Functional Modulation of Neurotransmitter Receptors using PET Imaging

Over the past two decades, there have been significant advances in the ability to study the neurochemistry of the living brain using neuroreceptor radiotracers with PET imaging. The greater availability of radiotracers for neurotransmitter synthesis/metabolism, enzymes, transporters and receptors, as well as neuromodulators and second messengers has enabled the evaluation of hypotheses regarding neurotransmitter function and regulation which are generated from basic neuroscience studies, and the investigation of the neurochemical substrates of neurological and psychiatric disorders. Fundamental observations have been made with respect to 1) detecting abnormalities in the availability of neurotransmitter transporter and receptor sites in neurological and psychiatric disorders; 2) evaluating the relationship of these neurochemical measures to symptomatology; and 3) assessing the magnitude of occupancy of the initial target sites of action of psychotropic medication relative to treatment response and drug concentrations. PET provides unique quantitative in vivo information to measure acute fluctuations of synaptic transmitter release and subsequent receptor occupation. These non-invasive studies span the pharmacokinetic/pharmacodynamic evaluation of potential drug candidates, receptor occupancy as an important determinant of efficacy, the pharmacological characterization of potential mechanisms of action, and the biological characterization of disease. PET neuroreceptor imaging combined with pharmacological challenges has been introduced to measure acute fluctuations of synaptic dopamine concentrations in the living human brain. Changes in the in vivo binding of radioligands following manipulation of transmitter levels are generally believed to be driven by binding competition between the radioligand and neurotransmitter. This imaging modality has been very successful in the study of dopamine transmission at D2 receptors. However, the extension of this technique to the study of other neurotransmitter systems has proven difficult. There is recent evidence suggesting that simple binding competition might not be the only phenomenon regulating transmitter-radioligand interactions in vivo. Emerging data indicate that receptor trafficking might also be involved. A better understanding of the mechanisms underlying these interactions should significantly increase our knowledge of neurotransmission and its pathological alterations.