Synthesis of novel WAY 100635 derivatives containing a norbornene group and radiofluorination of [<sup>18</sup>F]AH1.MZ as a serotonin 5‐HT<sub>1A</sub> receptor antagonist for molecular imaging

Herth, Matthias M.; Kramer, Vasko; Rösch, Frank

doi:10.1002/jlcr.1589

Cited by 8 publications

(7 citation statements)

References 16 publications

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“…The arylpiperazine derivatives applied were either commercially available or synthesized using previously published methods. 23,24 The development of a successful in vivo PET probe for neuroreceptor imaging requires a range of properties such as high selectivity for the target, the ability to cross the bloodbrain barrier (BBB), and low relative nonspecific binding. To guide the selection of suitable candidates for in vivo PET, the lipophilicity and in vitro affinity for the 5-HT 7 receptor was determined for all compounds.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Synthesis and In Vitro Evaluation of Oxindole Derivatives as Potential Radioligands for 5-HT₇ Receptor Imaging with PET

Herth

Volk

Pallagi

et al. 2012

ACS Chem. Neurosci.

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ABSTRACT:The most recently discovered serotonin (5-HT) receptor subtype, 5-HT 7 , is considered to be associated with several CNS disorders. Noninvasive in vivo positron emission tomography (PET) studies of cerebral 5-HT 7 receptors could provide a significant advance in the understanding of the neurobiology and eventual dysfunctions of the 5-HT 7 receptor. To date, no appropriate 5-HT 7 receptor PET ligand has been developed. Here, we modified known 5-HT 7 selective phenylpiperazinyl-butyloxindole derivatives so that they may be labeled either with carbon-11 or fluorine-18. A set of potential 5-HT 7 ligands for PET molecular imaging was successfully synthesized. Two compounds (10 and 14) were tested against a range of targets. Both compounds display a promising in vitro profile with respect to PET imaging of the 5-HT 7 receptor in thalamic regions. KEYWORDS: Oxindole, 5-HT 7 receptor distribution, PET T he relatively recently discovered G-protein coupled 5-HT 7 receptor has been implicated in various central nervous system (CNS) disorders such as schizophrenia, depression, epilepsy, migraine, and in the control of circadian rhythm. 1 For example, the atypical antipsychotic drug amisulpride has antidepressant effects, 2,3 and a study in 5-HT 7 receptor knockout mice supports that the 5-HT 7 receptor antagonism of amisulpride alleviates depression symptoms. 4 Other atypical antipsychotics also have relatively high affinity for the 5-HT 7 receptor, but their involvement in alleviating depressive symptoms through blocking the 5-HT 7 receptor remains to be investigated. 5,6 In vivo studies of cerebral 5-HT 7 receptor binding in humans would thus provide a significant advance in the understanding of the above-mentioned physiology and pathophysiology. Positron emission tomography (PET) is used to quantify neuroreceptor binding in vivo, and the availability of an appropriate PET radiotracer for the 5-HT 7 receptor would be of particular interest.Previous attempts of other groups to develop a 5-HT 7 receptor selective PET tracer have not been convincingly successful. 7,8 Most recently, 18 F-labeled SB-269970 derivatives were synthesized and evaluated in vivo in cats, 9,10 but in the absence of a validated reference region or an arterial input function it was not possible to fully evaluate the validity of those radiolabeled compounds. 11Several lead structures of 5-HT 7 receptor ligands have been identified within various structural classes. 12 Among these structures, phenylpiperazinyl-butyloxindoles display an interesting selectivity profile (Figure 1). 13,14 Some oxindoles showed inhibition constants (K i ) 2000-fold lower for the 5-HT 7 receptor than for the 5-HT 1A receptor. This large difference in K i is necessary because of low brain tissue 5-HT 7 receptor density (B max ) compared to 5-HT 1A receptor values in, e.g., hippocampus and cortical areas. 15,16 Received: July 31, 2012 Accepted: August 31, 2012 Published: August 31, 2012

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Section: ■ Results and Discussionmentioning

confidence: 99%

Synthesis and In Vitro Evaluation of Oxindole Derivatives as Potential Radioligands for 5-HT₇ Receptor Imaging with PET

Herth

Volk

Pallagi

et al. 2012

ACS Chem. Neurosci.

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“…A high specific activity radiosynthesis of [ 18 F]4 was developed according to the route shown in Scheme 2. The approach was based upon literature precedent, including (i) our previously described synthesis of 4 by coupling the methylphosphonic acid PNP-ester 6 with 2-fluoroethanol, 7 (ii) the availability of the high specific activity, radiolabeled prosthetic group [ 18 F]2tosyloxy-1-fluoroethane (7) 13,14 readily derived from 1,2-bistosyloxyethane (8); and (iii) the formation of radiolabeled carboxylic acid esters employing the radioprosthetic group 7 and select carboxylic acids in the presence of cesium carbonate under microwave-assisted esterification conditions. 15 The two step Scheme 2 radiosynthesis affords tracer [ 18 F]4 in an unoptimized, 6.5% decay corrected radiochemical yield based on 7, in >99% purity, and a specific activity of ∼2100 Ci/ mmol (avg, n = 10).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

A Novel Fluorine-18 β-Fluoroethoxy Organophosphate Positron Emission Tomography Imaging Tracer Targeted to Central Nervous System Acetylcholinesterase

James

Ahmed

Murphy

et al. 2014

ACS Chem. Neurosci.

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Radiosynthesis of a fluorine-18 labeled organophosphate (OP) inhibitor of acetylcholinesterase (AChE) and subsequent positron emission tomography (PET) imaging using the tracer in the rat central nervous system are reported. The tracer structure, which contains a novel β-fluoroethoxy phosphoester moiety, was designed as an insecticide-chemical nerve agent hybrid to optimize handling and the desired target reactivity. Radiosynthesis of the β-fluoroethoxy tracer is described that utilizes a [(18)F]prosthetic group coupling approach. The imaging utility of the [(18)F]tracer is demonstrated in vivo within rats by the evaluation of its brain penetration and cerebral distribution qualities in the absence and presence of a challenge agent. The tracer effectively penetrates brain and localizes to cerebral regions known to correlate with the expression of the AChE target. Brain pharmacokinetic properties of the tracer are consistent with the formation of an OP-adducted acetylcholinesterase containing the fluoroethoxy tracer group. Based on the initial favorable in vivo qualities found in rat, additional [(18)F]tracer studies are ongoing to exploit the technology to dynamically probe organophosphate mechanisms of action in mammalian live tissues.

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“…Herth et al reported one radioligand in a series of piperazine-substituted azatricyclo-dec-8-ene-3,5-diones targeting the serotonin 5-HT 1A 37,38 MedChemComm Review receptor, which was synthesized via [ 18 F]fluoroethylation with [ 18 F]FETs. 40 HPLC-purified [ 18 F]FETs was reacted for 20 min at 120 °C with the corresponding hydroxyl precursor (Fig. 15).…”

Section: O-[ 18 F]fluoroethyl Phenolsmentioning

confidence: 99%

“…37,38 receptor, which was synthesized via [ 18 F]fluoroethylation with [ 18 F]FETs 40. HPLC-purified[ 18 F]FETs was reacted for 20 min at 120°C with the corresponding hydroxyl precursor(Fig.…”

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2-[¹⁸F]Fluoroethyl tosylate – a versatile tool for building¹⁸F-based radiotracers for positron emission tomography

et al. 2015

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Synthesis of novel WAY 100635 derivatives containing a norbornene group and radiofluorination of [¹⁸F]AH1.MZ as a serotonin 5‐HT_1A receptor antagonist for molecular imaging

Cited by 8 publications

References 16 publications

Synthesis and In Vitro Evaluation of Oxindole Derivatives as Potential Radioligands for 5-HT₇ Receptor Imaging with PET

Synthesis and In Vitro Evaluation of Oxindole Derivatives as Potential Radioligands for 5-HT₇ Receptor Imaging with PET

A Novel Fluorine-18 β-Fluoroethoxy Organophosphate Positron Emission Tomography Imaging Tracer Targeted to Central Nervous System Acetylcholinesterase

2-[¹⁸F]Fluoroethyl tosylate – a versatile tool for building¹⁸F-based radiotracers for positron emission tomography

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Synthesis of novel WAY 100635 derivatives containing a norbornene group and radiofluorination of [18F]AH1.MZ as a serotonin 5‐HT1A receptor antagonist for molecular imaging

Cited by 8 publications

References 16 publications

Synthesis and In Vitro Evaluation of Oxindole Derivatives as Potential Radioligands for 5-HT7 Receptor Imaging with PET

Synthesis and In Vitro Evaluation of Oxindole Derivatives as Potential Radioligands for 5-HT7 Receptor Imaging with PET

A Novel Fluorine-18 β-Fluoroethoxy Organophosphate Positron Emission Tomography Imaging Tracer Targeted to Central Nervous System Acetylcholinesterase

2-[18F]Fluoroethyl tosylate – a versatile tool for building18F-based radiotracers for positron emission tomography

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Synthesis of novel WAY 100635 derivatives containing a norbornene group and radiofluorination of [¹⁸F]AH1.MZ as a serotonin 5‐HT_1A receptor antagonist for molecular imaging

Synthesis and In Vitro Evaluation of Oxindole Derivatives as Potential Radioligands for 5-HT₇ Receptor Imaging with PET

Synthesis and In Vitro Evaluation of Oxindole Derivatives as Potential Radioligands for 5-HT₇ Receptor Imaging with PET

2-[¹⁸F]Fluoroethyl tosylate – a versatile tool for building¹⁸F-based radiotracers for positron emission tomography