TY - JOUR
T1 - Imaging the TGFβ type I receptor in pulmonary arterial hypertension
AU - Rotteveel, Lonneke
AU - Poot, Alex J.
AU - Kooijman, Esther J. M.
AU - Schuit, Robert C.
AU - Schalij, Ingrid
AU - Sun, Xiaoqing
AU - Kurakula, Kondababu
AU - Happé, Chris
AU - Beaino, Wissam
AU - ten Dijke, Peter
AU - Lammertsma, Adriaan A.
AU - Bogaard, Harm Jan
AU - Windhorst, Albert D.
N1 - Funding Information:
We acknowledge the support from the Netherlands CardioVascular Research Initiative; the Dutch Heart Foundation, Dutch Federation of University Medical Centres, the Netherlands Organisation for Health Research and Development and the Royal Netherlands Academy of Sciences. PtD is supported by Cancer Genomics Centre Netherlands. We also acknowledge support for KK by the Dutch lung foundation grant.
Publisher Copyright:
© 2023, The Author(s).
PY - 2023
Y1 - 2023
N2 - Transforming growth factor β (TGFβ) activity is perturbed in remodelled pulmonary vasculature of patients with pulmonary arterial hypertension (PAH), cancer, vascular diseases and developmental disorders. Inhibition of TGFβ, which signals via activin receptor-like kinase 5 (ALK5), prevents progression and development of experimental PAH. The purpose of this study was to assess two ALK5 targeting positron emission tomography (PET) tracers ([11C]LR111 and [18F]EW-7197) for imaging ALK5 in monocrotaline (MCT)- and Sugen/hypoxia (SuHx)-induced PAH. Both tracers were subjected to extensive in vitro and in vivo studies. [11C]LR111 showed the highest metabolic stability, as 46 ± 2% of intact tracer was still present in rat blood plasma after 60 min. In autoradiography experiments, [11C]LR111 showed high ALK5 binding in vitro compared with controls, 3.2 and 1.5 times higher in SuHx and MCT, respectively. In addition, its binding could be blocked by SB431542, an adenosine triphosphate competitive ALK5 kinase inhibitor. However, [18F]EW-7197 showed the best in vivo results. 15 min after injection, uptake was 2.5 and 1.4 times higher in the SuHx and MCT lungs, compared with controls. Therefore, [18F]EW-7197 is a promising PET tracer for ALK5 imaging in PAH.
AB - Transforming growth factor β (TGFβ) activity is perturbed in remodelled pulmonary vasculature of patients with pulmonary arterial hypertension (PAH), cancer, vascular diseases and developmental disorders. Inhibition of TGFβ, which signals via activin receptor-like kinase 5 (ALK5), prevents progression and development of experimental PAH. The purpose of this study was to assess two ALK5 targeting positron emission tomography (PET) tracers ([11C]LR111 and [18F]EW-7197) for imaging ALK5 in monocrotaline (MCT)- and Sugen/hypoxia (SuHx)-induced PAH. Both tracers were subjected to extensive in vitro and in vivo studies. [11C]LR111 showed the highest metabolic stability, as 46 ± 2% of intact tracer was still present in rat blood plasma after 60 min. In autoradiography experiments, [11C]LR111 showed high ALK5 binding in vitro compared with controls, 3.2 and 1.5 times higher in SuHx and MCT, respectively. In addition, its binding could be blocked by SB431542, an adenosine triphosphate competitive ALK5 kinase inhibitor. However, [18F]EW-7197 showed the best in vivo results. 15 min after injection, uptake was 2.5 and 1.4 times higher in the SuHx and MCT lungs, compared with controls. Therefore, [18F]EW-7197 is a promising PET tracer for ALK5 imaging in PAH.
KW - ALK5
KW - Carbon-11
KW - Fluorine-18
KW - MCT
KW - Positron emission tomography
KW - Pulmonary arterial hypertension
KW - SuHx
KW - TGFβ type I receptor
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85150918569&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/36947258
U2 - 10.1186/s13550-023-00966-7
DO - 10.1186/s13550-023-00966-7
M3 - Article
C2 - 36947258
SN - 2191-219X
VL - 13
JO - EJNMMI Research
JF - EJNMMI Research
IS - 1
M1 - 23
ER -