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NEUROPHARMACOLOGY

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

Departments of Psychiatry (R.N., D.-R.H., M.S., Y.Hw., Y.Hu., J.E., O.G., E.S., D.M., M.L.) and Radiology (D.-R.H., M.L.), Columbia University College of Physicians and Surgeons and the New York State Psychiatric Institute, New York, New York

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.

Address correspondence to: Dr. R. Narendran, New York State Psychiatric Institute, 1051 Riverside Dr., Box #31, New York, NY 10032. E-mail: rn2012{at}columbia.edu