Journal of Neuropsychopharmacology

Dopamine D 3 receptors are preferentially localized in the limbic system and midbrain, and thus may be involved in the pathophysiology of neuropsychiatry disorders. [ 11 C](+)-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 [ 11 C](+)-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 4,140 =15.02, p<0.001). The fractions of [ 11 C](+)-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 ED 50 of ABT-925 was 4.37 mg/ml across regions. Our results demonstrate that [ 11 C](+)-PHNO binding can be blocked by a D 3 receptor antagonist and confirm preclinical findings that [ 11 C](+)-PHNO signal in the substantia nigra and globus pallidus is mainly reflective of its binding to D 3 receptors. Thus, [ 11 C](+)-PHNO seems a suitable PET radiotracer to estimate D 3 receptor occupancy in humans.