title: Whole-body biodistribution kinetics, metabolism, and radiation dosimetry estimates of 18F-PEG6-IPQA in nonhuman primates.
abstract: We recently developed the radiotracer 4-[(3-iodophenyl)amino]-7-(2-[2-{2-(2-[2-{2-((18)F-fluoroethoxy)-ethoxy}-ethoxy]-ethoxy)-ethoxy}-ethoxy]-quinazoline-6-yl-acrylamide) ((18)F-PEG(6)-IPQA) for noninvasive detection of active mutant epidermal growth factor receptor kinase-expressing non-small cell lung cancer xenografts in rodents. In this study, we determined the pharmacokinetics, biodistribution, metabolism, and radiation dosimetry of (18)F-PEG(6)-IPQA in nonhuman primates.
  
  
  METHODS
  Six rhesus macaques were injected intravenously with 141 ± 59.2 MBq of (18)F-PEG(6)-IPQA, and dynamic PET/CT images covering the thoracoabdominal area were acquired for 30 min, followed by whole-body static images at 60, 90, 120, and 180 min. Blood samples were obtained from each animal at several time points after radiotracer administration. Radiolabeled metabolites in blood and urine were analyzed using high-performance liquid chromatography. The (18)F-PEG(6)-IPQA pharmacokinetic and radiation dosimetry estimates were determined using volume-of-interest analysis of PET/CT image datasets and blood and urine time-activity data.
  
  
  RESULTS
  (18)F-PEG(6)-IPQA exhibited rapid redistribution and was excreted via the hepatobiliary and urinary systems. (18)F-PEG(6) was the major radioactive metabolite. The critical organ was the gallbladder, with an average radiation-absorbed dose of 0.394 mSv/MBq. The other key organs with high radiation doses were the kidneys (0.0830 mSv/MBq), upper large intestine wall (0.0267 mSv/MBq), small intestine (0.0816 mSv/MBq), and liver (0.0429 mSv/MBq). Lung tissue exhibited low uptake of (18)F-PEG(6)-IPQA due to the low affinity of this radiotracer to wild-type epidermal growth factor receptor kinase. The effective dose was 0.0165 mSv/MBq. No evidence of acute cardiotoxicity or of acute or delayed systemic toxicity was observed. On the basis of our estimates, diagnostic dosages of (18)F-PEG(6)-IPQA up to 128 MBq (3.47 mCi) per injection should be safe for administration in the initial cohort of human patients in phase I clinical PET studies.
  
  
  CONCLUSIONS
  The whole-body and individual organ radiation dosimetry characteristics and pharmacologic safety of diagnostic dosages of (18)F-PEG(6)-IPQA in nonhuman primates indicate that this radiotracer should be acceptable for PET/CT studies in human patients.
authors.affiliation: Department of Experimental Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. mei.tian@mdanderson.org
authors.forename: Mei
authors.initials: M
authors.lastname: Tian
authors.forename: Kazuma
authors.initials: K
authors.lastname: Ogawa
authors.forename: Richard
authors.initials: R
authors.lastname: Wendt
authors.forename: Uday
authors.initials: U
authors.lastname: Mukhopadhyay
authors.forename: Julius
authors.initials: J
authors.lastname: Balatoni
authors.forename: Nobuyoshi
authors.initials: N
authors.lastname: Fukumitsu
authors.forename: Rajesh
authors.initials: R
authors.lastname: Uthamanthil
authors.forename: Agatha
authors.initials: A
authors.lastname: Borne
authors.forename: David
authors.initials: D
authors.lastname: Brammer
authors.forename: James
authors.initials: J
authors.lastname: Jackson
authors.forename: Osama
authors.initials: O
authors.lastname: Mawlawi
authors.forename: Bijun
authors.initials: B
authors.lastname: Yang
authors.forename: Mian M
authors.initials: MM
authors.lastname: Alauddin
authors.forename: Juri G
authors.initials: JG
authors.lastname: Gelovani
mesh_terms: D000375:Aging / Q000502:physiology; D000818:Animals; D001835:Body Weight / Q000502:physiology; D005260:Female; D005704:Gallbladder / Q000000981:diagnostic imaging / Q000378:metabolism; D007091:Image Processing, Computer-Assisted; D008253:Macaca mulatta; D008297:Male; D049268:Positron-Emission Tomography; D011799:Quinazolines / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D011874:Radiometry; D019275:Radiopharmaceuticals / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed; D014915:Whole-Body Counting
chemical_list: C557742:4-((3-iodophenyl)amino)-7-(2-(2-(2-(2-(2-(2-(18F)fluoroethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)quinazoline-6-yl-acrylamide; D011799:Quinazolines; D019275:Radiopharmaceuticals