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Design and Synthesis of Selective Serotonin Receptor Agonists for Positron Emission Tomography Imaging of the Brain
Serotonin (5‐HT) is an important neurotransmitter that is responsible for the regulation of a number of behavioral effects such as mood, appetite and sleep. Abnormalities in the serotonin system are associated with a broad range of disorders in the central nervous system (CNS) such as schizophrenia, depression, anxiety and migraine. The 5‐HT2A receptor is the primary excitatory 5‐HT receptor in the human brain and mediates the hallucinogenic effects of drugs such as lysergic acid diethylamide (LSD) and is the target of atypical antipsychotics. Positron emission tomography (PET) is a powerful technique to study receptors in the living brain and is widely used for investigating 5‐HT receptors in both human and animal studies. Currently, only antagonist PET tracers are in use for the 5‐HT2A receptor. Agonist PET tracers could selectively label 5‐HT2A receptors in the high‐affinity state and thereby serve as a better functional measure of 5‐HT2A receptor function. Furthermore, agonist PET tracers are potentially more sensitive to changes in endogenous neurotransmitter levels than antagonist tracers. The aims of this project were: 1) To design and synthesize new 5‐HT2A agonists with the aim to increase affinity and selectivity for 5‐HT2A receptor. 2) To synthesize, radiolabel and evaluate a number of 5‐HT2A agonists for use as PET tracers. These were based on some known 5‐HT2A agonists from the literature as well as newly designed compounds. We synthesized four groups of compounds derived from the N‐benzylphenethylamine scaffold. Group 1, 2 and 4 compounds were synthesized by a general strategy comprising reductive amination of the appropriate phenethylamine and benzaldehyde building blocks. The more complicated Group 3 compounds were synthesized by a variety of methods. Group 1 compounds focused on the 4‐position of the phenethylamine‐moiety with minor variations in the N‐benzyl moiety. We found that most compounds had high affinity for the 5‐HT2A, 5‐HT2B and 5‐HT2C receptors. Compounds containing a cyano‐group in the 4‐position showed high selectivity towards the 5‐HT2A receptor, a property that has previously been elusive. Group 2 compounds were designed with the aim to further investigate the 2’‐ and 3´‐ position of the N‐benzyl moiety and many of these were designed as benzo‐fused heterocycles. When necessary, the required aldehydes were synthesized de novo. The preliminary biological screening showed a mix of good and passable compounds. Some of these compounds have the highest affinity for the 5‐HT2A receptor when compared to known compounds from the literature. Group 3‐compounds were designed as conformationally restricted analogues of the known agonists 25B‐NBOMe and 25B‐NB. Most of the compounds had significantly lower binding affinity at the 5‐HT2A when compared to group 2 or 3 compounds, but the study gave valuable information on the binding conformation of N‐benzylphenethylamines. One compound (4.7) showed good selectivity for the 5‐HT2A receptor as well as high affinity. IV Group 4 compounds were designed using a homology model of the 5‐HT2A receptor made using a template from an in silico‐activated model of the human β2‐adrenergic receptor. The predicted compounds were synthesized and submitted for biological evaluation. The results obtained so far, however, show that the predicted affinity does not correlate well with the experimental results, necessitating further refinement of the model. A total of nine compounds were selected for in vivo evaluation as PET‐tracers in pigs. 6.1 ([11C]‐CIMBI‐5) was able to label 5‐HT2A receptors in the brain and the cortical binding of 6.1 was blocked by treatment with the antagonist ketanserin. 6.1 had a non‐displaceable binding potential (BPND) in the pig brain comparable to [18F]‐altanserin. Using 6.1 as the lead compound, eight other compounds as well as the 6.1 isotopomer 6.2, were synthesized and tested. Compound 6.7 ([11C]‐CIMBI‐36) showed both better brain uptake and higher targetto‐ background ratio than 6.1. The cortical BPND of 6.7 was decreased by ketanserin, indicating high selectivity for 5‐HT2A receptors.