Title : Interaction of the preferential D3 agonist (+)PHNO with monoamine receptors: Relevance for PET imaging of the brain
Abstract:
(+)-4-Propyl-9-hydroxynaphthoxazine ((+)PHNO) is a high affinity agonist at dopamine D3 and, less potently, D2 receptors. In the nineteen eighties and nineties, this naphthoxazine compound was amongst the most promising, non-ergot derivatives in the pipeline for the treatment of Parkinson’s disease. Preliminary clinical trials showed that it improved motor symptoms of parkinsonism, like tremor, rigidity and bradykinesia. Though it has not been successful as a therapeutic agent, its use was rescued as a radiotracer for positron emission tomography (PET) studies; labeled with carbon-11, (+)PHNO has an excellent signal-to noise ratio and favorable kinetics for PET imaging in humans. In addition to hD3 and hD2L receptors, (+)PHNO revealed high affinity at hD4.4, h5-HT1A and h5-HT7. (+)PHNO behaved as a full agonist at hD4.4 and h5-HT1A receptors with potencies comparable to its actions at hD3 and hD2L receptors, and with less potency at 5-HT7 receptors. In binding assays with membranes derived from cells co-expressing hD3 and hD2L receptors and labeled with [3H]Nemonapride or [3H]Spiperone, the proportion of high affinity binding sites recognized by (+)PHNO was higher than an equivalent mixture of membranes from cells expressing hD3or hD2L receptors, suggesting that (+)PHNO promotes formation of hD3-hD2L heterodimers. Further, in cells co-expressing hD3 and hD2L receptors, (+)PHNO showed higher efficacy for inhibiting forskolin stimulated adenylyl cyclase and inducing adenylyl cyclase super-sensitization than in cells transfected with only hD2L receptors. In conclusion, (+)PHNO is a potent agonist at hD4.4, h5-HT1A and h5-HT7 as well as hD3 and hD2L receptors, and it potently activates dopamine hD3-hD2L heterodimers. These interactions should be considered when interpreting PET studies with [11C](+)PHNO and may be relevant to its functional and potential clinical properties in Parkinson's disease and other disorders.
Audience Take Away Notes:
- (+)PHNO is a radiotracer for positron emission tomography (PET) studies imaging in humans. Our radioligand binding studies indicate that PHNO is a potent agonist at hD4.4, h5-HT1A and h5-HT7 as well as hD3 and hD2L receptors, and it potently activates dopamine hD3-hD2L heterodimers.
- PHNO also recognizes D2/D3 receptors in heterodimeric form as high affinity sites in addition to the D3 receptor.
- Our data finally demonstrate that PHNO induces cAMP super sensitivity, a phenomenon linked to tolerance.
- These results are particularly relevant for the interpretation of [ 11C](+)PHNO occupancy in PET studies and may be relevant to its functional and potential clinical properties in neurological disorders.
