title: Imaging α4β2 Nicotinic Acetylcholine Receptors (nAChRs) in Baboons with [18F]XTRA, a Radioligand with Improved Specific Binding in Extra-Thalamic Regions.
abstract: Currently available positron-emitting radiotracers for imaging of the α4β2 subtype of nicotinic acetylcholine receptors (nAChRs) exhibit high and moderate specific binding in the thalamus and extra-thalamic brain regions, respectively. In many neuropsychiatric disorders, α4β2-nAChRs are altered in the extra-thalamic brain regions, but not necessarily in the thalamus. The purpose of this study was to evaluate [18F]XTRA, a new α4β2-nAChR positron emission tomography (PET) radioligand with improved specific binding in extra-thalamic brain regions, in non-human primates.
  
  
  
  The regional distribution of [18F]XTRA in the brain of Papio anubis baboons was evaluated in baseline and blocking experiments. Various PET modeling procedures were used for determination of volume of distribution (VT), binding potential (BPND), and receptor occupancy. Radiation dosimetry for [18F]XTRA was studied in male CD-1 mice and extrapolated to human dosimetry estimates using OLINDA/EXM software.
  
  
  
  [18F]XTRA was synthesized using an automated radiochemistry module with 25 % decay-corrected radiochemical yield. [18F]XTRA readily enters the baboon brain and specifically labels α4β2-nAChRs. Mathematical modeling demonstrates high binding potential values (BPND= 7 and 1.3 in the thalamus and frontal cortex, respectively). A PET scanning time of 90-120 min was sufficient to obtain stable VTvalues in the extra-thalamic regions. The extrapolated human effective dose was 0.041 mSv/MBq (0.15 Rem/mCi).
  
  
  
  [18F]XTRA exhibits improved specific binding in the baboon brain including extra-thalamic regions and it is considered radiologically acceptable for human studies. Further evaluations of [18F]XTRA in human subjects are under way.
authors: Department of Radiology, School of Medicine, The Johns Hopkins University, Baltimore, MD, USA. hkuwaba1@jhmi.edu.
authors: Hiroto
authors: 0000-0003-2082-9054
authors: H
authors: Kuwabara
authors: Department of Radiology, School of Medicine, The Johns Hopkins University, Baltimore, MD, USA.
authors: Yongjun
authors: Y
authors: Gao
authors: Department of Radiology and Radiological Sciences, Vanderbilt University, Nashville, TN, USA.
authors: Michael
authors: M
authors: Stabin
authors: Department of Psychiatry, School of Medicine, The Johns Hopkins University, Baltimore, MD, USA.
authors: Jennifer
authors: J
authors: Coughlin
authors: Department of Radiology, School of Medicine, The Johns Hopkins University, Baltimore, MD, USA.
authors: Sridhar
authors: S
authors: Nimmagadda
authors: Department of Radiology, School of Medicine, The Johns Hopkins University, Baltimore, MD, USA.
authors: Robert F
authors: RF
authors: Dannals
authors: Department of Radiology, School of Medicine, The Johns Hopkins University, Baltimore, MD, USA.|Department of Neuroscience, School of Medicine, The Johns Hopkins University, Baltimore, MD, USA.|Department of Environmental Health Sciences, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, MD, USA.
authors: Martin G
authors: MG
authors: Pomper
authors: Department of Radiology, School of Medicine, The Johns Hopkins University, Baltimore, MD, USA.
authors: Andrew G
authors: AG
authors: Horti
mesh_terms: D015082:2,2'-Dipyridyl / Q000031:analogs & derivatives / Q000737:chemistry; D000818:Animals; D053961:Azabicyclo Compounds / Q000737:chemistry; D008297:Male; D051379:Mice; D057054:Molecular Imaging / Q000379:methods*; D010215:Papio; D049268:Positron-Emission Tomography; D011874:Radiometry; D019275:Radiopharmaceuticals / Q000737:chemistry*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013788:Thalamus / Q000000981:diagnostic imaging*; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D053961:Azabicyclo Compounds; D019275:Radiopharmaceuticals; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; D015082:2,2'-Dipyridyl
keywords: Binding potential; Dosimetry; Non-human primates; PET imaging; Radioligands; α4β2 nicotinic acetylcholine receptors