Publication date: Jul 27, 2024
The angiotensin converting enzyme 2 (ACE2) plays a regulatory role in the cardiovascular system and serves SARS-CoV-2 as an entry receptor. The aim of this study was to synthesize and evaluate radiofluorinated derivatives of the ACE2 inhibitor MLN-4760. [F]F-MLN-4760 and [F]F-Aza-MLN-4760 were demonstrated to be suitable for non-invasive imaging of ACE2, potentially enabling a better understanding of its expression dynamics. Computational molecular modeling, based on the structures of human ACE2 (hACE2) and mouse ACE2 (mACE2), revealed that the ACE2-binding modes of F-MLN-4760 and F-Aza-MLN-4760 were similar to that of MLN-4760. Co-crystallization of the hACE2/F-MLN-4760 protein complex was performed for confirmation. Displacement experiments using [H]MLN-4760 enabled the determination of the binding affinities of the synthesized F-MLN-4760 and F-Aza-MLN-4760 to hACE2 expressed in HEK-ACE2 cells. Aryl trimethylstannane-based and pyridine-based radiofluorination precursors were synthesized and used for the preparation of the respective radiotracers. [F]F-MLN-4760 and [F]F-Aza-MLN-4760 were evaluated with regard to the uptake in HEK-ACE2 and HEK-ACE cells and in vitro binding to tissue sections of HEK-ACE2 xenografts and normal organs of mice. Biodistribution and PET/CT imaging studies of [F]F-MLN-4760 and [F]F-Aza-MLN-4760 were performed using HEK-ACE2 and HEK-ACE xenografted nude mice. Crystallography data revealed an equal hACE2-binding mode for F-MLN-4760 as previously found for MLN-4760. Moreover, computer-based modeling indicated that similar binding to hACE2 and mACE2 holds true for both, F-MLN-4760 and F-Aza-MLN-4760, as is the case for MLN-4760. The IC values were three-fold and seven-fold higher for F-MLN-4760 and F-Aza-MLN-4760, respectively, than for MLN-4760. [F]F-MLN-4760 and [F]F-Aza-MLN-4760 were obtained in 1. 4 +/- 0. 3 GBq and 0. 5 +/- 0. 1 GBq activity with > 99% radiochemical purity in a 5. 3% and 1. 2% radiochemical yield, respectively. Uptake in HEK-ACE2 cells was higher for [F]F-MLN-4760 (67 +/- 9%) than for [F]F-Aza-MLN-4760 (37 +/- 8%) after 3-h incubation while negligible uptake was seen in HEK-ACE cells (
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| Concepts | Keywords |
|---|---|
| Biodistribution | ACE |
| Ct | ACE2 |
| Mice | Crystallography |
| Negligible | Fluorine-18 |
| Radiofluorinated | MLN-4760 |
| PET | |
| SARS-CoV-2 |
Semantics
| Type | Source | Name |
|---|---|---|
| drug | DRUGBANK | Angiotensin II |
| disease | VO | regulatory role |
| drug | DRUGBANK | Tropicamide |
| drug | DRUGBANK | Aspartame |
| drug | DRUGBANK | Ethionamide |
| disease | VO | organization |
| disease | MESH | Covid 19 pandemic |
| disease | MESH | infections |
| disease | MESH | syndrome |
| drug | DRUGBANK | Bradykinin |
| disease | IDO | infection |
| disease | IDO | susceptibility |
| disease | MESH | hypertension |
| disease | MESH | ischemia |
| disease | MESH | atherosclerosis |
| drug | DRUGBANK | Fluorine F-18 |