The Molecular Imaging Branch (MIB) mainly aims to exploit positron emission tomography (PET) as a radiotracer imaging technique for investigating neuropsychiatric disorders, such as depression, schizophrenia and Alzheimer's disease. Fundamental to the mission of the MIB is the development of novel radiotracers that can be used with PET to deliver new and specific information on molecular entities and processes in the living human or animal brain (e.g. regional neuroreceptor concentrations, neurotransmitter synthesis, enzyme concentrations, regional metabolism, amyloid deposition). PET is uniquely powerful for this purpose provided that it can be coupled to appropriate radioactive probes (PET radiotracers). The chemical development of these probes is the key to exploiting the full potential of PET in neuropsychiatric research, but is also recognized as being highly challenging and demanding. The PET Radiopharmaceutical Sciences Section of the MIB opened in 2002 and is now fulfilling a pressing need for a concerted effort on PET radiotracer discovery (a process that has some parallels with drug discovery). The laboratories are equipped and functioning with modern facilities for medicinal/organic chemistry and automated radiochemistry with positron-emitting carbon-11 (t1/2 = 20 min) and fluorine-18 (t1/2 = 110 min). These short-lived radioisotopes are produced on a daily basis from the adjacent cyclotrons of the NIH Clinical Center in support of this research program. The scientific program focuses on developing novel radiotracers for brain receptors or proteins implicated in neuropsychiatric disorders [e.g. cannabinoid (CB-1), serotonin (5-HT1A), alpha-2, CRF, NET, PBR, glutamate (mGluR5) and beta-amyloid protein deposits]. Initial progress in some of these areas (e.g. NET, 5-HT1A, CB-1, PBR and mGluR5)continues to be encouraging for developing successful radioligands for eventual brain imaging in human subjects in support of clinical research. Thus many candidate radioligands were prepared and then found in PET experiments to give detectable receptor-specific signals in animals in vivo with PET. Methodology underpinning these developments was also advanced in areas such as the development of new radioactive labeling agents, polymer-supported labeling reactions, microwave-enhanced chemistry and radiochemistry and the development of micro-reactors for the miniaturization of radiochemistry. These advances are seen as vital for expanding the scope for generating new radiotracers and for facilitating their applications. New analytical methods, based on for example liquid chromatography coupled to mass spectrometry, have also been developed and exploited to understand the biochemical fate of radiotracers in vivo - information which is need to fully understand the results from PET experiments and to derive meaningful measures, such as brain receptor concentrations. Productive collaborations have been established with external academic chemistry and medicinal chemistry laboratories, nationally and internationally, and also with pharmaceutical companies through a series of CRADAs (Cooperative Research and Development Agreements). Productive collaborations also exist with other centers working with PET and its associated radiochemistry and radiotracer development. This laboratory also produces several radiotracers for regular PET investigations in animals {e.g. [11CCFT (for dopamine transporters) [11C]NNC 112 (for dopamine-type-1 receptor), [18F]SPA-RQ (for NK1-receptor), [18F]Fallypride (for dopamine type-2 receptor imaging), [11C]Rolipram (for PDE4 enzyme)} and some of these have been approved by the FDA and are available for brain imaging in human subjects and clinical research protocols.
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