Efficient radiosynthesis and non-clinical safety tests of the TSPO radioprobe [(18)F]FEDAC: Prerequisites for clinical application

Kazunori Kawamura; Katsushi Kumata; Makoto Takei; Kenji Furutsuka; Hiroki Hashimoto; Takehito Ito; Satoshi Shiomi; Tomoya Fujishiro; Ryuji Watanabe; Nobuyuki Igarashi; Masatoshi Muto; Tomoteru Yamasaki; Joji Yui; Lin Xie; Akiko Hatori; Yiding Zhang; Kazuyoshi Nemoto; Yasuhisa Fujibayashi; Ming-Rong Zhang

doi:10.1016/j.nucmedbio.2016.04.004

Efficient radiosynthesis and non-clinical safety tests of the TSPO radioprobe [(18)F]FEDAC: Prerequisites for clinical application

Nucl Med Biol. 2016 Jul;43(7):445-53. doi: 10.1016/j.nucmedbio.2016.04.004. Epub 2016 Apr 26.

Authors

Kazunori Kawamura¹, Katsushi Kumata², Makoto Takei², Kenji Furutsuka³, Hiroki Hashimoto², Takehito Ito³, Satoshi Shiomi⁴, Tomoya Fujishiro⁴, Ryuji Watanabe⁴, Nobuyuki Igarashi⁴, Masatoshi Muto⁴, Tomoteru Yamasaki², Joji Yui², Lin Xie², Akiko Hatori², Yiding Zhang², Kazuyoshi Nemoto², Yasuhisa Fujibayashi², Ming-Rong Zhang²

Affiliations

¹ 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.
² Department of Radiopharmaceuticals Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan.
³ 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.
⁴ 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.

PMID: 27183465
DOI: 10.1016/j.nucmedbio.2016.04.004

Abstract

Introduction: [(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.

Methods: [(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.

Results: 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).

Conclusion: 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.

Keywords: (18)F; Extended single-dose toxicity study; FEDAC; PET; TSPO.

MeSH terms

Acetamides / chemical synthesis
Acetamides / chemistry
Acetamides / metabolism*
Acetamides / toxicity*
Animals
Carrier Proteins / metabolism*
Chemistry Techniques, Synthetic
Dose-Response Relationship, Drug
Humans
Microsomes, Liver / metabolism
Positron-Emission Tomography
Purines / chemical synthesis
Purines / chemistry
Purines / metabolism*
Purines / toxicity*
Radiochemistry
Rats
Rats, Sprague-Dawley
Receptors, GABA-A / metabolism*
Safety*

Substances

Acetamides
Carrier Proteins
N-benzyl-N-methyl-2-(7,8-dihydro-7-(2-fluoroethyl)-8-oxo-2-phenyl-9H-purin-9-yl)acetamide
Purines
Receptors, GABA-A
Tspo protein, rat