Targeting of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Protein with a Technetium‐99m Imaging Probe |
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| Authors: | Vera F C Ferreira Dr Bruno L Oliveira João D Santos Dr João D G Correia Prof?Dr Carlos M Farinha Dr Filipa Mendes |
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| Affiliation: | 1. C2TN—Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Bobadela LRS, Portugal;2. Current address: Department of Chemistry, University of Cambridge, Cambridge, UK;3. BioISI—Biosystems and Integrative Sciences Institute, Faculty of Sciences, Universidade de Lisboa, Lisboa, Portugal |
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| Abstract: | Cystic fibrosis (CF) is caused by mutations in the gene that encodes the CF transmembrane conductance regulator (CFTR) protein. The most common mutation, F508del, leads to almost total absence of CFTR at the plasma membrane, a defect potentially corrected via drug‐based therapies. Herein, we report the first proof‐of‐principle study of a noninvasive imaging probe able to detect CFTR at the plasma membrane. We radiolabeled the CFTR inhibitor, CFTRinh‐172a, with technetium‐99m via a pyrazolyl‐diamine chelating unit, yielding a novel 99mTc(CO)3 complex. A non‐radioactive surrogate showed that the structural modifications introduced in the inhibitor did not affect its activity. The radioactive complex was able to detect plasma membrane CFTR, shown by its significantly higher uptake in wild‐type versus mutated cells. Furthermore, assessment of F508del CFTR pharmacological correction in human cells using the radioactive complex revealed differences in corrector versus control uptake, recapitulating the biochemical correction observed for the protein. |
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| Keywords: | CFTR cystic fibrosis imaging agents radiopharmaceuticals technetium |
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