The dopamine hypothesis of schizophrenia proposed that at least some of the symptoms of the illness are related to hyperactivity of dopamine transmission. This hypothesis was recently supported by three studies, which demonstrated that the amphetamine-induced reduction in [123I] IBZM or [11C] raclopride binding potential (BP) is elevated in patients with schizophrenia. However, the increased displacement of these D2 antagonists following amphetamine challenge in patients with schizophrenia could result from either a greater increase in synaptic dopamine concentration following amphetamine (i.e. presynaptic factors), from an increased affinity of D2 receptors for dopamine (i.e. postsynaptic factors), or from some combination of both factors. Furthermore, currently available data methods cannot tease apart the respective contributions of these factors, due to the lack of in vivo methods for measuring affinity of D2 receptors for agonists. The present application proposes to develop a probe needed to address this important issue, by developing a D2 receptor agonist as a new PET radiotracer. R-(-)-N-propyl-norapomorphine (NPA) has been chosen as the lead compound and there is preliminary data demonstrating the feasibility of labeling NPA with C-11, thus supporting the potential of [11C]NPA as a PET imaging agent. The radiolabeling procedure requires an innovative radiochemistry approach based on N-propionylation followed by reduction. This application proposes to improve the radiolabeling procedure, to characterize the in vivo binding of [11C]NPA both in rodents (to examine D2-D3 selectivity) and in baboons (to examine relative contribution of high and low agonist affinity sites to in vivo binding, vulnerability to endogenous dopamine, and vulnerability to D1-D2 interactions), and to determine the whole body dosimetry. The overall goal of this application is to develop and validate a method that will make it possible to characterize the pre- or post-synaptic nature of the dysregulation of dopamine transmission revealed by the amphetamine challenge in patients with schizophrenia. If this development is successful, clinical studies using the radiotracer will be proposed in the competitive renewal of this application. In addition to schizophrenia, this radiotracer will provide a useful tool for characterization of dopamine transmission at the D2 receptor in a variety of other conditions, such as ADHD, Parkinson's disease, and substance abuse.
| Hwang, Dah-Ren; Narendran, Raj; Laruelle, Marc (2005) Positron-labeled dopamine agonists for probing the high affinity states of dopamine subtype 2 receptors. Bioconjug Chem 16:27-31 |
| Narendran, Rajesh; Hwang, Dah-Ren; Slifstein, Mark et al. (2005) 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. J Pharmacol Exp Ther 315:80-90 |
| Hwang, Dah-Ren; Narendran, Rajesh; Huang, Yiyun et al. (2004) Quantitative analysis of (-)-N-(11)C-propyl-norapomorphine in vivo binding in nonhuman primates. J Nucl Med 45:338-46 |
| Narendran, Rajesh; Hwang, Dah-Ren; Slifstein, Mark et al. (2004) In vivo vulnerability to competition by endogenous dopamine: comparison of the D2 receptor agonist radiotracer (-)-N-[11C]propyl-norapomorphine ([11C]NPA) with the D2 receptor antagonist radiotracer [11C]-raclopride. Synapse 52:188-208 |
