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Metabolism of a Bioorthogonal PET Tracer Candidate [19F/18F]SiFA-Tetrazine in Mouse Liver Microsomes: Biotransformation Pathways and Defluorination Investigated by UHPLC-HRMS
Version 2 2020-07-07, 13:11
Version 1 2020-07-01, 21:03
journal contribution
posted on 2020-07-07, 13:11 authored by Sofia Otaru, Hanna Niemikoski, Mirkka Sarparanta, Anu J. AiraksinenOrganofluorosilicon based 18F-radiolabeling is an efficient
method for incorporating fluorine-18 into 18F-radiopharmaceuticals
for positron emission tomography (PET) by 19F/18F isotopic exchange (IE). The first PET radiopharmaceutical, 18F-SiFAlin-TATE, radiolabeled with a silicon-based
[18F]fluoride acceptor (SiFA), namely, a para-substituted
di-tert-butyl[18F]fluorosilylbenzene,
has entered clinical trials, and is paving the way for other potential
[18F]SiFA-labeled radiopharmaceuticals for diagnostic use.
In this study, we report the in vitro metabolism
of an oxime-linked SiFA tetrazine (SiFA–Tz), a new PET-radiotracer
candidate, recently evaluated for pretargeted PET imaging and macromolecule
labeling. Metabolism of SiFA–Tz was studied in mouse liver
microsomes (MLM) for elucidating its major biotransformation pathways.
Nontargeted screening by ultrahigh performance liquid chromatography
high-resolution mass spectrometry (UHPLC-HRMS) was utilized for detection
of unknown metabolites. The oxime bond between the SiFA and Tz groups
forms two geometric (E/Z) isomers,
which underwent the same biotransformations, but unexpectedly with
different kinetics. In total, nine proposed metabolites of SiFA–Tz
from phase I and II reactions were detected, five of which were defluorinated
in MLMs, elucidating the metabolic pathway leading to previously reported
defluorination of [18F]SiFA–Tz in vivo. Based on the HRMS studies a biotransformation pathway is proposed:
hydroxylation (+O) to tert-butyl group adjacent to
the silicon, followed by oxidative defluorination (+OH/-F) cleaving
the fluorine off the silicon. Interestingly, eight proposed metabolites
of a reduced dihydrotetrazine analogue, SiFA–H2Tz,
from phase I and II reactions were additionally detected. To the best
of our knowledge, this is the first reported comprehensive investigation
of enzyme mediated metabolic pathway of tetrazines and para-substituted
di-tert-butylfluorosilylbenzene fluoride acceptors,
providing novel structural information on the biotransformation and
fragmentation patterns of radiotracers bearing these structural motifs.
By investigating the metabolism preceding defluorination, structurally
optimized new SiFA compounds can be designed for expanding the portfolio
of efficient 19F/18F isotopic exchange labeling
probes for PET imaging.
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Tz groups formsmetabolitepara-substituted diOHdefluorinationTATEtertII reactionspositron emission tomographyUHPLC-HRMSMouse Liver Microsomesbiotransformationoxime-linked SiFA tetrazinemouse liver microsomespretargeted PET imagingBioorthogonal PET Tracer CandidatepathwayMLMIE18 F-SiFA linHRMSbutylfluorosilylbenzene fluoride ac...
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