Abstract
384
Objectives: Although [11C]-(+)-PHNO was developed as a D2 agonist PET ligand, evidence has accrued that it may be a D3-preferring ligand [1]. As [11C]-(+)-PHNO PET signal is a mixture of D2 and D3 binding, accurate interpretation of PET data requires knowledge of regional D2 and D3 components of [11C]-(+)-PHNO binding. An examination of regional [3H]-(+)-PHNO binding in mice lacking D2 or D3 receptors (D2KO or D3KO) should provide data on the brain regional components of the [11C]PHNO signal. Methods: Three groups of 12 mice each - wild type (WT), D2KO and D3KO- were injected i.v. with [3H]-(+)-PHNO. Half of each group received 10mg/kg of SB-277011 i.p., 60 min before the [3H]-(+)-PHNO injection. SB-277011 is a D3 antagonist with 100-fold selectivity over D2 in vitro. Sixty minutes after the [3H]-(+)-PHNO injection the mice were sacrificed, their brains extracted and [3H]-(+)-PHNO binding measured in striatal and extra-striatal regions using quantitative autoradiography. Results: In D3KO specific (+)-PHNO binding was completely abolished in extra-striatal regions and in the ventral striatum, while in the caudate-putamen it was reduced by 50% compared to WT mice. In D2KO SB-277011 decreased the specific binding of [3H]-(+)-PHNO by 96% compared to WT mice, while in D3KO no change in specific binding was seen, confirming the high selectivity of SB-277011 for D3 over D2 at this dose. In WT mice regional decreases in specific [3H]-(+)-PHNO binding following SB-277011 varied from 49%, in the caudate-putamen to 70% in the ventral striatum, 87% in the ventral pallidum, and 100% in the habenula, midbrain, cerebellum lobes IX & X and the hypothalamus. Conclusions: Our results are consistent with the data of Narendran [1], indicating that in vivo PHNO has preferential affinity for D3 over D2high receptors, (contra Seeman [2]). In extra-striatal regions [11C]-(+)-PHNO binding represents the D3 component only, and can be used to estimate D3 drug occupancy without confounds of the D2 component. 1.Narendran, R., et al., Synapse, 2006. 60(7): p.485-95. 2.Seeman, P., et al., Synapse, 2005. 58(2): p.122-8.
Research Support (if any): This study was funded by GlaxoSmithKline.
- Society of Nuclear Medicine, Inc.