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肺动脉高压中转化生长因子βⅠ型受体的成像

Imaging the TGFβ type I receptor in pulmonary arterial hypertension.

作者信息

Rotteveel Lonneke, Poot Alex J, Kooijman Esther J M, Schuit Robert C, Schalij Ingrid, Sun Xiaoqing, Kurakula Kondababu, Happé Chris, Beaino Wissam, Ten Dijke Peter, Lammertsma Adriaan A, Bogaard Harm Jan, Windhorst Albert D

机构信息

Department Radiology and Nuclear Medicine(s), (Amsterdam Cardiovascular Sciences), Amsterdam UMC, VU University Medical Center, de Boelelaan 1117, Amsterdam, The Netherlands.

Department Pulmonary Medicine, (Amsterdam Cardiovascular Sciences), Amsterdam UMC, VU University Medical Center, de Boelelaan 1117, Amsterdam, The Netherlands.

出版信息

EJNMMI Res. 2023 Mar 22;13(1):23. doi: 10.1186/s13550-023-00966-7.

DOI:10.1186/s13550-023-00966-7
PMID:36947258
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10033812/
Abstract

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 ([C]LR111 and [F]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. [C]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, [C]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, [F]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, [F]EW-7197 is a promising PET tracer for ALK5 imaging in PAH.

摘要

在肺动脉高压（PAH）、癌症、血管疾病和发育障碍患者的重塑肺血管中，转化生长因子β（TGFβ）活性受到干扰。通过激活素受体样激酶5（ALK5）发出信号的TGFβ的抑制可预防实验性PAH的进展和发展。本研究的目的是评估两种靶向ALK5的正电子发射断层扫描（PET）示踪剂（[C]LR111和[F]EW-7197）用于在野百合碱（MCT）和Sugen/低氧（SuHx）诱导的PAH中对ALK5进行成像。两种示踪剂都进行了广泛的体外和体内研究。[C]LR111表现出最高的代谢稳定性，60分钟后大鼠血浆中仍有46±2%的完整示踪剂。在放射自显影实验中，与对照组相比，[C]LR111在体外显示出高ALK5结合，在SuHx和MCT中分别高3.2倍和1.5倍。此外，其结合可被SB431542（一种三磷酸腺苷竞争性ALK5激酶抑制剂）阻断。然而，[F]EW-7197显示出最佳的体内结果。注射后15分钟，与对照组相比，SuHx和MCT肺中的摄取分别高2.5倍和1.4倍。因此，[F]EW-7197是一种有前途的用于PAH中ALK5成像的PET示踪剂。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e174/10033812/888dc2694167/13550_2023_966_Fig9_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e174/10033812/7143f3f95c05/13550_2023_966_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e174/10033812/fc3469de83f5/13550_2023_966_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e174/10033812/ced34fc05f4a/13550_2023_966_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e174/10033812/888dc2694167/13550_2023_966_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e174/10033812/d39740443950/13550_2023_966_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e174/10033812/2408c43343ba/13550_2023_966_Fig2_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e174/10033812/f3434d0729b0/13550_2023_966_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e174/10033812/5611ae869e8d/13550_2023_966_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e174/10033812/7143f3f95c05/13550_2023_966_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e174/10033812/fc3469de83f5/13550_2023_966_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e174/10033812/ced34fc05f4a/13550_2023_966_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e174/10033812/888dc2694167/13550_2023_966_Fig9_HTML.jpg

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