Binding characteristics of high-affinity dopamine D2/D3 receptor agonists,11C-PPHT and11C-ZYY-339 in rodents and imaging in non-human primates by PET

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Abstract
We have evaluated the in vitro autoradiographic binding characteristics and in vivo brain distribution of two high‐affinity dopamine D2/D3 receptor agonists, (±)‐2‐(N‐phenethyl‐N‐1′‐11C‐propyl)amino‐5‐hydroxytetralin (11C‐PPHT) and (±)‐2‐(N‐cyclohexylethyl‐N‐1′‐11C‐propyl)amino‐5‐hydroxytetralin (11C‐ZYY‐339) in rodents and in monkeys using positron emission tomography (PET). In vitro autoradiograms in rat brain slices with 11C‐PPHT and 11C‐ZYY‐339 revealed binding to dopaminergic regions in the striata, which was substantially (>90%) displaced by 10 μM sulpiride. Striatal binding was also removed in the presence of 5‐guanylylimidophosphate (Gpp(NH)p), indicative of binding of these radiotracers to the high‐affinity (HA) state. The results of in vivo studies in rats exhibited binding of the two radiotracers to the striata (striata/cerebellum approached 2 in 30 min). The regional selectivity to the striata was reduced by preadministration of haloperidol. PET studies in male rhesus monkeys using an ECAT EXACT HR+ scanner indicated localization of 11C‐PPHT and 11C‐ZYY‐339 in the striata and thalamus. Striata to cerebellum and thalamus to cerebellum ratios were low (1.5 and 1.3, respectively, at 30 min postinjection) for both 11C‐PPHT and 11C‐ZYY‐339, apparently due to the slower nonspecific clearance from cerebellum. These findings with 11C‐PPHT and 11C‐ZYY‐339 indicate the possibility of in vivo imaging of high‐affinity state of dopamine D2/D3 receptors in both the striata and the thalamus. Synapse 54:83–91, 2004.

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