1 research outputs found
Characterization of Structurally Diverse <sup>18</sup>F‑Labeled d‑TCO Derivatives as a PET Probe for Bioorthogonal Pretargeted Imaging
Background: The pretargeted
imaging
strategy using inverse electron demand Diels–Alder (IEDDA)
cycloaddition between a trans-cyclooctene (TCO) and
tetrazine (Tz) has emerged and rapidly grown as a promising concept
to improve radionuclide imaging and therapy in oncology. This strategy
has mostly relied on the use of radiolabeled Tz together with TCO-modified
targeting vectors leading to a rapid growth of the number of available
radiolabeled tetrazines, while only a few radiolabeled TCOs are currently
reported. Here, we aim to develop novel and structurally diverse 18F-labeled cis-dioxolane-fused TCO (d-TCO) derivatives to
further expand the bioorthogonal toolbox for in vivo ligation and evaluate their potential for positron emission tomography
(PET) pretargeted imaging. Results: A small series of d-TCO derivatives were synthesized and
tested for their reactivity against tetrazines, with all compounds
showing fast reaction kinetics with tetrazines. A fluorescence-based
pretargeted blocking study was developed to investigate the in vivo ligation of these compounds without labor-intensive
prior radiochemical development. Two compounds showed excellent in vivo ligation results with blocking efficiencies of 95
and 97%. Two novel 18F-labeled d-TCO radiotracers were
developed, from which [18F]MICA-214 showed good in vitro stability,
favorable pharmacokinetics, and moderate in vivo stability.
Micro-PET pretargeted imaging with [18F]MICA-214 in mice bearing LS174T tumors treated
with tetrazine-modified CC49 monoclonal antibody (mAb) (CC49-Tz) showed
significantly higher uptake in tumor tissue in the pretargeted group
(CC49-Tz 2.16 ± 0.08% ID/mL) when compared to the control group
with nonmodified mAb (CC49 1.34 ± 0.07% ID/mL). Conclusions: A diverse series of fast-reacting
fluorinated d-TCOs were synthesized. A pretargeted blocking approach
in tumor-bearing mice allowed the choice of a lead compound with fast
reaction kinetics with Tz. A novel 18F-labeled d-TCO tracer
was developed and used in a pretargeted PET imaging approach, allowing
specific tumor visualization in a mouse model of colorectal cancer.
Although further optimization of the radiotracer is needed to enhance
the tumor-to-background ratios for pretargeted imaging, we anticipate
that the 18F-labeled d-TCO will find use in studies where
increased hydrophilicity and fast bioconjugation are required