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

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• 作者：Kazunori Kawamura^a ; ^{kawamura.kazunori@qst.go.jp" class="auth_mail" title="E-mail the corresponding author} ; Katsushi Kumata^a ; Makoto Takei^a ; Kenji Furutsuka^a ; ^b ; Hiroki Hashimoto^a ; Takehito Ito^a ; ^b ; Satoshi Shiomi^a ; ^c ; Tomoya Fujishiro^a ; ^c ; Ryuji Watanabe^a ; ^c ; Nobuyuki Igarashi^a ; ^c ; Masatoshi Muto^a ; ^c ; Tomoteru Yamasaki^a ; Joji Yui^a ; Lin Xie^a ; Akiko Hatori^a ; Yiding Zhang^a ; Kazuyoshi Nemoto^a ; Yasuhisa Fujibayashi^a ; Ming-Rong Zhang^a
• 关键词：FEDAC ; 18F ; TSPO ; PET ; Extended single-dose toxicity study
• 刊名：Nuclear Medicine and Biology
• 出版年：2016
• 出版时间：July 2016
• 年：2016
• 卷：43
• 期：7
• 页码：445-453
• 全文大小：745 K

文摘

[¹⁸F]FEDAC ([¹⁸F]1) has potent binding affinity and selectivity for translocator protein (18 kDa, 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 [¹⁸F]1 in two steps: (i) preparation of [¹⁸F]fluoroethyl bromide and (ii) coupling of [¹⁸F]fluoroethyl bromide with the appropriate precursor (2) for labeling. In this study, to clinically utilize [¹⁸F]1 as a PET radiopharmaceutical and to transfer the production technique of [¹⁸F]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

[¹⁸F]1 was prepared via direct ¹⁸F-fluorination by heating the corresponding tosylated derivative (3) with [¹⁸F]fluoride as its Kryptofix 222 complex in dimethyl sulfoxide at 110 °C for 15 min, 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 [¹⁸F]1, compatible with clinical applications, were obtained. At the end of irradiation, the decay-corrected radiochemical yield of [¹⁸F]1 using 1 and 5 mg of precursor based on [¹⁸F]fluoride was 18.5 ± 7.9% (n = 10) and 52.0 ± 5.8% (n = 3), respectively. A single-dose of [¹⁸F]1 did not show toxicological effects for 14 days after the injection in male and female rats. In human liver microsomal incubations, [¹⁸F]1 was easily metabolized to [¹⁸F]desbenzyl-FEDAC ([¹⁸F]10) by CYPs (4.2% of parent compound left 60 min after incubation).

Conclusion

We successfully synthesized clinical grade batches of [¹⁸F]1 and verified the absence of innocuity of this radiotracer. [¹⁸F]1 will be used to first-in-human studies in our facility.