Antibody-Based In Vivo Imaging of Central Nervous System Targets-Evaluation of a Pretargeting Approach Utilizing a TCO-Conjugated Brain Shuttle Antibody and Radiolabeled Tetrazines.
Pharmaceuticals (Basel)
; 15(12)2022 Nov 22.
Article
en En
| MEDLINE
| ID: mdl-36558900
ABSTRACT
Bioorthogonal pretargeted imaging using the inverse-electron-demand Diels-Alder (IEDDA) reaction between a tetrazine (Tz) and a trans-cyclooctene (TCO) represents an attractive strategy for molecular imaging via antibodies. The advantages of using a pretargeted imaging approach are on the one hand the possibility to achieve a high signal-to-noise ratio and imaging contrast; on the other hand, the method allows the uncoupling of the biological half-life of antibodies from the physical half-life of short-lived radionuclides. A brain-penetrating antibody (mAb) specific for ß-amyloid (Aß) plaques was functionalized with TCO moieties for pretargeted labeling of Aß plaques in vitro, ex vivo, and in vivo by a tritium-labeled Tz. The overall aim was to explore the applicability of mAbs for brain imaging, using a preclinical model system. In vitro clicked mAb-TCO-Tz was able to pass the blood-brain barrier of transgenic PS2APP mice and specifically visualize Aß plaques ex vivo. Further experiments showed that click reactivity of the mAb-TCO construct in vivo persisted up to 3 days after injection by labeling Aß plaques ex vivo after incubation of brain sections with the Tz in vitro. An attempted in vivo click reaction between injected mAb-TCO and Tz did not lead to significant labeling of Aß plaques, most probably due to unfavorable in vivo properties of the used Tz and a long half-life of the mAb-TCO in the blood stream. This study clearly demonstrates that pretargeted imaging of CNS targets via antibody-based click chemistry is a viable approach. Further experiments are warranted to optimize the balance between stability and reactivity of all reactants, particularly the Tz.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Idioma:
En
Revista:
Pharmaceuticals (Basel)
Año:
2022
Tipo del documento:
Article
País de afiliación:
Suiza