Measurement of the proportion of D₂ receptors configured in state of high affinity for agonists in vivo: A positron emission tomography study using [¹¹C]N-propyl-norapomorphine and [¹¹C] raclopride in baboons

Dopamine D₂ receptors are configured in interconvertible states of high (D_{2 high}) or low (D_{2 low}) affinity for agonists. The in vivo proportion of sites in high-affinity state remains poorly documented. Previous studies have established the D2 agonist [ ¹¹C]N-propyl-norapomorphine (NPA) as a suitable positron emission tomography radiotracer for imaging D_{2 high} in the living brain. To elucidate the proportion of D₂ receptors configured in D _{2 high} states in vivo, imaging studies were conducted in three baboons with both [¹¹C]NPA and the D₂ receptor antagonist [¹¹C]raclopride. These studies were performed under noncarrier-and carrier-added conditions, to compare the B_max of [¹¹C]NPA and [¹¹C]raclopride in the same animals. [¹¹C]raclopride in vivo K_D and B_max were 1.59 ± 0.28 nM (n = 3) and 27.3 ± 3.9 nM (n = 3), respectively. The in vivo K_D of [ ¹¹C]NPA was 0.16 ± 0.01 nM (n = 3), consistent with its affinity for D_{2 high} reported in vitro. The maximal density of sites for [¹¹C]NPA was 21.6 ± 2.8 nM (n = 3), i.e., 79% of the [¹¹C]raclopride B_max. This result suggested that 79% of D₂ receptors are configured as D_{2 high} in vivo. This large proportion of D_{2 high} sites might explain the vulnerability of D₂ radiotracers to competition by endogenous dopamine, and is consistent with a previous report that the in vivo binding of agonist radiotracer [¹¹C]NPA is more vulnerable to competition by endogenous dopamine than that of antagonist radiotracer [¹¹C]raclopride.