title: Strategy for improved [(11)C]DAA1106 radiosynthesis and in vivo peripheral benzodiazepine receptor imaging using microPET, evaluation of [(11)C]DAA1106.
abstract: BACKGROUND
  The peripheral benzodiazepine receptor (PBR) has shown considerable potential as a clinical marker of neuroinflammation and tumour progression. [(11)C]DAA1106 ([(11)C]N-(2,5-dimethoxybenzyl)-N-(5-fluoro-2-phenoxyphenyl)-acetamide) is a promising positron emission tomography (PET) radioligand for imaging PBRs.
  
  
  METHODS
  A four-step synthetic route was devised to prepare DAA1123, the precursor for [(11)C]DAA1106. Two robust, high yielding methods for radiosynthesis based on [(11)C]-O-methylation of DAA1123 were developed and implemented on a nuclear interface methylation module, producing [(11)C]DAA1106 with up to 25% radiochemical yields at end-of-synthesis based on [(11)C]CH(3)I trapped. Evaluation of [(11)C]DAA1106 for in vivo imaging was performed in a rabbit model with microPET, and the presence of PBR receptor in the target organ was further corroborated by immunohistochemistry.
  
  
  RESULTS
  The standard solution method produced 2.6-5.2 GBq (n=19) of [(11)C]DAA1106, whilst the captive solvent method produced 1.6-6.3 GBq (n=10) of [(11)C]DAA1106. Radiochemical purities obtained were 99% and specific radioactivity at end-of-synthesis was up to 200 GBq/micromol for both methods. Based on radiochemical product, shorter preparation times and simplicity of synthesis, the captive solvent method was chosen for routine productions of [(11)C]DAA1106. In vivo microPET [(11)C]DAA1106 scans of rabbit kidney demonstrated high levels of binding in the cortex. The subsequent introduction of nonradioactive DAA1106 (0.2 micromol) produced considerable displacement of the radioactive signal in this region. The presence of PBR in kidney cortex was further corroborated by immunohistochemistry.
  
  
  CONCLUSIONS
  A robust, high yielding captive solvent method of [(11)C]DAA1106 production was developed which enabled efficacious in vivo imaging of PBR expressing tissues in an animal model.
authors.affiliation: Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Addenbrooke's Hospital, CB2 2QQ Cambridge, UK. kp296@wbic.cam.ac.uk
authors.forename: Katrin C
authors.initials: KC
authors.lastname: Probst
authors.forename: David
authors.initials: D
authors.lastname: Izquierdo
authors.forename: Joseph L E
authors.initials: JL
authors.lastname: Bird
authors.forename: Laurent
authors.initials: L
authors.lastname: Brichard
authors.forename: Dominic
authors.initials: D
authors.lastname: Franck
authors.forename: John R
authors.initials: JR
authors.lastname: Davies
authors.forename: Tim D
authors.initials: TD
authors.lastname: Fryer
authors.forename: Hugh K
authors.initials: HK
authors.lastname: Richards
authors.forename: John C
authors.initials: JC
authors.lastname: Clark
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Davenport
authors.forename: Peter L
authors.initials: PL
authors.lastname: Weissberg
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Warburton
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D000818:Animals; D001331:Automation; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D007150:Immunohistochemistry; D007202:Indicators and Reagents; D007553:Isotope Labeling / Q000379:methods; D007672:Kidney Cortex / Q000000981:diagnostic imaging / Q000378:metabolism; D008745:Methylation; D010647:Phenyl Ethers / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography / Q000379:methods*; D011817:Rabbits; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D011963:Receptors, GABA-A / Q000378:metabolism*; D012997:Solvents
chemical_list: D000081:Acetamides; C118942:DAA 1106; D007202:Indicators and Reagents; D010647:Phenyl Ethers; D019275:Radiopharmaceuticals; D011963:Receptors, GABA-A; D012997:Solvents