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 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.
Hoepping
Alexander
A
ABX advanced biochemical compounds GmbH, H.-Gläser-Str. 10-14, D-01454 Radeberg, Germany. hoepping@abx.de
Diekers
Michael
M
Deuther-Conrad
Winnie
W
Scheunemann
Matthias
M
Fischer
Steffen
S
Hiller
Achim
A
Wegner
Florian
F
Steinbach
Jörg
J
Brust
Peter
P
D000818:Animals; D005260:Female; D005461:Fluorine / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D049268:Positron-Emission Tomography / Q000379:methods*; D011720:Pyrazoles / Q000737:chemistry*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism*; D013329:Structure-Activity Relationship
D011720:Pyrazoles; D011743:Pyrimidines; D011963:Receptors, GABA-A; D005461:Fluorine; C031280:pyrazole; C030986:pyrimidine