Dopamine D2 receptor radiotracers [11C] (+)-PHNO and [3H]raclopride are indistinguishably inhibited by D2 agonists and antagonists ex vivo

Introduction: In vitro, the dopamine D2 receptor exists in two states, with high and low affinity for agonists. The high-affinity state is the physiologically active state thought to be involved in dopaminergic illnesses such as schizophrenia. The positron emission tomography radiotracer [C-11](+)-PHNO [C-11](+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol), being a D2 agonist, should selectively label the high-affinity state at tracer dose and therefore be more susceptible to competition by agonist as compared to the antagonist [H-3]raclopride, which binds to both affinity states. Methods: We tested this prediction using ex vivo dual-radiotracer experiments in conscious rats. D2 antagonists (haloperidol or clozapine), a partial agonist (aripiprazole), a full agonist [(-)-NPA] or the dopamine-releasing drug amphetamine (AMPH) were administered to rats prior to an intravenous coinjection of [C-11](+)-PHNO and [H-3]raclopride. Rats were sacrificed 60 min after radiotracer injection. Striatum, cerebellum and plasma samples were counted for C-11 and H-3. The specific binding ratio {SBR, i.e., [%ID/g (striatum)-%ID/g (cerebellum)]/(%ID/g (cerebellum)l was used as the outcome measure. Results: In response to D2 antagonists, partial agonist or full agonist, [C-11](+)-PHNO and [H-3]raclopride SBRs responded indistinguishably in terms of both ED50 and Hill slope (e.g., (-)-NPA ED50 values are 0.027 and 0.023 mg/kg for [C-11](+)-PHNO and[H-3]raclopride, respectively). In response to AMPH challenge, [C-11](+)-PHNO and [H-3]raclopride SBRs were inhibited to the same degree. Conclusions: We have shown that the SBRs of [C-11](+)-PHNO- and [H-3]raclopride do not differ in their response to agonist challenge. These results do not support predictions of the in vivo binding behavior of a D2 agonist radiotracer and cast some doubt on the in vivo applicability of the D2 two-state model, as described by in vitro binding experiments. (C) 2008 Elsevier Inc. All rights reserved.