The D2-agonist radiotracer [¹¹C]-(+)-PHNO shows a marked increase in sensitivity to amphetamine challenges when compared to [¹¹C]raclopride in the cat brain

Imaging the high affinity state of the D2-receptor using agonist radioligands has aroused considerable interest recently as it could allow for measurements of the functional state of the receptor rather than the total receptor population as measured by antagonist radioligands. Here we report on the evaluation of [11C]-(+)-PHNO as a potential radioligand for in vivo study of the high affinity state D2-receptor using positron emission tomography (PET) in the cat brain. Five cats were anesthetized with isoflurane and scanned using the high resolution PET camera system CPS-HRRT. At baseline conditions, high levels of radioactivity were observed in the striatum whereas low levels of radioactivity were observed in cerebellum. Radioactivity in cerebellum peaked within two minutes post-injection and decreased rapidly thereafter. Radioactivity in striatum peaked at 8–10 minutes post-injection, demonstrating that [11C]-(+)-PHNO binding in this structure is reversible and reaches equilibrium within the time frame of a PET experiment. The striatal binding potential (BP) approximated using the ratio of specific/non-specific (specific = striatum – cerebellum, non-specific = cerebellum) between 31 and 60 minutes post-injection was 3.75 0.51 (n=5). Pretreatment with raclopride (1 mg/kg; i.v.) or haloperidol (0.5 mg/kg; i.v.) reduced [11C]-(+)-PHNO striatal BP by 85% and 94%, respectively, indicating that the majority of radioligand binding in striatum represents specific binding to D2-receptors. Pretreatment with SCH23390 had no effect on [11C]-(+)-PHNO binding. A direct comparison of [11C]-(+)-PHNO and [11C]NPA binding in the same cat showed that [11C]-(+)-PHNO displayed a higher striatal BP than [11C]NPA (3.41 versus 1.59), suggesting that [11C]-(+)-PHNO may be more sensitive than [11C]NPA for in vivo imaging of the high-affinity D2-receptors. Comparison of the dose-effect of amphetamine (0.1, 0.5 and 2 mg/kg i.v.) on both [11C]-(+)-PHNO and [11C]raclopride binding in striatum showed than [11C]-(+)-PHNO was more sensitive to the dopamine releasing effect of the drug. The highest dose of amphetamine induced a 83-88% inhibition of [11C]-(+)-PHNO binding (n=3) and a 60-63% inhibition of [11C]raclopride binding (n=2). Preliminary data showed that the ED50 of amphetamine for inhibiting [11C]-(+)-PHNO and [11C]raclopride striatal bindings were 0.25 mg/kg and 0.63 mg/kg, respectively. Interestingly, the hyperbolic function used to fit the dose-effect data and derive ED50 values best fitted the experimental data when the maximal occupancy value was set at 100% for [11C]-(+)-PHNO and when it was set at only 80% for [11C]raclopride. These results suggest that, in contrast to what is observed with the antagonist radioligand, amphetamine-released dopamine had access to the entire population of D2-receptors recognized by [11C]-(+)-PHNO. Preliminary human PET scans with [11C]-(+)-PHNO are underway. Initial results obtained in 2 healthy volunteers show high striatal uptake with a BP of 2.66 and 2.86, respectively, as approximated using the simplified reference tissue model. These data indicate that [11C]-(+)-PHNO binding in striatum is specific for D2-receptors. The high penetration of [11C]-(+)-PHNO in brain, its high signal to noise ratio, its favourable in vivo kinetics as well as its high sensitivity to amphetamine shows that [11C]-(+)-PHNO has highly suitable characteristics for probing the high-affinity state of D2-receptors with PET.

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