Positron emission tomography (PET) studies of neuroreceptors in vivo in man hold great promise in helping to identify the role of receptor defects in many diseases. This research is aimed at developing radiopharmaceuticals which localize in discrete regions of the brain based upon their selective affinity for the postsynaptic dopamine D2 receptor. 18F- and 11C-labeled spiperone and its analogs continue to be used for PET studies of the D2 receptor despite problems such as non-selectivity, high non-specific binding, and the difficult radiochemical synthesis of ring fluorinated spiperone. The absence of a substantially better D2 ligand is a primary reason for the use of spiperone. The work proposed here is aimed at the synthesis and evaluation of agents possessing substantially improved properties over spiperone. The goal of this work is to demonstrate the applicability of these agents for future in vivo studies in human subjects. It is anticipated that the development of these radiopharmaceuticals, their in vivo characterization, and their use will eventually aid in the study of Parkinson's disease and schizophrenia in which abnormalities in dopaminergic transmission are believed to play a role. In addition, these agents may well prove useful in studying various changes of the D2 system in aging. Non-radioactive phenyl ring fluoroalkylated benzamide compounds will be synthesized and the characterized in vitro using competitive displacement binding techniques. Those agents possessing suitable in vitro binding properties will be further assessed in vivo to determine their potential as radiopharmaceuticals for quantitative PET studies of the dopamine D2 receptor. The desired in vivo characteristics of these ligands include: good brain penetration to provide adequate counting statistics for PET studies; regional localization in D2 receptor rich areas; retention of activity in those specific areas to allow for adequate PET data acquisition; rapid clearance of non-specific uptake in non-target areas such as the cerebellum; pharmacological specificity for the dopamine D2 receptor; uptake site saturability; absence of lipophilic metabolites in the blood; and few metabolites in the brain. Those compounds which demonstrate a selective, potent binding site affinity to the D2 receptor will be radiolabeled with tritium. The tritium-labeled compound will be used in further studies to assess in vitro binding parameters of the agent. Those compounds displaying promising characteristics in vitro and in vivo will be labeled with high specific activity 18F (a short-lived positron emitter with a 110 min half-life) and utilized in PET regional localization investigations in monkeys. The dopamine D2 site densities and dissociation binding constant for the agent will be determined. PET studies in animals will determine the efficacy of the compounds as potential dopamine D2 receptor ligands for investigations in human subjects. A series of pilot experiments will be conducted in normal subjects to assess the properties of the 18F-labeled ligands in vivo to determine dopamine D2 binding parameters.
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| Mathis, C A; Bishop, J E; Gerdes, J M et al. (1992) Synthesis and evaluation of high affinity, aryl-substituted [18F]fluoropropylbenzamides for dopamine D-2 receptor studies. Int J Rad Appl Instrum B 19:571-88 |
