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Design and Synthesis of Selective Serotonin Receptor Agonists for Positron Emission Tomography Imaging of the Brain

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Design and Synthesis of Selective Serotonin Receptor Agonists for Positron Emission Tomography Imaging of the Brain FACULTY OF PHARMACEUTICAL SCIENCES UNIVERSITY OF COPENHAGEN PhD thesis Martin Hansen Design and Synthesis of Selective Serotonin Receptor Agonists for Positron Emission Tomography Imaging of the Brain Academic advisor: Associate Professor, Jesper Langgaard Kristensen Submitted: 2010-12-16 I Author: Martin Hansen Title: Design and Synthesis of Selective Serotonin Receptor Agonists for Positron Emission Tomography Imaging of the Brain Print: Det Samfundsvidenskabelige Fakultets Reprocenter ISBN: 978-87-92719-00-3 9 7 8 8 7 9 2 7 1 9 0 0 3 > Advisors: Jesper Langgaard Kristensen (primary advisor) Department of Medicinal Chemistry Faculty of Pharmaceutical Sciences University of Copenhagen Mikael Begtrup Department of Medicinal Chemistry Faculty of Pharmaceutical Sciences University of Copenhagen Thomas Balle Department of Medicinal Chemistry Faculty of Pharmaceutical Sciences University of Copenhagen Nic Gillings PET and Cyclotron Unit Copenhagen University Hospital (Rigshospitalet) Assessment committee: Markus Piel Department of Nuclear Chemistry Johannes Gutenberg University Mainz Jan Kehler H. Lundbeck A/S Rasmus Prætorius Clausen Department of Medicinal Chemistry Faculty of Pharmaceutical Sciences University of Copenhagen II Abstract 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. III 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 11 ([ C]‐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 18 binding potential (BPND) in the pig brain comparable to [ F]‐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 target‐ to‐background ratio than 6.1. The cortical BPND of 6.7 was decreased by ketanserin, indicating high selectivity for 5‐HT2A receptors. IV Abstrakt Serotonin (5‐HT) er et vigtigt signalstof som er ansvarligt for regulering af en række adfærdsmæssige karaktertræk såsom humør, appetit og søvn. Uregelmæssigheder i serotoninsystemet er sammenkædet med en lang række lidelser i centralnervesystemet (CNS) såsom skizofreni, depression, angst og migræne. 5‐HT2A‐receptoren er den primære excitatoriske 5‐HT‐receptor i menneskets hjerne og tilvejebringer de hallucinogene påvirkninger medført af stoffer såsom lysergsyre diethylamid (LSD) og er et molekylært mål for atypiske antipsykotika. Positronemissionstomografi (PET) er en effektiv metode til studier af receptorer i hjernen og er vidt udbredt til undersøgelse af 5‐HT receptorer i både mennesker og forsøgsdyr. Hidtil, har kun antagonist PET sporstoffer været anvendt til studier af 5‐HT2A‐receptoren. Agonist PET sporstoffer er i stand til selektivt at radiomærke 5‐HT2A‐receptorer i højaffinitetstilstanden og dermed udgøre en bedre funktionel målemetode for 5‐HT2A receptorfunktion. Agonist PET sporstoffer er endvidere potentielt mere følsomme overfør ændringer i koncentration af endogene signalstoffer end antagonist sporstoffer. Formålet med dette projekt har været: 1) At syntetisere, radiomærke og evaluere en række 5‐HT2A‐agonister som PET sporstoffer. Disse stoffer var baseret på kendte 5‐HT2A‐agonister fra litteraturen så vel som nyligt designede stoffer. 2) At designe og syntetisere nye 5‐HT2A‐ agonister med henblik på at øge affinitet og sektivitet for 5‐HT2A‐receptoren. Vi syntetiserede fire grupper af stoffer baseret på N‐benzylphenethylamin‐skelettet. Gruppe 1‐, 2‐ og 4‐stoffer blev syntetiseret udfra en general strategi bestående af reduktiv aminering af de tilsvarende phenethylamin og benzaldehyd byggeblokke. De mere komplicerede Gruppe 3‐stoffer blev syntetiseret ved hjælp af en række metoder. Gruppe 1‐stofferne fokuserede på 4‐stillingen af phenethylamin‐kernen med mindre variationer af N‐benzyl‐delen. De fleste af disse stoffer viste sig at have høj affinitet for 5‐ HT2A, 5‐HT2B and 5‐HT2C receptorer. Stoffer indeholdende en cyano‐gruppe i 4‐stillingen udviste god selektivitet for 5‐HT2A‐receptorer, en egenskab der hidtil har været vanskelig at opnå. Gruppe 2‐stofferne blev designet med henblik på yderligere undersøgelser af 2’‐ og 3’‐ stillingen i N‐benzyl‐delen og mange af disse blev designet som benzannelerede heterocykler. De anvedte aldehyder blev om nødvendigt syntetiseret de novo. De indtil videre opnåede resultater fra den biologiske screening viste en blanding af gode og middelmådige stoffer. Nogle af disse stoffer udviste den højest målte affinitet for 5‐HT2A‐ receptoren sammenlignet med stoffer kendt fra litteraturen. Gruppe 3‐stofferne blev designet som konformationelt begrænsede analoger af de kendte 5‐HT2A agonister 25B‐NBOMe og 25B‐NB. De fleste af stofferne havde betydelig lavere bindingsaffinitet for 5‐HT2A‐receptoren sammenlignet med gruppe 2‐ og 3‐stofferne, men undersøgelsen gav vigtig information om den aktive bindingskonformation af N‐ V benzylphenethylaminerne. Et af stofferne (4.7) udviste både god affinitet samt høj selektivitet for 5‐HT2A‐receptoren. Gruppe 4‐stofferne blev designet ved hjælp af en homologimodel af 5‐HT2A‐receptoren lavet ved brug af en skabelon af en computeraktiveret model af den humane β2‐adrenerge receptor. De foreslåede stoffer blev syntetiseret og underkastet biologisk evaluering. De hidtil opnåede resultater viste imidlertid at den beregnede affinitet ikke stemte særlig godt overens med de eksperimentelle resultater hvilket betyder at yderligere udvikling af modellen er nødvendig. Ni stoffer blev udvalgt til evaluering som PET‐sporstoffer i levende grise. 6.1 ([11C]CIMBI‐5) var i stand til at radiomærke 5‐HT2A‐receptorer i hjernen og den kortikale binding blev blokeret ved behandling med antagonisten ketanserin. 6.1 havde et ikke‐displacérbart 18 bindingspotentiale (BPND) der var sammenligneligt med [ F]altanserin i grisehjernen. På baggrund af 6.1‐strukturen blev otte andre stoffer designet, syntetiseret og testet og ligeså blev 6.1‐isotopomeren 6.2. Stof 6.7 ([11C]CIMBI‐36) havde både et højere optag i hjernen samt forbedret target‐to‐background‐forhold
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