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Improved Metabolic Stability for 18F PET Probes Rapidly Constructed via Tetrazine trans-Cyclooctene Ligation
journal contribution
posted on 2015-03-18, 00:00 authored by Ramajeyam Selvaraj, Benjamin Giglio, Shuanglong Liu, Hui Wang, Mengzhe Wang, Hong Yuan, Srinivasa
R. Chintala, Li-Peng Yap, Peter S. Conti, Joseph M. Fox, Zibo LiThe
fast kinetics and bioorthogonal nature of the tetrazine trans-cyclooctene (TCO) ligation makes it a unique tool
for PET probe construction. In this study, we report the development
of an 18F-labeling system based on a CF3-substituted
diphenyl-s-tetrazine derivative with the aim of maintaining
high reactivity while increasing in vivo stability. c(RGDyK) was tagged
by a CF3-substituted diphenyl-s-tetrazine
derivative via EDC-mediated coupling. The resulting tetrazine-RGD
conjugate was combined with a 19F-labeled TCO derivative
to give HPLC standards. The analogous 18F-labeled TCO derivative
was combined with the diphenyl-s-tetrazine-RGD at
μM concentration. The resulting tracer was subjected to in vivo
metabolic stability assessment, and microPET studies in murine U87MG
xenograft models. The diphenyl-s-tetrazine-RGD combines
with an 18F-labeled TCO in high yields (>97% decay-corrected
on the basis of TCO) using only 4 equiv of tetrazine-RGD relative
to the 18F-labeled TCO (concentration calculated based
on product’s specific activity). The radiochemical purity of
the 18F-RGD peptides was >95% and the specific activity
was 111 GBq/μmol. Noninvasive microPET experiments demonstrated
that 18F-RGD had integrin-specific tumor uptake in subcutaneous
U87MG glioma. In vivo metabolic stability of 18F-RGD in
blood, urine, and major organs showed two major peaks: one corresponded
to the Diels–Alder conjugate and the other was identified as
the aromatized analog. A CF3-substituted diphenyl-s-tetrazine displays excellent speed and efficiency in 18F-PET probe construction, providing nearly quantitative 18F labeling within minutes at low micromolar concentrations.
The resulting conjugates display improved in vivo metabolic stability
relative to our previously described system.
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bioorthogonal natureμ M concentrationmicromolar concentrationsPET probe construction18 FTCOsubcutaneous U 87MG gliomaaromatized analog18 F PET Probes Rapidly ConstructedMetabolic Stabilityvivo stabilityHPLC standardsmurine U 87MG xenograft modelsstability assessmentCFmicroPET studiesconjugates displayradiochemical purity4 equiv
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