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

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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. 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.
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... [3][4][5][6] Though drawing less scrutiny than better known psychedelics like LSD or psilocybin, strictly speaking these are not novel materials. [7,8] In contrast, N-benzyl phenylethanamines progressed from earliest published reports [9][10][11][12][13][14] and subsequent research [15,16] to ready grey-market availability and ultimately prohibition -in the UK [17,18] and the USA [19] -in less than 20 years. ...
... This signal may result from intramolecular hydrogen bonding and proton exchange between the phenolic ortho-hydroxyl group of the NBOH moiety and the protonated amine, perhaps facilitated by the hydrogen-bond accepting solvent. However, both Heim [15] and Hansen [16,37] report a discrete and sharp phenolic peak in DMSO-d6. ...
... Also, the α-and β-methylene groups have coalesced into a 4H multiplet, the familiar splitting pattern of the NBOMe/NBOH benzyl protons is absent, and a 2H singlet from the benzodioxole methylene group is seen at 5.96 ppm. 1 H NMR spectra have been reported for 2C-B in DMSO-d6, [29] in CDCl3, [15,40] in CD3OD, [41][42][43] and in D2O [31,32,42,44] ; for 2C-C in CDCl3 [45,46] and in D2O [31,46] ; for 2C-I in CDCl3 [43] and in D2O [31,32,47,48] ; for bk-2C-B in DMSO-d6 [38,39] and in CDCl3. [49] 1 H NMR spectra have been reported for 25B-NBOMe in DMSO-d6 [16,37] and in CDCl3 [15,50] ; for 25C-NBOMe in DMSO-d6, [37] in CDCl3, [51] and in CD3OD [16,52] ; for 25I-NBOMe in DMSO-d6, [16,37,53] in CDCl3, [15,[54][55][56] and in CD3OD [57] ; for 25I-NBOH in DMSO-d6 [15,16,37] ; for 25I-NBMD in DMSO-d6. [16,37] The 4-R family: 4-alkyl-2,5-dimethoxyphenyl pattern In the P3: 2C-E spectrum, the classical ethyl group splitting pattern is seen: a 2H quartet and 3H triplet. ...
... [24,34] Of particular importance is 2-(4-bromo-2,5-dimethoxyphenyl)-N-(2methoxybenzyl)ethan-1-amine (25B-NBOMe, see Scheme 2.), also known as CIMBI-36, which was developed as a positron emission tomography (PET) tracer for visualization of 5-HT2AR in the human brain. [37,38] This radioligand has been used to image and quantify 5-HT2AR receptor levels in the human brain, and it has been used in several PET studies in both animals and humans. [39][40][41][42][43] ...
... [25,26] 25CN-NBOH displays high binding affinity to the 5-HT2AR and robust selectivity for 5-HT2AR over 5-HT2BR and 5-HT2CR in various radioligand binding assays and functional assay, see detailed discussion below. [3,25,38,45,46] Synthesis and availability 25CN-NBOH is commercially available from several vendors, but also accessible through simple chemical transformations from inexpensive starting materials. The original procedure was recently improved, providing access to the compound from the commercially available 2,5-dimethoxyphenethylamime (2C-H) in 5 steps, as illustrated in Scheme 4. [47,48] Scheme 4. Synthetic overview for synthesis of 25CN-NBOH. ...
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4-(2-((2-hydroxybenzyl)amino)ethyl)-2,5-dimethoxybenzonitrile (25CN-NBOH) was first reported as a potent and selective serotonin 2A receptor (5-HT 2A R) agonist in 2014, and it has since found extensive use as a pharmacological tool in a variety of in vitro, ex vivo and in vivo studies. 25CN-NBOH is readily available from a synthetic perspective using standard chemical transformations, and displays favorable physiochemical properties in terms of stability and solubility. Due to its superior selectivity for 5-HT 2A R, 25CN-NBOH has been used to investigate the effects of selective 5-HT 2A R activation in vivo, and has thus become an important pharmacological tool for the exploration of 5-HT 2A R signaling in a range of animal models. In the present review, we outline the discovery of 25CN-NBOH, its pharmacological profile and major findings from studies where it has been used.
... Efforts in the pursuit of novel diagnostic, therapeutic, and research tools resulted in several notable implementations of N-benzylphenethylamines (NBPEAs), such as utilization of 2-(4-bromo-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethan-1-amine (25B-NBOMe) as a positron emission tomography (PET) radiolabeled tracer known as [ 11 C]Cimbi-36, which has been used for visualization and quantification of serotonin 2A Metabolites 2021, 11, 212 2 of 18 receptor in the human brain [2,3], or the discovery of 4-(2-((2-hydroxybenzyl)amino)ethyl)-2,5-dimethoxybenzonitrile (25CN-NBOH) as one of the most selective agonist ligands for the 5-HT2A receptor known to date [4][5][6]. ...
... The synthesis of 25CN-NBOMe was first published in the literature in 2010 among a series of tenths of compounds with structural variations, determining their effects on receptor binding affinities and functional activities at 5-HT2A and 5-HT2C receptors [4,5]. ...
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N-Benzylphenethylamines are novel psychedelic substances increasingly used for research, diagnostic, or recreational purposes. To date, only a few metabolism studies have been conducted for N-2-methoxybenzylated compounds (NBOMes). Thus, the available 2,5-dimethoxy-4-(2-((2-methoxybenzyl)amino)ethyl)benzonitrile (25CN-NBOMe) metabolism data are limited. Herein, we investigated the metabolic profile of 25CN-NBOMe in vivo in rats and in vitro in Cunninghamella elegans (C. elegans) mycelium and human liver microsomes. Phase I and phase II metabolites were first detected in an untargeted screening, followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) identification of the most abundant metabolites by comparison with in-house synthesized reference materials. The major metabolic pathways described within this study (mono- and bis-O-demethylation, hydroxylation at different positions, and combinations thereof, followed by the glucuronidation, sulfation, and/or N-acetylation of primary metabolites) generally correspond to the results of previously reported metabolism of several other NBOMes. The cyano functional group was either hydrolyzed to the respective amide or carboxylic acid or remained untouched. Differences between species should be taken into account in studies of the metabolism of novel substances.
... In summary, our results show that 25CN-NBOH induces a temperature-dependant increase in heart rate, decrease in respiration rate, and increase in arterial blood flow, as measured by pulse oximetry drawn from brain-supplying (most likely carotid) arteries. 25CN-NBOH is the most selective 5-HT 2 R agonist at present, with robust preference for 5-HT 2A R over 5-HT 2B and 5-HT 2C receptors and lack of appreciable affinity for adrenergic receptors (Hansen, 2010;Halberstadt et al., 2016;Jensen et al., 2017). Given the primary relevance of 5-HT 2A Rs for the psychedelic principle along with the immediacy of neck-arterial blood flow to the brain's metabolic demands, our results might contribute to a more systemic understanding of how psychedelic-5-HT 2A R interactions translates into the brain (haemo-)dynamics characteristic for psychedelia. ...
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Background Serotonin 2A receptors, the molecular target of psychedelics, are expressed by neuronal and vascular cells, both of which might contribute to brain haemodynamic characteristics for the psychedelic state. Aim Aiming for a systemic understanding of psychedelic vasoactivity, here we investigated the effect of N-(2-hydroxybenzyl)-2,5-dimethoxy-4-cyanophenylethylamine – a new-generation agonist with superior serotonin 2A receptor selectivity – on brain-supplying neck-arterial blood flow. Methods We recorded core body temperature and employed non-invasive, collar-sensor based pulse oximetry in anesthetised mice to extract parameters of local blood perfusion, oxygen saturation, heart and respiration rate. Hypothesising an overlap between serotonergic pulse- and thermoregulation, recordings were done under physiological and elevated pad temperatures. Results N-(2-hydroxybenzyl)-2,5-dimethoxy-4-cyanophenylethylamine (1.5 mg/kg, subcutaneous) significantly increased the frequency of heart beats accompanied by a slight elevation of neck-arterial blood flow. Increasing the animal-supporting heat-pad temperature from 37°C to 41°C enhanced the drug’s effect on blood flow while counteracting tachycardia. Additionally, N-(2-hydroxybenzyl)-2,5-dimethoxy-4-cyanophenylethylamine promoted bradypnea, which, like tachycardia, quickly reversed at the elevated pad temperature. The interrelatedness of N-(2-hydroxybenzyl)-2,5-dimethoxy-4-cyanophenylethylamine’s respiro-cardiovascular effects and thermoregulation was further corroborated by the drug selectively increasing the core body temperature at the elevated pad temperature. Arterial oxygen saturation was not affected by N-(2-hydroxybenzyl)-2,5-dimethoxy-4-cyanophenylethylamine at either temperature. Conclusions Our findings imply that selective serotonin 2A receptor activation modulates systemic cardiovascular functioning in orchestration with thermoregulation and with immediate relevance to brain-imminent neck (most likely carotid) arteries. As carotid branching is a critical last hub to channel cardiovascular output to or away from the brain, our results might have implications for the brain haemodynamics associated with psychedelia.
... 7 These substances were found to be potent 5HT 2A receptor agonists. [8][9][10][11] Furthermore, Braden et al could show that the addition of the N-methoxybenzyl group to 2C-X compounds significantly increases their affinity to the 5-HT 2A receptor and therefore results in higher behavioral responses. 12 NBOMes and their homologues produce psycho-and cardiovascular stimulant effects in addition to hallucinations. ...
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Numerous 2,5‐dimethoxy‐N‐benzylphenethylamines (NBOMe), carrying a variety of lipophilic substituents at the 4‐position, are potent agonists at 5‐hydroxytryptamine (5HT2A) receptors and show hallucinogenic effects. The present study investigated the metabolism of 25D‐NBOMe, 25E‐NBOMe and 25N‐NBOMe using the microsomal model of pooled human liver microsomes (pHLM) and the microbial model of the fungi Cunninghamella elegans (C. elegans). Identification of metabolites was performed using liquid chromatography‐high resolution‐tandem mass spectrometry (LC‐HR‐MS/MS) with a QqToF instrument. In total, 36 25D‐NBOMe phase I metabolites, 26 25E‐NBOMe phase I metabolites and 24 25N‐NBOMe phase I metabolites were detected and identified in pHLM. Furthermore, 14 metabolites of 25D‐NBOMe, eleven 25E‐NBOMe metabolites and nine 25N‐NBOMe metabolites could be found in C. elegans. The main biotransformation steps observed were oxidative deamination, oxidative N‐dealkylation also in combination with hydroxylation, oxidative O‐demethylation possibly combined with hydroxylation, oxidation of secondary alcohols, mono‐ and dihydroxylation, oxidation of primary alcohols and carboxylation of primary alcohols. Additionally, oxidative di‐O‐demethylation for 25E‐NBOMe and reduction of the aromatic nitro group and N‐acetylation of the primary aromatic amine for 25N‐NBOMe took place. The resulting 25N‐NBOMe metabolites were unique for NBOMe compounds. For all NBOMes investigated, the corresponding 2,5‐dimethoxyphenethylamine (2C‐X) metabolite was detected. This study reports for the first time 25X‐NBOMe N‐oxide metabolites and hydroxylamine metabolites, which were identified for 25D‐NBOMe and 25N‐NBOMe and all three investigated NBOMes, respectively. C. elegans was capable of generating all main biotransformation steps observed in pHLM and might therefore be an interesting model for further studies of new psychoactive substances (NPS) metabolism.
... Amongst these, as indicated by an extensive follow-up in vitro receptor binding screening, the newly designed N-(2-hydroxy)benzyl substituted 4-cyano-2,5-dimethoxyphenethylamine (25CN-NBOH) turned out to be one of the most promising candidates: 25CN-NBOH is characterized by a high affinity for 5-HT 2A receptors (in vitro radioligand competition binding, av. Ki: ∼1.72 nM), by a ≥ 100-fold selectivity for binding to this receptor as compared to a plethora of non-5-HT 2 targets (including other G-protein coupled receptors, ion channels, transporters, and enzymes), and robust 5-HT 2A selectivity over 5-HT 2B/2C receptors (K i in vitro [averaged across studies]: ∼56 nM for 5-HT 2B and ∼83 nM for 5-HT 2C , respectively) (Hansen, 2010;Halberstadt et al., 2016;Jensen et al., 2017). Therefore, 25CN-NBOH appears advantageous over other currently used 5-HT 2A agonists subjected to a similarly scrutinous receptor profiling (Ray, 2010; see also Ki database). ...
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The serotonin (5-HT) 2A receptor is the primary molecular target of serotonergic hallucinogens, which trigger large-scale perturbations of the cortex. Our understanding of how 5-HT2A activation may cause the effects of hallucinogens has been hampered by the receptor unselectivity of most of the drugs of this class. Here we used 25CN-NBOH (N-(2-hydroxybenzyl)-2,5-dimethoxy-4-cyanophenylethylamine), a newly developed selective 5-HT2A agonist, and tested it with regard to the head-twitch-response (HTR) model of 5-HT2A activity and effects on locomotion. 25CN-NBOH evoked HTRs with an inverted u-shape-like dose-response curve and highest efficacy at 1.5 mg/kg, i.p. HTR occurrence peaked within 5 min after agonist injection, and exponentially decreased to half-maximal frequency at ~11 min. Thorough habituation to the experimental procedures (including handling, saline injection, and exposure to the observational boxes 1 day before the experiment) facilitated the animals' response to 25CN-NBOH. 25CN-NBOH (1.5 mg/kg, i.p.) induced HTRs were blocked by the 5-HT2A antagonist ketanserin (0.75 mg/kg, 30 min pre), but not by the 5-HT2C antagonist SB-242084 (0.5 mg/kg, i.p., 30 min pre). SB-242084 instead slightly increased the number of HTRs occurring at a 3.0-mg/kg dose of the agonist. Apart from HTR induction, 25CN-NBOH also modestly increased locomotor activity of the mice. Repeated once-per-day injections (1.5 mg/kg, i.p.) led to reduced occurrence of 25CN-NBOH induced HTRs. This intermediate tolerance was augmented when a second (higher) dose of the drug (3.0 mg/kg) was interspersed. Short-interval tolerance (i.e., tachyphylaxis) was observed when the drug was injected twice at intervals of 1.0 and 1.5 h at either dose tested (1.5 mg/kg and 0.75 mg/kg, respectively). Inducing ketanserin-sensitive HTRs, which are dependent on environmental valences and which show signs of tachyphylaxis and tolerance, 25CN-NBOH shares striking features common to serotonergic hallucinogens. Given its distinct in vitro selectivity for 5-HT2A over non5-HT2 receptors and its behavioral dynamics, 25CN-NBOH appears to be a powerful tool for dissection of receptor-specific cortical circuit dynamics, including 5-HT2A related psychoactivity.
... 25C-NBOMe (2-(4-chloro-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethan-1amine) and 25I-NBOMe (2-(4-iodo-2,5-dimethoxyphenyl)-N-[(2methoxyphenyl)methyl]ethan-1-amine) are structurally related potent hallucinogenic drugs. Originating from research on serotonergic receptors, 25I-NBOMe was discovered by Ralf Heim and is described in his PhD thesis from 2003 [1] while 25C-NBOMe and its effects were first reported by Ettrup et al. and Hansen in 2010 [2][3] . Recreational NBOMe consumption is known since 2010 [4] and has led to non-fatal and fatal intoxications [5][6][7][8][9][10][11][12][13][14][15][16][17][18] . ...
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Background: Although the principal brain target that all antipsychotic drugs attach to is the dopamine D2 receptor, traditional or typical antipsychotics, by attaching to it, induce extrapyramidal signs and symptoms (EPS). They also, by binding to the D2 receptor, elevate serum prolactin. Atypical antipsychotics given in dosages within the clinically effective range do not bring about these adverse clinical effects. To understand how these drugs work, it is important to examine the atypical antipsychotics' mechanism of action and how it differs from that of the more typical drugs. Method: This review analyzes the affinities, the occupancies, and the dissociation time-course of various antipsychotics at dopamine D2 receptors and at serotonin (5-HT) receptors, both in the test tube and in live patients. Results: Of the 31 antipsychotics examined, the older traditional antipsychotics such as trifluperazine, pimozide, chlorpromazine, fluphenazine, haloperidol, and flupenthixol bind more tightly than dopamine itself to the dopamine D2 receptor, with dissociation constants that are lower than that for dopamine. The newer, atypical antipsychotics such as quetiapine, remoxipride, clozapine, olanzapine, sertindole, ziprasidone, and amisulpride all bind more loosely than dopamine to the dopamine D2 receptor and have dissociation constants higher than that for dopamine. These tight and loose binding data agree with the rates of antipsychotic dissociation from the human-cloned D2 receptor. For instance, radioactive haloperidol, chlorpromazine, and raclopride all dissociate very slowly over a 30-minute time span, while radioactive quetiapine, clozapine, remoxipride, and amisulpride dissociate rapidly, in less than 60 seconds. These data also match clinical brain-imaging findings that show haloperidol remaining constantly bound to D2 in humans undergoing 2 positron emission tomography (PET) scans 24 hours apart. Conversely, the occupation of D2 by clozapine or quetiapine has mostly disappeared after 24 hours. Conclusion: Atypicals clinically help patients by transiently occupying D2 receptors and then rapidly dissociating to allow normal dopamine neurotransmission. This keeps prolactin levels normal, spares cognition, and obviates EPS. One theory of atypicality is that the newer drugs block 5-HT2A receptors at the same time as they block dopamine receptors and that, somehow, this serotonin-dopamine balance confers atypicality. This, however, is not borne out by the results. While 5-HT2A receptors are readily blocked at low dosages of most atypical antipsychotic drugs (with the important exceptions of remoxipride and amisulpride, neither of which is available for use in Canada) the dosages at which this happens are below those needed to alleviate psychosis. In fact, the antipsychotic threshold occupancy of D2 for antipsychotic action remains at about 65% for both typical and atypical antipsychotic drugs, regardless of whether 5-HT2A receptors are blocked or not. At the same time, the antipsychotic threshold occupancy of D2 for eliciting EPS remains at about 80% for both typical and atypical antipsychotics, regardless of the occupancy of 5-HT2A receptors. Relevance: The "fast-off-D2" theory, on the other hand, predicts which antipsychotic compounds will or will not produce EPS and hyperprolactinemia and which compounds present a relatively low risk for tardive dyskinesia. This theory also explains why L-dopa psychosis responds to low atypical antipsychotic dosages, and it suggests various individualized treatment strategies.