Introduction
We have previously reported the development of a new high affinity dopamine D2 agonist, [11C]MNPA 1 . (R)-2-CH3O-N-n-propylnorapomorphine (MNPA) is a highly selective D2 agonist with an IC50 of 1.0 nM compared to NPA with 4.8 nM. Recently, PET imaging with D2 agonist radioligands supports preferential labeling of D2 receptors in the high affinity state2, 3. The aim of the present study was to assess the vulnerability of the in vivo binding of [11C]MNPA to pharmacological manipulation in synaptic DA assessed with PET in cynomolgus monkey and compared to that of the D2 receptor antagonist radiotracer [11C]raclopride.
Methods
A total of 32 PET measurements were performed using i.v. bolus injection of [11C]MNPA (n = 24) and [11C]raclopride (n = 8) in four cynomolgus monkeys. In each monkey a baseline measurement was followed by a pretreatment measurement in which amphetamine (AMPH at 0.1, 0.2, 0.5, and 1.0 mg/kg) was injected i.v. approximately 20 min prior to the radioligand. For each dose of AMPH, the same monkey was used in the comparison between the two radioligands. For [11C]MNPA, the mean injected radioacitivy was 55 ± 7 MBq at baseline and 56 ± 5 MBq for AMPH pretreatment. The total mass injected for [11C]MNPA was 0.55 ± 0.68 μg at baseline and 0.42 ± 0.46 μg during AMPH pretreatment. Data were analyzed with the multilinear reference tissue model (MRTM2) 4 .
Results
AMPH caused a dose-dependent reduction in [11C]MNPA binding potential of 10 ± 9% at 0.1 mg/kg, 23 ± 6% at 0.2 mg/kg, 26 ± 2% at 0.5 mg/kg and 39 ± 17% at 1.0 mg/kg. [11C]Raclopride binding was unchanged at 0.1 mg/kg but was decreased by 23% at 0.2 mg/kg, 17% at 0.5 mg/kg and 26% at 1.0 mg/kg. AMPH reduced [11C]MNPA binding to D2 receptors more profoundly than did [11C]raclopride to D2 binding at both high and low doses of amphetamine, indicating that the agonist radioligand is more sensitive to changes in endogenous dopamine concentration. Based on these results, the percentage of D2 receptors in high affinity state was calculated to be 63%.
Conclusions
These results show that the agonist radioligand [11C]MNPA is more sensitive than the antagonist radioligand [11C]raclopride to displacement by endogenous dopamine. For this reason, an agonist radioligand may contribute more to understanding dysfunction in the dopamine system in illnesses such as schizophrenia and Parkinson's disease.