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Targeting of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Protein with a Technetium‐99m Imaging Probe
Author(s) -
Ferreira Vera F. C.,
Oliveira Bruno L.,
Santos João D.,
Correia João D. G.,
Farinha Carlos M.,
Mendes Filipa
Publication year - 2018
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201800187
Subject(s) - cystic fibrosis transmembrane conductance regulator , cystic fibrosis , chemistry , transmembrane protein , technetium 99m , mutation , regulator , technetium , biophysics , microbiology and biotechnology , biochemistry , gene , biology , medicine , scintigraphy , receptor , nuclear chemistry
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, CFTR inh ‐172a, with technetium‐99m via a pyrazolyl‐diamine chelating unit, yielding a novel 99m Tc(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.