Derivatives of dibenzothiophene for positron emission tomography imaging of α7-nicotinic acetylcholine receptors.
A new series of derivatives of 3-(1,4-diazabicyclo[3.2.2]nonan-4-yl)dibenzo[b,d]thiophene 5,5-dioxide with high binding affinities and selectivity for α7-nicotinic acetylcholine receptors (α7-nAChRs) (Ki = 0.4-20 nM) has been synthesized for positron emission tomography (PET) imaging of α7-nAChRs. Two radiolabeled members of the series [(18)F]7a (Ki = 0.4 nM) and [(18)F]7c (Ki = 1.3 nM) were synthesized. [(18)F]7a and [(18)F]7c readily entered the mouse brain and specifically labeled α7-nAChRs. The α7-nAChR selective ligand 1 (SSR180711) blocked the binding of [(18)F]7a in the mouse brain in a dose-dependent manner. The mouse blocking studies with non-α7-nAChR central nervous system drugs demonstrated that [(18)F]7a is highly α7-nAChR selective. In agreement with its binding affinity the binding potential of [(18)F]7a (BPND = 5.3-8.0) in control mice is superior to previous α7-nAChR PET radioligands. Thus, [(18)F]7a displays excellent imaging properties in mice and has been chosen for further evaluation as a potential PET radioligand for imaging of α7-nAChR in non-human primates.
Russell H. Morgan Department of Radiology and Radiological Sciences, Division of Nuclear Medicine, The Johns Hopkins University School of Medicine , 600 North Wolfe Street, Baltimore, Maryland 21287-0816, United States.
Yongjun
Y
Gao
Kenneth J
KJ
Kellar
Robert P
RP
Yasuda
Thao
T
Tran
Yingxian
Y
Xiao
Robert F
RF
Dannals
Andrew G
AG
Horti
D000818:Animals; D053961:Azabicyclo Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D002491:Central Nervous System Agents / Q000494:pharmacology; D003499:Cyclic S-Oxides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D003553:Cystine / Q000494:pharmacology; D005462:Fluorine Radioisotopes; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D044406:Receptors, Serotonin, 5-HT3 / Q000378:metabolism; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D014018:Tissue Distribution; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000378:metabolism*
C585155:3-(1,4-diazabicyclo(3.2.2)nonan-4-yl)-6-fluorodibenzo(b,d)thiophene 5,5-dioxide; D053961:Azabicyclo Compounds; D002491:Central Nervous System Agents; D003499:Cyclic S-Oxides; D005462:Fluorine Radioisotopes; D018722:Nicotinic Agonists; D019275:Radiopharmaceuticals; D044406:Receptors, Serotonin, 5-HT3; D013876:Thiophenes; D064569:alpha7 Nicotinic Acetylcholine Receptor; D003553:Cystine; D009538:Nicotine