APJ has been extensively described in the pathophysiology of angiogenesis and cell proliferation. The prognostic value of APJ overexpression in many diseases is now established. This study aimed to design a PET radiotracer that specifically binds to APJ. Apelin-F13A-NODAGA (AP747) was synthesized and radiolabeled with gallium-68 ([68Ga]Ga-AP747). Radiolabeling purity was excellent (> 95%) and stable up to 2 h. Affinity constant of [67Ga]Ga-AP747 was measured on APJ-overexpressing colon adenocarcinoma cells and was in nanomolar range. Specificity of [68Ga]Ga-AP747 for APJ was evaluated in vitro by autoradiography and in vivo by small animal PET/CT in both colon adenocarcinoma mouse model and Matrigel plug mouse model. Dynamic of [68Ga]Ga-AP747 PET/CT biodistributions was realized on healthy mice and pigs for two hours, and quantification of signal in organs showed a suitable pharmacokinetic profile for PET imaging, largely excreted by urinary route. Matrigel mice and hindlimb ischemic mice were submitted to a 21-day longitudinal follow-up with [68Ga]Ga-AP747 and [68Ga]Ga-RGD2 small animal PET/CT. [68Ga]Ga-AP747 PET signal in Matrigel was significantly more intense than that of [68Ga]Ga-RGD2. Revascularization of the ischemic hind limb was followed by LASER Doppler. In the hindlimb, [68Ga]Ga-AP747 PET signal was more than twice higher than that of [68Ga]Ga-RGD2 on day 7, and significantly superior over the 21-day follow-up. A significant, positive correlation was found between the [68Ga]Ga-AP747 PET signal on day 7 and late hindlimb perfusion on day 21. We developed a new PET radiotracer that specifically binds to APJ, [68Ga]Ga-AP747 that showed more efficient imaging properties than the most clinically advanced tracer of angiogenesis, [68Ga]Ga-RGD2.
Keywords: APJ; Angiogenesis; Apelin; PET imaging; Theranostics.
© 2023. The Author(s).