title: Synthesis and evaluation of new radioligands [(11)C]A-833834 and [(11)C]A-752274 for positron-emission tomography of α7-nicotinic acetylcholine receptors.
abstract: BACKGROUND
  α7-nicotinic acetylcholine receptor (α7-nAChR) is one of the major neuronal nAChR subtypes. α7-nAChR is involved in variety of neuronal processes and disorders including schizophrenia and Alzheimer's disease. A number of α7-nAChR PET radioligands have been developed, but a quality radiotracer remains to be discovered.
  
  
  METHODS
  High binding affinity α7-nAChR ligands A-833834 and A-752274 were radiolabeled with (11)C. Baseline and blockade biodistribution studies in the mouse brain of [(11)C]A-833834 (5-(6-(5-[(11)C]methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin-3-yl)-1H-indole) and [(11)C]A-752274 (2-(6-[(11)C]methyl-3,6-diazabicyclo[3.2.0]heptan-3-yl)-7-(6-methyl-3,6-diazabicyclo[3.2.0]heptan-3-yl)-9H-fluoren-9-one) were performed. [(11)C]A-752274 was evaluated in a baseline baboon PET study.
  
  
  RESULTS
  [(11)C]A-833834 and [(11)C]A-752274 were synthesized by radiomethylation of corresponding des-methyl precursors. The radioligands were prepared with radiochemical yield of 12%-32%, high specific radioactivity (330-403GBq/μmol) and radiochemical purity>95%. Dissection studies with [(11)C]A-833834 demonstrated low specific α7-nAChR binding in the mouse brain. [(11)C]A-752274 specifically (~50%) labeled α7-nAChR in the mouse thalamus. However, [(11)CA-752274 exhibited low brain uptake in baboon (%SUV<100).
  
  
  CONCLUSIONS
  Two novel α7-nAChR ligands radioligands were synthesized and studied in animals. Specific binding of [(11)C]A-833834 in the mouse brain is low due to the insufficient binding affinity of the radioligand. The very high binding affinity [(11)C]A-752274 exhibited good specific binding in the α7-nAChR-rich mouse brain regions. The low uptake of [(11)C]A-752274 in the baboon brain is due to its high hydrophilicity, rapid metabolism or other properties. Future development of α7-nAChR PET radioligands will be based on compounds with high binding affinities and good blood-brain barrier permeability.
authors.affiliation: Division of Nuclear Medicine, Department of Radiology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA. ahorti1@jhmi.edu
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Horti
authors.forename: Hayden T
authors.initials: HT
authors.lastname: Ravert
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Gao
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Holt
authors.forename: William H
authors.initials: WH
authors.lastname: Bunnelle
authors.forename: Michael R
authors.initials: MR
authors.lastname: Schrimpf
authors.forename: Tao
authors.initials: T
authors.lastname: Li
authors.forename: Jianguo
authors.initials: J
authors.lastname: Ji
authors.forename: Heather
authors.initials: H
authors.lastname: Valentine
authors.forename: Ursula
authors.initials: U
authors.lastname: Scheffel
authors.forename: Hiroto
authors.initials: H
authors.lastname: Kuwabara
authors.forename: Dean F
authors.initials: DF
authors.lastname: Wong
authors.forename: Robert F
authors.initials: RF
authors.lastname: Dannals
mesh_terms: D000818:Animals; D053961:Azabicyclo Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D060326:Chemistry Techniques, Synthetic; D005449:Fluorenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D008297:Male; D051379:Mice; D010215:Papio; D049268:Positron-Emission Tomography / Q000379:methods*; D011719:Pyrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D011854:Radiochemistry; D011978:Receptors, Nicotinic / Q000378:metabolism*; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C583369:2-(6-methyl-3,6-diazabicyclo(3.2.0)heptan-3-yl)-7-(6-methyl-3,6-diazabicyclo(3.2.0)heptan-3-yl)-9H-fluoren-9-one; C583368:5-(6-(5-methylhexahydropyrrolo(3,4-c)pyrrol-2(1H)-yl)pyridazin-3-yl)-1H-indole; D053961:Azabicyclo Compounds; D001643:Bridged Bicyclo Compounds; C579166:Chrna7 protein, mouse; D005449:Fluorenes; D007211:Indoles; D008024:Ligands; D011719:Pyrazines; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor