Radiosynthesis and biological evaluation of an 18F-labeled derivative of the novel pyrazolopyrimidine sedative–hypnotic agent indiplon

Hoepping, Alexander; Scheunemann, Matthias; Fischer, Steffen; Deuther‐Conrad, Winnie; Hiller, Achim; Wegner, Florian; Diekers, Michael; Steinbach, Jörg; Brust, Peter

doi:10.1016/j.nucmedbio.2007.03.011

Cited by 11 publications

(8 citation statements)

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“…[206] , or GABA A receptors [180] , preventing the use of these radiotracers for neuroimaging. Interestingly, it was found that fl uoroacetate is defluorinated by glutathione S-transferases [207] which are highly expressed in brain tissue [208] .…”

Section: For [ 18 F]fecnt N-dealkylation Has Been Shownmentioning

confidence: 99%

“…The approximate order of increasing suitability for aliphatic reactions is: I > Br > Cl > F, which is the reverse of that found in aromatic nucleophilic substitution reactions [156] . In the radiolabeling of various fl uoro-alkyl indiplon derivatives, the use of bromine as the leaving group has an RCY (38-43%) similar to the use of a tosylate leaving group [157][158][159] . Notably, depending on the length of the alkyl chain, O-tosyl-containing precursor molecules gradually decompose over months [159] .…”

Section: Preparation Of Labeling Precursors and Radio Labelingmentioning

confidence: 99%

“…By contrast, [ 18 F]fl uoroacetamides have proven to be metabolically unstable due to hydrolytic cleavage [169] . Thus, high-affinity and selective radiotracers for the VAChT [179] and the GABA A receptor [180] , respectively, are not suitable for in vivo imaging because metabolites that cross the BBB are generated. The metabolic instability is caused by the action of hydrolytic enzymes, e.g.…”

Section: Preparation Of Labeling Precursors and Radio Labelingmentioning

confidence: 99%

“…15. Notably, for the σ 1 receptor, as for metabotropic glutamate receptor 1 (mGluR1) [59] and the GABA A receptor [180] , the cerebellum is among the regions with the highest expression and cannot be used as a reference region in this case. The ratio between the region with lowest radiotracer accumulation (olfactory bulb) and that with highest accumulation (facial nucleus) was chosen for the estimation of specifi c receptor binding.…”

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Development of 18F-labeled radiotracers for neuroreceptor imaging with positron emission tomography

2014

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Positron emission tomography (PET) is an in vivo molecular imaging tool which is widely used in nuclear medicine for early diagnosis and treatment follow-up of many brain diseases. PET uses biomolecules as probes which are labeled with radionuclides of short half-lives, synthesized prior to the imaging studies. These probes are called radiotracers. Fluorine-18 is a radionuclide routinely used in the radiolabeling of neuroreceptor ligands for PET because of its favorable half-life of 109.8 min. The delivery of such radiotracers into the brain provides images of transport, metabolic, and neurotransmission processes on the molecular level. After a short introduction into the principles of PET, this review mainly focuses on the strategy of radiotracer development bridging from basic science to biomedical application. Successful radiotracer design as described here provides molecular probes which not only are useful for imaging of human brain diseases, but also allow molecular neuroreceptor imaging studies in various small-animal models of disease, including geneticallyengineered animals. Furthermore, they provide a powerful tool for in vivo pharmacology during the process of pre-clinical drug development to identify new drug targets, to investigate pathophysiology, to discover potential drug candidates, and to evaluate the pharmacokinetics and pharmacodynamics of drugs in vivo.Keywords: Alzheimer's disease; autoradiography; blood-brain barrier; brain tumor; cholinergic system; kinetic modeling; metabolism; molecular imaging; neurodegeneration; positron emission tomography; precursor; psychiatric disorder; radiotracer; sigma receptor ·Review· IntroductionPositron emission tomography (PET) is an in vivo molecular imaging tool widely used in nuclear medicine for early diagnosis and treatment follow-up of many brain diseases. Positron-emitting radionuclide-labeled substances allow the visualization, characterization, and measurement of biological processes at the molecular and cellular levels in humans and other living systems by highly sensitive coincidence-detection [1] . This is based on 511 keV photons (gamma radiation) originating from positronelectron annihilation. PET differs in that aspect from other modalities such as single-photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), optical imaging, and ultrasound. Because of their high sensitivity (~10 -9 to 10 -12 M) PET and SPECT offer advantages over the other methods. Therefore, in the past, they were the only modalities that allowed noninvasive imaging of biochemical receptor sites. Nowadays, the other imaging modalities compete in that aspect although precise absolute quantitation in terms of biochemical parameters has not been achieved yet. fusion accuracy, provides an advanced diagnostic tool and research platform [2,3] .PET and SPECT use biomolecules as probes, labeled with radionuclides of short half-lives, synthesized prior to the imaging studies. These probes are called radiotracers. According to the concept developed by George ...

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Section: For [ 18 F]fecnt N-dealkylation Has Been Shownmentioning

confidence: 99%

Section: Preparation Of Labeling Precursors and Radio Labelingmentioning

confidence: 99%

Section: Preparation Of Labeling Precursors and Radio Labelingmentioning

confidence: 99%

mentioning

confidence: 99%

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Development of 18F-labeled radiotracers for neuroreceptor imaging with positron emission tomography

2014

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“…17,18 In this article, we describe the radiosynthesis of four novel 18 F-labelled indiplon derivatives.…”

Section: Introductionmentioning

confidence: 99%

Radiosynthesis of novel ¹⁸F‐labelled derivatives of indiplon as potential GABA_A receptor imaging tracers for PET

Fischer¹,

Hiller²,

Scheunemann³

et al. 2008

Labelled Comp Radiopharmac

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The involvement of gamma amino butyric acid (GABA) receptors in a variety of neurological and psychiatric diseases has promoted the development and use of radiolabelled benzodiazepines (BZ) for brain imaging by PET. However, these radioligands are unable to distinguish between the various subtypes of GABA A receptors. Novel non-BZ such as the pyrazolo-pyrimidine indiplon proved to be selective for the a 1 -subunit of the GABA A receptor. Here, we describe the syntheses of four novel 18 F-labelled indiplon derivatives. Radiosyntheses were performed via n.c.a. 18 F-nucleophilic substitution starting from the tosyl, bromo, and 4-nitrobenzoyl precursors to obtain fluorine substituted N-alkylamide side chain derivatives of indiplon, followed by multistep purification using semi-preparative high-performance liquid chromatography and solid phase extraction. Tosyl and bromo precursors were converted into 18 F-labelled indiplon derivatives with good and reproducible radiochemical yield (RCY) (35-70%, decay corrected), high radiochemical purity (X X98.5%), and high specific activity ( > 150 GBq/lmol). By contrast, a low RCY (5-10%) and specific activity (10-15 GBq/ lmol) were achieved for the 4-nitrobenzoyl precursor.

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Ethyl {4‐[2‐(saccharin‐2‐yl)acetylsulfamoyl]phenylazo}cyanoacetate in the synthesis of polyfunctionally heteroaromatic derivatives

Aly

2009

Journal of Heterocyclic Chem

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magnified imageAn efficient and direct one‐pot reaction of ethyl saccharinylcyanoacetate derivative 3 with a variety of active methylene reagents and nitrogen nucleophiles afforded novel series of polyfunctionally substituted heteroaromatic derivatives 5–13, respectively. The pyrazole derivative 13 was seemed to be the excellent precursors for the synthesis of pyrazolo[1,5‐a]pyrimidine derivatives 14–24. The antimicrobial screening of some synthesized products was evaluated against some selected bacteria and fungi. The structures of the synthesized derivatives were established by elemental and spectral data. J. Heterocyclic Chem., (2009).

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Radiosynthesis and biological evaluation of an 18F-labeled derivative of the novel pyrazolopyrimidine sedative–hypnotic agent indiplon

Cited by 11 publications

References 55 publications

Development of 18F-labeled radiotracers for neuroreceptor imaging with positron emission tomography

Development of 18F-labeled radiotracers for neuroreceptor imaging with positron emission tomography

Radiosynthesis of novel ¹⁸F‐labelled derivatives of indiplon as potential GABA_A receptor imaging tracers for PET

Ethyl {4‐[2‐(saccharin‐2‐yl)acetylsulfamoyl]phenylazo}cyanoacetate in the synthesis of polyfunctionally heteroaromatic derivatives

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Radiosynthesis and biological evaluation of an 18F-labeled derivative of the novel pyrazolopyrimidine sedative–hypnotic agent indiplon

Cited by 11 publications

References 55 publications

Development of 18F-labeled radiotracers for neuroreceptor imaging with positron emission tomography

Development of 18F-labeled radiotracers for neuroreceptor imaging with positron emission tomography

Radiosynthesis of novel 18F‐labelled derivatives of indiplon as potential GABAA receptor imaging tracers for PET

Ethyl {4‐[2‐(saccharin‐2‐yl)acetylsulfamoyl]phenylazo}cyanoacetate in the synthesis of polyfunctionally heteroaromatic derivatives

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Radiosynthesis of novel ¹⁸F‐labelled derivatives of indiplon as potential GABA_A receptor imaging tracers for PET