Serotonin abnormalities have been related to brain disorders which afflict a large number of people and include depressive disorders which affect over 18 million and Alzheimer's disease (AD) which affects over 5 million of the American population. Serotonin 5HT1A receptors have been implicated in these disorders and are being intensively studied. Our long-term goal is to develop noninvasive imaging methods of positron emission tomography (PET) that will aid in the early diagnosis of these disorders and may therefore be useful in treatment planning. Human studies of 5-HT1A receptor have been underway using 11C-WAY-100635, 18F- MPPF and 18F-FCWAY. Although these imaging agents have provided excellent insights into several human conditions, applications have been limited due to difficulty in production, short half-life, metabolic instability and moderate signal-to-noise ratios. With the support of an NIH R21 grant application, we have developed and evaluated a new imaging agent, 18F-Mefway which contains a fluorine-18 on a primary carbon to make the compound more stable to defluorination. Mefway has high affinity for 5HT1A receptors and in rodent brain imaging studies exhibited selective binding in hippocampus and cortex with limited binding in the cerebellum. PET studies in rhesus monkeys showed 18F-Mefway binding to temporal cortex, hippocampus, raphe and other brain regions with ratios of hippocampus to cerebellum = 10. Plasma analysis indicated the presence of approx. 20-30% of 18F-Mefway and no observed defluorination. The high ratios in specific brain regions such as the hippocampus suggest that 18F-Mefway has good potential as a PET imaging agent for 5HT1A receptors in humans. Our toxicity results of Mefway suggest that a radiotracer injection of 18F-Mefway is suitable for human use. Therefore, our overall goal in this NIH R33 application is to carry out first human studies with 18F- Mefway. Initial human radiation dosimetry studies will be carried out using a PET/CT scanner on 6 subjects. The toxicity data, radiation dosimetry and chemistry standard operating procedures will all be made available through the NIMH/SNIDD Tracer database for investigators at other institutions to use 18F-Mefway for their applications. Brain distribution of 18F-Mefway will be evaluated in normal volunteers in a test-retest paradigm to establish reproducibility and imaging methodology for quantitative analysis. In order to assess the diagnostic value of 18F-Mefway in aging and mild cognitive impairment (MCI) and AD, two important areas of expertise at UCI have come together in this application. Specific hypotheses will be tested using multidisciplinary approaches that include expertise in brain imaging techniques and the Alzheimer's Disease Research Center (ADRC) at the institute for Mental Impairments and Neurological Disorders (MIND). 18F-Mefway will be evaluated in well-characterized groups of control, MCI and AD subjects and results will be correlated with clinical outcome measures of 18F-FDG, MRI and neuropsychological tests.
Development of human imaging methods for serotonin receptors will help understand several brain disorders, including anxiety, depression, epilepsy and Alzheimer's disease. This grant application will specifically have implications in the potential diagnosis, treatment planning and therapeutics development for Alzheimer's disease.
