The impact of in vivo receptor PET measurement on neuropharmacology
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文摘
Positron emission tomography (PET) is a direct, quantitative approach to explore relationships among central neuroreceptor occupancy, psychotropic drug blood levels and clinical effects. In the development of new drugs PET may be used to define dose-response relationships and to explore mechanisms of atypical effects. We have used the radioligands [11C]raclopride and [11C]NMSP to study antipsychotic drug binding to central D2- and 5-HT2 receptors in man. Clinical treatment with classical neuroleptics induces a uniformly high (70-90 % ) D2 receptor occupancy. The risk of extrapyramidal side-effects was significantly increased in patients with D2 receptor occupancy above 80 % , whereas patients with low (below 50 % ) occupancy were less likely to receive antipsychotic effect. Receptor occupancy was high already at low drug plasma concentrations. Schizophrenic patients in remission treated with haloperidol decanoate had only an intermittently high (> 70 % ) occupancy during a 4-week injection interval. A continuously high D2 receptor occupancy may thus not be required to prevent schizophrenic relapses. Our observations point to the need to re-evaluate dose-response characteristics of the conventional neuroleptics, in particular, at doses considerably lower than previously examined.