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Imaging the TGFβ type I receptor in pulmonary arterial hypertension

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.

 

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The purpose of this study was to evaluate the efficacy of two ALK5-targeting PET tracers ([11C]LR111 and [18F]EW-7197) for imaging ALK5 in monocrotaline (MCT)- and Sugen/hypoxia (SuHx)-induced pulmonary arterial hypertension (PAH). The authors found that both tracers exhibited strong binding to ALK5 in vitro, with [11C]LR111 demonstrating greater metabolic stability in vivo, while [18F]EW-7197 exhibited superior in vivo imaging results.

The study highlights the potential of ALK5-targeting PET tracers for diagnosing and monitoring PAH, as inhibition of TGFβ via ALK5 signaling has been shown to prevent the development and progression of experimental PAH. The results of this study suggest that [18F]EW-7197 may be a promising PET tracer for ALK5 imaging in PAH, given its strong in vivo performance. However, further research is needed to determine the clinical utility of these tracers and their potential applications in the diagnosis and treatment of PAH and other diseases characterized by perturbed TGFβ activity.

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S3812 Monocrotaline Monocrotaline (MCT, Crotaline) is an 11-membered macrocyclic pyrrolizidine alkaloid (PA) that causes a pulmonary vascular syndrome in rats characterized by proliferative pulmonary vasculitis, pulmonary hypertension, and cor pulmonale.Monocrotaline can be used to induce animal models of Pulmonary Hypertension.

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