Synthesis of fluorine substituted pyrazolopyrimidines as potential leads for the development of PET-imaging agents for the GABAA receptors

Neuroimaging of GABA(A) receptors offers the potential for a better diagnosis of diseases related to a dysfunction of the GABAergic neurotransmission. A series of potent fluorinated analogues of the pyrazolopyrimidine Indiplon has been synthesized and evaluated in vitro as potential agents for imagi...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2008-02, Vol.16 (3), p.1184-1194
Main Authors: HOEPPING, Alexander, DIEKERS, Michael, DEUTHER-CONRAD, Winnie, SCHEUNEMANN, Matthias, FISCHER, Steffen, HILLER, Achim, WEGNER, Florian, STEINBACH, Jörg, BRUST, Peter
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Contrast media. Radiopharmaceuticals
Female
Fluorine - chemistry
Gabaergic and benzodiazepinic system
Inhibitory Concentration 50
Medical sciences
Molecular Structure
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Pharmacology. Drug treatments
Positron-Emission Tomography - methods
Pyrazoles - chemistry
Pyrimidines - chemical synthesis
Pyrimidines - chemistry
Rats
Rats, Sprague-Dawley
Receptors, GABA-A - metabolism
Structure-Activity Relationship
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Summary:Neuroimaging of GABA(A) receptors offers the potential for a better diagnosis of diseases related to a dysfunction of the GABAergic neurotransmission. A series of potent fluorinated analogues of the pyrazolopyrimidine Indiplon has been synthesized and evaluated in vitro as potential agents for imaging the GABA(A) receptor by means of positron emission tomography (PET). The most promising compound N-(3-fluoropropyl)-N-[3-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl]-acetamide (5b) showed an IC(50) value of 2.78+/-0.63 nM comparable to the lead compound Indiplon (IC(50) 3.29+/-0.37 nM), thus making it an interesting candidate for further investigations. In addition to the fluorinated reference compounds, suitable precursors for (18)F-radiolabelling studies have been synthesized.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2007.10.079