title: Efficient radiosynthesis and non-clinical safety tests of the TSPO radioprobe [(18)F]FEDAC: Prerequisites for clinical application.
abstract: [(18)F]FEDAC ([(18)F]1) has potent binding affinity and selectivity for translocator protein (18kDa, TSPO), and has been used to noninvasively visualize neuroinflammation, lung inflammation, acute liver damage, nonalcoholic fatty liver disease, and liver fibrosis. We had previously synthesized [(18)F]1 in two steps: (i) preparation of [(18)F]fluoroethyl bromide and (ii) coupling of [(18)F]fluoroethyl bromide with the appropriate precursor (2) for labeling. In this study, to clinically utilize [(18)F]1 as a PET radiopharmaceutical and to transfer the production technique of [(18)F]1 to other PET centers, we simplified its preparation by using a direct, one-step, tosyloxy-for-fluorine substitution. We also performed an acute toxicity study as a major non-clinical safety test, and determined radiometabolites using human liver microsomes.
  
  
  
  [(18)F]1 was prepared via direct (18)F-fluorination by heating the corresponding tosylated derivative (3) with [(18)F]fluoride as its Kryptofix 222 complex in dimethyl sulfoxide at 110°C for 15min, following by HPLC purification. Non-clinical safety tests were performed for the extended single-dose toxicity study in rats, and for the in vitro metabolite analysis with human liver microsomal incubation.
  
  
  
  High quality batches of [(18)F]1, compatible with clinical applications, were obtained. At the end of irradiation, the decay-corrected radiochemical yield of [(18)F]1 using 1 and 5mg of precursor based on [(18)F]fluoride was 18.5±7.9% (n=10) and 52.0±5.8% (n=3), respectively. A single-dose of [(18)F]1 did not show toxicological effects for 14 days after the injection in male and female rats. In human liver microsomal incubations, [(18)F]1 was easily metabolized to [(18)F]desbenzyl-FEDAC ([(18)F]10) by CYPs (4.2% of parent compound left 60min after incubation).
  
  
  
  We successfully synthesized clinical grade batches of [(18)F]1 and verified the absence of innocuity of this radiotracer. [(18)F]1 will be used to first-in-human studies in our facility.
authors.affiliation: Department of Radiopharmaceuticals Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan. Electronic address: kawamura.kazunori@qst.go.jp.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kawamura
authors.affiliation: Department of Radiopharmaceuticals Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan.
authors.forename: Katsushi
authors.initials: K
authors.lastname: Kumata
authors.affiliation: Department of Radiopharmaceuticals Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Takei
authors.affiliation: Department of Radiopharmaceuticals Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan; SHI Accelerator Service Ltd., Tokyo 141-0032, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Furutsuka
authors.affiliation: Department of Radiopharmaceuticals Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Hashimoto
authors.affiliation: Department of Radiopharmaceuticals Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan; SHI Accelerator Service Ltd., Tokyo 141-0032, Japan.
authors.forename: Takehito
authors.initials: T
authors.lastname: Ito
authors.affiliation: Department of Radiopharmaceuticals Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan; Tokyo Nuclear Services, Tokyo 110-0016, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Shiomi
authors.affiliation: Department of Radiopharmaceuticals Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan; Tokyo Nuclear Services, Tokyo 110-0016, Japan.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Fujishiro
authors.affiliation: Department of Radiopharmaceuticals Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan; Tokyo Nuclear Services, Tokyo 110-0016, Japan.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Watanabe
authors.affiliation: Department of Radiopharmaceuticals Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan; Tokyo Nuclear Services, Tokyo 110-0016, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Igarashi
authors.affiliation: Department of Radiopharmaceuticals Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan; Tokyo Nuclear Services, Tokyo 110-0016, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Muto
authors.affiliation: Department of Radiopharmaceuticals Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan.
authors.forename: Tomoteru
authors.initials: T
authors.lastname: Yamasaki
authors.affiliation: Department of Radiopharmaceuticals Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan.
authors.forename: Joji
authors.initials: J
authors.lastname: Yui
authors.affiliation: Department of Radiopharmaceuticals Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan.
authors.forename: Lin
authors.initials: L
authors.lastname: Xie
authors.affiliation: Department of Radiopharmaceuticals Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Hatori
authors.affiliation: Department of Radiopharmaceuticals Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan.
authors.forename: Yiding
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Radiopharmaceuticals Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan.
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Nemoto
authors.affiliation: Department of Radiopharmaceuticals Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan.
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Fujibayashi
authors.affiliation: Department of Radiopharmaceuticals Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan.
authors.forename: Ming-Rong
authors.initials: MR
authors.lastname: Zhang
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity*; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D060326:Chemistry Techniques, Synthetic; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D049268:Positron-Emission Tomography; D011687:Purines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity*; D011854:Radiochemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism*; D012449:Safety
chemical_list: D000081:Acetamides; D002352:Carrier Proteins; C578604:N-benzyl-N-methyl-2-(7,8-dihydro-7-(2-fluoroethyl)-8-oxo-2-phenyl-9H-purin-9-yl)acetamide; D011687:Purines; D011963:Receptors, GABA-A; C069997:Tspo protein, rat
keywords: (18)F; Extended single-dose toxicity study; FEDAC; PET; TSPO