Pretargeted imaging beyond the blood-brain barrier

Vladimir Shalgunov, Sara Lopes van den Broek, Ida Vang Andersen, Rocío García Vázquez, Nakul Ravi Raval, Mikael Palner, Yuki Mori, Gabriela Schäfer, Barbara Herrmann, Hannes Mikula, Natalie Beschorner, Maiken Nedergaard, Stina Syvänen, Matthias Barz, Gitte Moos Knudsen, Umberto Maria Battisti*, Matthias Manfred Herth*

*Corresponding author af dette arbejde
11 Citationer (Scopus)

Abstract

Pretargeting is a powerful nuclear imaging strategy to achieve enhanced imaging contrast for nanomedicines and reduce the radiation burden to healthy tissue. Pretargeting is based on bioorthogonal chemistry. The most attractive reaction for this purpose is currently the tetrazine ligation, which occurs between trans-cyclooctene (TCO) tags and tetrazines (Tzs). Pretargeted imaging beyond the blood-brain barrier (BBB) is challenging and has not been reported thus far. In this study, we developed Tz imaging agents that are capable of ligating in vivo to targets beyond the BBB. We chose to develop 18F-labeled Tzs as they can be applied to positron emission tomography (PET) - the most powerful molecular imaging technology. Fluorine-18 is an ideal radionuclide for PET due to its almost ideal decay properties. As a non-metal radionuclide, fluorine-18 also allows for development of Tzs with physicochemical properties enabling passive brain diffusion. To develop these imaging agents, we applied a rational drug design approach. This approach was based on estimated and experimentally determined parameters such as the BBB score, pretargeted autoradiography contrast, in vivo brain influx and washout as well as on peripheral metabolism profiles. From 18 initially developed structures, five Tzs were selected to be tested for their in vivo click performance. Whereas all selected structures clicked in vivo to TCO-polymer deposited into the brain, [18F]18 displayed the most favorable characteristics with respect to brain pretargeting. [18F]18 is our lead compound for future pretargeted neuroimaging studies based on BBB-penetrant monoclonal antibodies. Pretargeting beyond the BBB will allow us to image targets in the brain that are currently not imageable, such as soluble oligomers of neurodegeneration biomarker proteins. Imaging of such currently non-imageable targets will allow early diagnosis and personalized treatment monitoring. This in turn will accelerate drug development and greatly benefit patient care.

OriginalsprogEngelsk
TidsskriftRSC medicinal chemistry
Vol/bind14
Udgave nummer3
Sider (fra-til)444-453
Antal sider10
ISSN2632-8682
DOI
StatusUdgivet - 22 mar. 2023

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