Abstract
Alterations of serotonin transporters (SERT) densities have been implicated in a number of neuropsychiatric disorders, including major depression, anxiety disorders, schizophrenia, drug abuse, alcoholism, eating disorders, Alzheimer’s disease and Parkinson’s disease. In addition, it is also the primary target for widely prescribed antidepressant agents. Thus, in vivo imaging the regional brain distribution of SERT with Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) will provide an important tool to study the role of the serotonergic system in the pathophysiology and treatment of neuropsychiatric disorders. The overall objective of this dissertation is to develop and evaluate the F-18 labelled SERT imaging agents. Recently, N,N-dimethyl -2-(2-amino-4-[18F]fluorophenylthio)benzylamine (4-[18F]-ADAM) has been proved to be a potent 18F-labelled SERT imaging agent and is suitable for animal and preclinical studies. However, its low radiochemical yield (RCY) has hampered its widespread use. Hence, we have developed a method to improve its RCY. The method is based on molecular orbital calculation to derive the electron charges on carbon atom at which the nucleophilic aromatic fluorination will occur. Based on this method, we have developed an improved method to prepare 4-[18F]-ADAM in a better yield than the one previously reported (15% v.s. 6%). The calculation method thus has been used as a tool to predict the position of nucleophilic aromatic fluorination and the results show it is applicable to other class of compounds. 4-[18F]-ADAM was further characterized in rats and Formosa Rock monkeys as a potential SERT imaging agent with autoradiography and microPET. The results show 4-[18F]-ADAM is indeed a potent F-18 labelled SERT imaging agent. Toxicity and radiation dosimetry studies in rats and monkeys show that 4-[18F]-ADAM is suitable for use in human PET imaging studies (In the rats, neither the single dose nor the five daily doses of 4-[18F]-ADAM produced overt adverse effects clinically. In the monkeys, the radiation doses received by most organs ranged between 7.1 and 35.7 μGy/MBq, and the urinary bladder was considered to be the critical organ). Human studies show that 4-[18F]-ADAM PET may be a useful tool in assessing the status of SERT in human brain. In addition to 4-[18F]-ADAM, a series of its analogs, [18F]-AFM, 2-[18F]-ADAM and 4-[18F]-NMADAM were synthesized and evaluated in rats as potential SERT imaging agents. The results show that [18F]-AFM is also a potent SERT imaging agent although the low RCY (∼1%) may hamper its usage as a SERT imaging agent. In contrast, both 2-[18F]-ADAM and 4-[18F]-NMADAM are not potent SERT imaging agents.