Radiosynthesis of 11C-phenytoin Using a DEGDEE Solvent for Clinical PET Studies

Document Type : Original Article


1 Molecular Imaging in Medicine, Graduate school of medicine, Osaka University, Suita, Japan

2 Department of Bio-Medical Imaging, National Cerebral and Cardiovascular Center Research Insititute.

3 Osaka University Graduate School of Medicine


Objective(s): Phenytoin is an antiepileptic drug that is used worldwide. The whole-body pharmacokinetics of this drug have been extensively studied using 11C-phenytoin in small animals. However, because of the limited production amounts that are presently available, clinical 11C-phenytoin PET studies to examine the pharmacokinetics of phenytoin in humans have not yet been performed. We aimed to establish a new synthesis method to produce large amounts of 11C-phenytoin to conduct human studies.
Methods: 11C-methane was produced using an in-house cyclotron by the 14N (p, α) 11C nuclear reaction of 5 % of hydrogen containing 95 % of nitrogen gas. About 30 GBq of 11C-methane was then transferred to a
homogenization cell containing Fe2O3 powder mixed with Fe granules heated at 320 0C to yield 11C-phosgene. Xylene, 1,4-dioxane, and diethylene glycol diethyl ether (DEGDEE) were investigated as possible reaction solvents.
Results: The ratio of 11C-phenytoin radioactivity to the total 11C radioactivity in the reaction vessel (reaction efficiency) was 7.5% for xylene, 11% for 1,4-dioxane, and 37% for DEGDEE. The synthesis time was within 45 min from the end of bombardment until obtaining the final product. The radioactivity produced was more than 4.1 GBq in 10 mL of saline at the end of synthesis. The specific activity of the product ranged from 1.7 to 2.2
GBq/μmol. The quality of the 11C-phenytoin injection passed all criteria required for clinical use.
Conclusion: The use of DEGDEE as a solvent enabled the production of a large amount of 11C-phenytoin sufficient to enable PET studies examining the human pharmacokinetics of phenytoin.


Main Subjects

  1. Buchthal F, Svensmark O, Schller PJ. Clinical and electroencephalographic correlations with serum levels of diphenylhydantoin. Arch Neurol. 1960;2(6):624-30.
  2. Noach EL, Woodbury DM, Goodman LS. Studies on the absorption, distribution, fate and excretion of 4-C14-labeled diphenyhydantoin, J Pharmacol Exp Therap. 1958;122(3):301-14.
  3. Noach EL, Vanrees HV. Intestinal distribution of intravenously administered diphyenythydontoin in the rat. Arch Int Pharmacodyn Ther. 1964; 150:52-61.
  4. Winstead MB, Parr SJ, Rogal MJ, Brockman PS, Lubcher R, Khentigan A, et al. Relationship of molecular structure to in vivo scintigraphic distribution patterns of carbon-11-labeled compound. 3. [11C] hydantoins. J Med Chem. 1976;19(2):279-86.
  5. Stavchansky SA, Tilbur RS, McDonald JM, Ting CT, Kostenbauder HB. In vivo distribution of carbon-11 phenytoin and its major metabolite, and their use in scintigraphic imaging. J Nucl Med. 1978;19(8):936-41.
  6. Emran AM, Boothe TE, Finn RD, Vora MM, Kothari PJ. Use of 11C as a tracer for studying the synthesis of radiolabelled compounds-II: 2-[11C]-5, 5-diphenylhydantoin from [11C] cyanide. Int J Radiat Appl Instrument A. 1986;37(10):1033-8.
  7. Roeda D, Westera G. The synthesis of some 11C-labeled antiepileptic drugs with potential utility as radiopharmaceuticals: hydantoins and barbiturates. Int J Appl Radiat Isotopes. 1981;32(11):843-5.
  8. Hasegawa Y, Kanai Y, Hasegawa S, Okamoto T, Matsui T, Shimosegawa E, et al. Evaluation of brain and whole-body pharmacokinetics of 11C-labeled diphenylhydantoin in rats by means of planar positron imaging system. Ann Nucl Med. 2008;22(4):301-7.
  9. Baron JC, Roeda D, Munari C, Crouzel C, Chodkiewicz JP, Comar D. Brain regional pharmacokinetics of 11C-labeled diphenylhydantoin: positron emission tomography in humans. Neurology. 1983;33(5):580-5.

10. Nishijima K, Kuge Y, Seki K. Ohkura K. Motoki N. Nagatsu K, et al. A simplified and improved synthesis of [11C]phosgene with iron and iron (III) oxide. Nucl Med Biol. 2002;29(3):345-50.

11. EU/EMEA/CPMP: position paper on non-clinical safety studies to support clinical trials with a single microdose. London: The European Medicines Agency (EMEA), Evaluation of Medicines for Human Use, CPMP/SWP/2599/02; 2003.

12. FDA US. Guidance for industry, investigators and reviewers, exploratory IND studies, US Department of Health and Human Services. New York: FDA, CDER; 2006

13. Mochida I, Shimosegawa E, Kanai Y, Naka S, Matsunaga K, Isohashi K, et al. Whole-body distribution of donepezil as an acetylcholinesterase inhibitor after oral administration in normal human subjects: a 11c-donepezil PET study. Asia Ocean J Nucl Med Biol. 2017;5(1):3-9.

14. Takano K, Kinoshita M, Arita H, Okita Y, Chiba Y, Kagawa N, et al. Diagnostic and prognostic value of 11c-methionine PET for nonenhancing gliomas. Am J Neuroradiol. 2016;37(1):44-50.