The broad long-term objectives of the application is to increase knowledge concerning pathophysiological mechanisms in the schizophrenias.
The specific aim i s to develop a PET-scan procedure for quantitative studies on the distribution, density and affinity characteristics of Dl- dopamine receptors in the major basal ganglia and other regions in the living human brain. The methodology will be applied to a comparison between Dl receptor characteristics in drug naive schizophrenic patients and healthy volunteers. Schizophrenic patients treated with chemically different types of antipsychotic drugs will also be examined with regard to Dl-dopamine receptor characteristics. Changes in Dl-dopamine receptor characteristics during long-term neuroleptic treatment and after the determination of such treatment will also be examined. For the PET- scanning procedure the highly potent and selective Dl-dopamine receptor antagonist SCH 23390 will be used. Our preliminary results indicate that this ligand, (1) has a high selectivity for Dl receptors, (2) has a high ratio of specific to non specific binding in vivo and (3) exhibits stereospecificity with regard to binding. This ligand has been shown to have excellent kinetic properties after intravenous administration to man for quantitative PET-scan analysis or Dl receptor characteristics as Bmax and Kd. Our preliminary results indicate saturability of 11-C-SCH 23390 binding to Dl receptors in the human putamen. Bmax-values in the order of 25 pmol/g tissue were obtained. These values are similar to those we obtained in preliminary experiments using the 3H-labelled ligand (eH-SCH 23390) in human putamen obtained postmortem. The project aims at comparing PET-scan results with regard to Dl-dopamine receptor characteristics with those obtained during in vitro conditions in schizophrenic patients and healthy volunteers. The project also aims at developing a quantitative autoradiographic technique based on the use of 11-C-labelled ligands. PET-scan experiments will be performed using our new high resolution PET camera system allowing the resolution of structures in the living human brain in the order of about 5 mm. This new camera system may allow quantitation of Dl-dopamine receptor characteristics also in several limbic and cortical cerebral areas as well as in large brain stem nuclei (substantia nigra) of living human subjects.
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