Design, synthesis and biological evaluation of small molecule-based PET radioligands for the 5-hydroxytryptamine 7 receptor

Tiwari, Anjani K.; Yui, Joji; Pooja, .; Aggarwal, Swati; Yamasaki, Tomoteru; Xie, Lin; Chadha, Nidhi; Zhang, Y.; Fujinaga, Masayuki; Shimoda, Yoko; Kumata, Katsushi; Mishra, Anil K.; Ogawa, Michio; Zhang, M.-R.

doi:10.1039/c4ra15833d

Cited by 10 publications

(12 citation statements)

References 27 publications

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“…2) a literature search made us realize that an arylimidazole 5-HT 7 R ligand was recently described, although no SAR studies were reported 46 . The compound, 5-(4-([ 11 C]methoxyphenyl)-1-methyl-4-nitro-1 H -imidazole, 2a , has been developed as a PET radioligand.…”

Section: Resultsmentioning

confidence: 99%

“…After acquiring highly encouraging initial results for compounds 1a and 1b ( K i 5-HT7 = 385 nM and 50 nM, respectively, selectivity over 5-HT 1A R > 11-fold, Fig. 2 ) a literature search made us realize that an arylimidazole 5-HT 7 R ligand was recently described, although no SAR studies were reported 46 . The compound, 5-(4-([ 11 C]methoxyphenyl)-1-methyl-4-nitro-1 H -imidazole, 2a , has been developed as a PET radioligand.…”

Section: Resultsmentioning

confidence: 99%

“…However, we were not able to reproduce the results presented by Tiwari et al . 46 . In our radioligand displacement binding assays compound 2a did not bind to 5-HT 7 R and 5-HT 1A R (binding curves of compound 2a can be found in Supporting Information).…”

Section: Resultsmentioning

confidence: 99%

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Low-basicity 5-HT7 Receptor Agonists Synthesized Using the van Leusen Multicomponent Protocol

Hogendorf

Kurczab

et al. 2017

Sci Rep

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A series of 5-aryl-1-alkylimidazole derivatives was synthesized using the van Leusen multicomponent reaction. The chemotype is the first example of low-basicity scaffolds exhibiting high affinity for 5-HT 7 receptor together with agonist function. The chosen lead compounds 3-(1-ethyl-1H-imidazol-5-yl)-5-iodo-1H-indole (AGH-107, 1o, K i 5-HT7 = 6 nM, EC 50 = 19 nM, 176-fold selectivity over 5-HT 1A R) and 1e (5-methoxy analogue, K i 5-HT7 = 30 nM, EC 50 = 60 nM) exhibited high selectivity over related CNS targets, high metabolic stability and low toxicity in HEK-293 and HepG2 cell cultures. A rapid absorption to the blood, high blood-brain barrier permeation and a very high peak concentration in the brain (C max = 2723 ng/g) were found for 1o after i.p. (5 mg/kg) administration in mice. The compound was found active in novel object recognition test in mice, at 0.5, 1 and 5 mg/kg. Docking to 5-HT 7 R homology models indicated a plausible binding mode which explain the unusually high selectivity over the related CNS targets. Halogen bond formation between the most potent derivatives and the receptor is consistent with both the docking results and SAR. 5-Chlorine, bromine and iodine substitution resulted in a 13, 27 and 89-fold increase in binding affinities, respectively, and in enhanced 5-HT 1A R selectivity.Within the serotonergic system, 5-HT 7 , the last identified serotonin receptor, is one of the most valuable drug targets 1 . Discovered independently by three laboratories in 1993 2-4 , 5-HT 7 R was thought to function by being coupled to G s to stimulate intracellular production of cAMP, but it was later found to also be coupled to G 12 which is an alternative signal transduction pathway 5 . 5-HT 7 R is expressed in the central nervous system (thalamus, hypothalamus, hippocampus and cortex) as well as peripherally (pancreas, spleen, coronary artery, ileum and intestine) [3][4][5][6] . Experiments using animal models have shown that the receptor is involved in many physiological processes, i.e. the regulation of body temperature 7 , smooth muscle relaxation of cerebral arteries 8 , circadian rhythm, learning and memory 9-13 , as well as pathophysiological processes such as mood disorders, anxiety 14 , inflammatory processes in the CNS 15 , schizophrenia 16 and pain 17,18 . 5-HT 7 R antagonists have been proposed as potential drugs targeting depression 19,20 . There have been less conclusive reports on potential anxiolytic 21,22 , analgesic 17 and antipsychotic properties of the receptor ligands 23,24 . It was established that 5-HT 7 R blockade can induce promnesic effects indicating the possibility of developing atypical procognitive antidepressants 25 .There are several 5-HT 7 R agonists available to serve as molecular probes. These include small, low-weight molecules, e.g. AS-19 26 , RA-7 7 , 5-carboxyamidotryptamine (5-CT), 5-methoxytryptamine, 8-OH-DPAT 27 , and lysergic acid derivatives 28 and long-chain diphenylpiperazines (LP-12, LP-44, LP-211) developed by . None of these compounds qualify as perfect...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Low-basicity 5-HT7 Receptor Agonists Synthesized Using the van Leusen Multicomponent Protocol

Hogendorf

Kurczab

et al. 2017

Sci Rep

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“…The binding affinity of receptor‐ligands was calculated in terms of glide XP score. Interaction with 5HT 1A and 5HT 7 was performed with homology modelling as mentioned in our previous work [27] . The best pose was selected on the basis of glide score (G‐score) and the interactions formed between the designed ligands and active site of PDB.…”

Section: Resultsmentioning

confidence: 99%

Gd(III)‐DO3A‐SBMPP: An Effort to Develop the MRI Contrast Agent with Enhanced Relaxivity

et al. 2016

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Rational design of a new class of MR (magnetic resonance) contrast agent for enhance relaxivity has been described. The click chemistry was employed to incorporate two moieties of 1‐(2‐methoxyphenyl)piperazine and serinol as a linker to enhance the affinity at the recognition sites. The designed ligand was attached to DO3A to synthesize DO3A‐serinol‐bis‐MPP (SBMPP) in 89 % yield. Gd‐DO3A‐SBMPP showed enhanced relaxivity r1 of 10.85±0.04 mM−1s−1 as compare to known gadolinium based contrast agents in clinics. The potentiometric titration of gadolinium loaded SBMPP exhibited strong selectivity for Gd3+ over physiological metal ions such as Zn2+ and Cu2+. Thus, the synthesis of bis‐conjugate could be observed as novel, instructive and initial proof of concept for the synthesis of MR contrast agent with enhanced relaxivity. The preliminary findings show the good biocompatibility and potential functionalities of MPP analogue to target brain regions through MRI.

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“…Another specific agonist of 5‐HT 7, [ 11 C]PM20, has been evaluated in small animals which showed promising results. Subsequently, a new biaryl derivative 5‐(4‐(methoxyphenyl)‐1‐methyl‐4‐nitro‐1H‐imidazole with substituted azoles is also studied as a 5‐HT 7 PET ligand (Di Pilato et al, 2014; Shimoda et al, 2013; Tiwari et al, 2015). Unfortunately, both ligands were unable to reach the ideal level as a 5‐HT 7 PET ligand.…”

Section: Introductionmentioning

confidence: 99%

Benzoxazolone‐arylpiperazinyl scaffold‐based PET ligand for 5‐HT₇: Synthesis and biological evaluation

Kumari

Adhikari

Singh

et al. 2022

Drug Development Research

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Efforts are underway to improve the diagnosis and treatment for neurological disorders like depression, anxiety, epilepsy, and schizophrenia. The G-protein-coupled receptors (GPCRs) 5-HT 7 receptor, the most recently identified member of 5-HT receptor family dysregulation has an association with various central nervous system (CNS) disorders and its ligands have an edge as potential therapeutics. Here, we report the synthesis, characterization, and biological evaluation of diversely substituted methoxy derivatives of 2-benzoxazolone arylpiperazine for targeting 5-HT 7 receptors. Out of all derivatives, only C-2 substituted derivative, 3-(4-(4-(2methoxyphenyl)piperazin-1-yl)butyl)benzoxazol-2(3H)-one/ABO demonstrate a high affinity for human 5-HT 7 receptors. [ 11 C]ABO was obtained by O-methylation of desmethyl-precursor using [ 11 C]CH 3 OTf in the presence of NaOH giving a high radiochemical yield of 25 ± 12% (decay-corrected, n = 7) with stability up to 1.5 h postradiolabeling. In vitro autoradiography displays binding of [ 11 C]ABO in accordance with 5-HT 7 distribution with a decrease of approximately 80% and 40% activity in the hippocampus and cerebellum brain region when administered with 10 µM cold ligand. Prefatory positron emission tomography scan results in Sprague-Dawley (SD) rat brain revealed fast and high radioactivity build-up in 5-HT 7 receptor-rich regions, namely, the hippocampus (2.75 ± 0.16 SUV) and the cerebral cortex (2.27 ± 0.02 SUV) establishing selective targeting of [ 11 C]ABO. In summary, these pieces of data designate [ 11 C]ABO as a promising 5-HT 7 receptor ligand that can have possible roles in clinics after its further optimization on different animal models. K E Y W O R D S benzoxazolone, long chain arylpiperazine, PET, serotonin receptors 1 | INTRODUCTION 5-Hydroxytryptamine (5-HT) is the oldest monoamine neurotransmitters, and is found throughout the central nervous system (CNS) and normally implicated in various psychological and behavioral dysfunctions. It has been classified into seven families (5-HT 1−7 )based on their functions and structure. 5-HT 7 was the last entry in this family which was found quite similar to 5-HT 1A (Bard et al., 1993;Plassat et al., 1993). Based on these structural similarities, the design, and development of specific 5-HT 7 ligand have been found a tedious assignment for researchers.In the human brain, the subregion diencephalon (hypothalamus and thalamus) and hippocampus depict elevated concentrations of 5-HT 7 while in periphery stomach, liver, pancreas, kidney, spleen,

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Design, synthesis and biological evaluation of small molecule-based PET radioligands for the 5-hydroxytryptamine 7 receptor

Abstract: A new prospective approach for PET imaging of 5-HT7 by a small molecule ligand.

Cited by 10 publications

References 27 publications

Low-basicity 5-HT7 Receptor Agonists Synthesized Using the van Leusen Multicomponent Protocol

Low-basicity 5-HT7 Receptor Agonists Synthesized Using the van Leusen Multicomponent Protocol

Gd(III)‐DO3A‐SBMPP: An Effort to Develop the MRI Contrast Agent with Enhanced Relaxivity

Benzoxazolone‐arylpiperazinyl scaffold‐based PET ligand for 5‐HT₇: Synthesis and biological evaluation

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Design, synthesis and biological evaluation of small molecule-based PET radioligands for the 5-hydroxytryptamine 7 receptor

Abstract: A new prospective approach for PET imaging of 5-HT7 by a small molecule ligand.

Cited by 10 publications

References 27 publications

Low-basicity 5-HT7 Receptor Agonists Synthesized Using the van Leusen Multicomponent Protocol

Low-basicity 5-HT7 Receptor Agonists Synthesized Using the van Leusen Multicomponent Protocol

Gd(III)‐DO3A‐SBMPP: An Effort to Develop the MRI Contrast Agent with Enhanced Relaxivity

Benzoxazolone‐arylpiperazinyl scaffold‐based PET ligand for 5‐HT7: Synthesis and biological evaluation

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Benzoxazolone‐arylpiperazinyl scaffold‐based PET ligand for 5‐HT₇: Synthesis and biological evaluation