title: Human brain imaging of α7 nAChR with [(18)F]ASEM: a new PET radiotracer for neuropsychiatry and determination of drug occupancy.
abstract: OBJECTIVE
  Using the α7-nAChR radiotracer, [(18)F]ASEM, we present the first successful human positron emission tomography (PET) studies. Rodent occupancy with three clinically employed α7-nAChR drugs confirms the specificity of the radiotracer.
  
  
  METHODS
  Five healthy male subjects were imaged for 90 min following IV [(18)F]ASEM. Two subjects were scanned for the second time (test/retest; TRV). Mouse biodistribution of [(18)F]ASEM was carried out in CD1 mice injected with using human equivalent doses of DMXB-A, EVP-6124, and varenicline to block specific binding.
  
  
  RESULTS
  [(18)F]ASEM readily entered the brain and peaked at 15 min post-injection with reversible kinetics and a peak %SUV of about 400 %. The regional human brain distribution of [(18)F]ASEM matched previous in vitro data and baboon PET results. The precuneus, parietal, occipital, cingulate cortexes, putamen, and thalamus showed high values of distribution volume (>20 ml/ml) and binding potentials >1 with TRV averaged 10.8 ± 5.1 %. In mouse distribution studies, there was significant dose-dependent blockade in the mouse brain with DMXB-A as well as the other two α7-nAChR drugs.
  
  
  CONCLUSIONS
  The characteristics of [(18)F]ASEM are consistent with the ability to quantify α7-nAChR in the human brain. [(18)F]ASEM is suitable for imaging neuropsychiatric disorders and target engagement (receptor occupancy) of potential α7-nAChR drugs.
authors.affiliation: Department of Radiology, School of Medicine, The Johns Hopkins University, Baltimore, MD, USA, dfwong@jhmi.edu.
authors.forename: Dean F
authors.initials: DF
authors.lastname: Wong
authors.forename: Hiroto
authors.initials: H
authors.lastname: Kuwabara
authors.forename: Martin
authors.initials: M
authors.lastname: Pomper
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Holt
authors.forename: James R
authors.initials: JR
authors.lastname: Brasic
authors.forename: Noble
authors.initials: N
authors.lastname: George
authors.forename: Boris
authors.initials: B
authors.lastname: Frolov
authors.forename: William
authors.initials: W
authors.lastname: Willis
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Gao
authors.forename: Heather
authors.initials: H
authors.lastname: Valentine
authors.forename: Ayon
authors.initials: A
authors.lastname: Nandi
authors.forename: Lorena
authors.initials: L
authors.lastname: Gapasin
authors.forename: Robert F
authors.initials: RF
authors.lastname: Dannals
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Horti
mesh_terms: D000328:Adult; D000818:Animals; D053961:Azabicyclo Compounds / Q000097:blood / Q000737:chemistry; D001597:Benzylidene Compounds; D001921:Brain / Q000000981:diagnostic imaging*; D003499:Cyclic S-Oxides / Q000097:blood / Q000737:chemistry; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D058027:Neuropsychiatry; D049268:Positron-Emission Tomography; D011725:Pyridines; D019275:Radiopharmaceuticals; D013997:Time Factors; D014018:Tissue Distribution; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000378:metabolism*
chemical_list: C585155:3-(1,4-diazabicyclo(3.2.2)nonan-4-yl)-6-fluorodibenzo(b,d)thiophene 5,5-dioxide; D053961:Azabicyclo Compounds; D001597:Benzylidene Compounds; D003499:Cyclic S-Oxides; D011725:Pyridines; D019275:Radiopharmaceuticals; D064569:alpha7 Nicotinic Acetylcholine Receptor; C088936:3-(2,4-dimethoxybenzylidene)anabaseine