Synthesis and in Vivo Evaluation of Fluorine-18 and Iodine-123 Labeled 2β-Carbo(2-fluoroethoxy)-3β-(4‘-((<i>Z</i>)-2-iodoethenyl)phenyl)nortropane as a Candidate Serotonin Transporter Imaging Agent

Plisson, Christophe; Js, Stehouwer; Rj, Voll; Howell, LL; Votaw,; Mj, Owens; Goodman, Murray

doi:10.1021/jm061303s

Cited by 14 publications

(14 citation statements)

References 21 publications

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“…Stepwise treatment of 13 with Troc-Cl in the presence of proton sponge followed by removal of the Troc group with Zn/AcOH gave the secondary amine 15 . [8, 9] The N -phenethyl moiety was introduced by reacting 15 with 2-(bromoethyl)benzene and sodium bicarbonate in DMF at 50°C. Removal of the O-methyl protecting group with BBr 3 gave the N -phenethyl substituted compound 3b .…”

Section: Chemistrymentioning

confidence: 99%

Probes for narcotic receptor mediated phenomena. 44. Synthesis of an N-substituted 4-hydroxy-5-(3-hydroxyphenyl)morphan with high affinity and selective μ-antagonist activity

Iyer

Lee

Deschamps

et al. 2012

European Journal of Medicinal Chemistry

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A simple three-step synthesis of 5-(3-hydroxyphenyl)-2-methyl-2-azabicyclo[3.3.1]nonan-4-ol (3a) was achieved using an osmium tetroxide mediated oxidation of the known intermediate 6. A pyrrolidine-ring variant of 3a (3-(7-(hydroxymethyl)-6-methyl-6-azabicyclo[3.2.1]octan-1-yl)phenol (5)) was isolated when other routes were used. The epimeric hydroxy analogue 4a was synthesized by simple inversion of the stereochemistry at C-4. Both N-methyl (3a and 4a) and N-phenethyl (3b and 4b) derivatives were synthesized. The compounds were examined for their opioid receptor affinity and the N-phenethyl analogue 3b was found to have relatively weak affinity for the μ-opioid receptor (Ki = 74 nM). However, the N-phenethyl analogue of the C-4 epimer, 4b, had about 15 fold higher affinity than 3b and was selective for the μ-opioid receptor (Ki = 4.6 nM). Compound 4b was a moderately potent μ-opioid antagonist (Ke = 12 nM), as determined by [35S]GTP-γ-S assays. Compounds 3b and 4b were energy minimized at the level of B3LYP/6-31G*, and then overlaid onto the 5-phenylmorphan, the (1R,5R,9S)-(−)-enantiomer of 2b (Fig. 1) with the α or β-OH group at the C-9 position. The spatial orientation of the hydroxyl moiety in 3b, 4b, 2a, and 2b is proposed to be the structural requirement for high μ-opioid receptor binding affinity and their agonist or antagonist activity. The modest change in spatial position of the hydroxyl moiety, and not the N-substituent, induced the change from potent agonist to an antagonist of moderate potency.

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Section: Chemistrymentioning

confidence: 99%

Probes for narcotic receptor mediated phenomena. 44. Synthesis of an N-substituted 4-hydroxy-5-(3-hydroxyphenyl)morphan with high affinity and selective μ-antagonist activity

Iyer

Lee

Deschamps

et al. 2012

European Journal of Medicinal Chemistry

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“…Significant efforts in the development of 18 F (t 1/2 , 109 min)-labeled SERT tracers based on various core structures have been made (12)(13)(14)(15)(16)(17). However, there has been limited success because of suboptimal ligand properties or poor radiochemical yields.…”

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confidence: 99%

In Vivo Characterization of a Series of ¹⁸F-Diaryl Sulfides (¹⁸F-2-(2′-((Dimethylamino)Methyl)-4′-(Fluoroalkoxy)Phenylthio)Benzenamine) for PET Imaging of the Serotonin Transporter

Wang

Parhi

Oya³

et al. 2009

J Nucl Med

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PET of the serotonin transporter (SERT) in the brain is a useful tool for examining normal physiologic functions as well as disease states involving the serotonergic system. The goal of this study was to further develop and refine a series of 49-fluoroalkoxy-substituted, 18 F-radiolabeled SERT imaging agents. 2-(29-((Dimethylamino)methyl)-49-(4-18 F-fluorobutoxy)phenylthiol)-benzenamine (3) and 2-(29-((dimethylamino)methyl)-49-(5-18 Ffluoropentoxy)phenylthiol)benzenamine (4) were synthesized and evaluated along with 2 previously reported compounds of this series, 2-(29-((dimethylamino)methyl)-49-(2-18 F-fluoroethoxy)-phenylthiol)benzenamine (1) and 2-(29-((dimethylamino)methyl)-49-(3-18 F-fluoropropoxy)phenylthiol)benzenamine (2). Methods: The in vitro binding affinities of compounds 3 and 4 were determined in monoamine transporter-transfected LLC-PK 1 cell homogenates. In vivo localization of the respective 18 F-labeled compounds was evaluated by biodistribution studies in male Sprague-Dawley rats. Compound 3 was selected for further examination by autoradiographic and PET studies in rats. Results: The corresponding mesylate precursors of 3 and 4 were radiolabeled with 18 F within 75-90 min. Radiochemical yield was 6%235%, specific activity was 15-170 GBq/mmol, and radiochemical purity was greater than 97% (end of synthesis). The compounds showed subnanomolar binding affinities for SERT (inhibition constants, 0.51 and 0.76 nM, respectively), had brain uptake at 2 min of 1.25 and 0.68 percentage injected dose per gram, respectively, and possessed high target-to-nontarget (hypothalamus-to-cerebellum) ratios at 120 min after injection (6.51 and 5.70, respectively). Autoradiographic studies of 18 F-3 showed selective localization in SERT-rich brain regions. PET studies of 18 F-3 showed clear localization in the midbrain, thalamus, and striatum. Conclusion: This compound series was found to have potential for producing a suitable 18 F-radiolabeled PET radiotracer for SERT. Compound 4, the pentoxy derivative, had the lowest brain uptake and target-to-nontarget ratio. Compound 3, the butoxy derivative, had a lower target-to-nontarget ratio than compounds 1 (ethoxy derivative) and 2 (propoxy derivative). Compounds 1 and 2 both hold promise as SERT radioimaging agents, but because of cost limitations, only compound 2 will be evaluated in further studies.

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“…16,17 The mixture was heated to 110 °C in an oil bath for 40 min and then cooled in an ice bath. The crude mixture was diluted with 5 ml of HPLC mobile phase (50:50:0.1 ethanol:water:triethylamine) and purified via reverse phase HPLC on a C 18 xterra prep column (25 × 100 mm).…”

Section: Methodsmentioning

confidence: 99%

Synthesis and evaluation of C-11, F-18 and I-125 small molecule radioligands for detecting oxytocin receptors

Smith

Freeman²,

Stehouwer

et al. 2012

Bioorganic & Medicinal Chemistry

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Compounds 1–4 were synthesized and investigated for selectivity and potency for the oxytocin receptor (OTR) to determine their viability as radioactive ligands. Binding assays determined 1–4 to have high binding affinity for both the human and rodent OTR and also have high selectivity for the human OTR over human vasopressin V1a receptors (V1aR). Inadequate selectivity for OTR over V1aR was found for rodent receptors in all four compounds. The radioactive (C-11, F-18, and I-125) derivatives of 1–4 were synthesized and investigated for use as autoradiography and positron emission tomography (PET) ligands. Receptor autoradiography performed with [125I]1 and [125I]2 on rodent brain slices provided the first small molecule radioligand images of the OTR and V1aR. Biodistribution studies determined [125I]1 and [125I]2 were adequate for in vivo peripheral investigations, but not for central investigations due to low uptake within the brain. A biodistribution study with [18F]3 suggested brain uptake occurred slowly over time. PET imaging studies with [18F]3 and [11C]4 using a rat model provided insufficient uptake in the brain over a 90 and 45 min scan times respectively to merit further investigations in non-human primates.

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Synthesis and in Vivo Evaluation of Fluorine-18 and Iodine-123 Labeled 2β-Carbo(2-fluoroethoxy)-3β-(4‘-((Z)-2-iodoethenyl)phenyl)nortropane as a Candidate Serotonin Transporter Imaging Agent

Cited by 14 publications

References 21 publications

Probes for narcotic receptor mediated phenomena. 44. Synthesis of an N-substituted 4-hydroxy-5-(3-hydroxyphenyl)morphan with high affinity and selective μ-antagonist activity

Probes for narcotic receptor mediated phenomena. 44. Synthesis of an N-substituted 4-hydroxy-5-(3-hydroxyphenyl)morphan with high affinity and selective μ-antagonist activity

In Vivo Characterization of a Series of ¹⁸F-Diaryl Sulfides (¹⁸F-2-(2′-((Dimethylamino)Methyl)-4′-(Fluoroalkoxy)Phenylthio)Benzenamine) for PET Imaging of the Serotonin Transporter

Synthesis and evaluation of C-11, F-18 and I-125 small molecule radioligands for detecting oxytocin receptors

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Synthesis and in Vivo Evaluation of Fluorine-18 and Iodine-123 Labeled 2β-Carbo(2-fluoroethoxy)-3β-(4‘-((Z)-2-iodoethenyl)phenyl)nortropane as a Candidate Serotonin Transporter Imaging Agent

Cited by 14 publications

References 21 publications

Probes for narcotic receptor mediated phenomena. 44. Synthesis of an N-substituted 4-hydroxy-5-(3-hydroxyphenyl)morphan with high affinity and selective μ-antagonist activity

Probes for narcotic receptor mediated phenomena. 44. Synthesis of an N-substituted 4-hydroxy-5-(3-hydroxyphenyl)morphan with high affinity and selective μ-antagonist activity

In Vivo Characterization of a Series of 18F-Diaryl Sulfides (18F-2-(2′-((Dimethylamino)Methyl)-4′-(Fluoroalkoxy)Phenylthio)Benzenamine) for PET Imaging of the Serotonin Transporter

Synthesis and evaluation of C-11, F-18 and I-125 small molecule radioligands for detecting oxytocin receptors

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Product

Resources

About

In Vivo Characterization of a Series of ¹⁸F-Diaryl Sulfides (¹⁸F-2-(2′-((Dimethylamino)Methyl)-4′-(Fluoroalkoxy)Phenylthio)Benzenamine) for PET Imaging of the Serotonin Transporter