De Dominicis Carlo, Perrotta Paola, Dall'Angelo Sergio, Wyffels Leonie, Staelens Steven, De Meyer G R Y, Zanda Matteo
Kosterlitz Centre for Therapeutics, University of Aberdeen, AB25 2ZD Foresterhill, Aberdeen, U.K.
Laboratory of Physiopharmacology, University of Antwerp, 2610 Antwerpen, Belgium.
ACS Med Chem Lett. 2020 Feb 19;11(5):933-939. doi: 10.1021/acsmedchemlett.9b00677. eCollection 2020 May 14.
PFKFB3, a glycolysis-related enzyme upregulated in inflammatory conditions and angiogenesis, is an emerging target for diagnosis and therapy of atherosclerosis. The fluorinated phenoxindazole [F] was synthesized, radiolabeled in 17 ± 5% radiochemical yield and >99% radiochemical purity, and formulated for preclinical PET/CT imaging in mice. stability analysis showed no significant metabolite formation. Biodistribution studies showed high blood pool activity and slow hepatobiliary clearance. Significant activity was detected in the lung 2 h postinjection (pi) (11.0 ± 1.5%ID/g), while at 6 h pi no pulmonary background was observed. autoradiography at 6 h pi showed significant high uptake of [F] in the arch region and brachiocephalic artery of atherosclerotic mice, and no uptake in control mice, matching plaques distribution seen by lipid staining along with PFKFB3 expression seen by immunofluorescent staining. PET scans showed higher aortic region uptake of [F] in atherosclerotic ApoEFbn1 than in control mice (0.78 ± 0.05 vs 0.44 ± 0.09%ID/g). [F] was detected in aortic arch and brachiocephalic artery of ApoE (with moderate atherosclerosis) and ApoEFbn1 (with severe, advanced atherosclerosis) mice, suggesting this tracer may be useful for the noninvasive detection of atherosclerotic plaques .
磷酸果糖激酶-2/果糖-2,6-二磷酸酶3（PFKFB3）是一种在炎症和血管生成过程中上调的糖酵解相关酶，是动脉粥样硬化诊断和治疗的新兴靶点。合成了氟化苯并异吲哚酮[F]，其放射性标记的放射化学产率为17±5%，放射化学纯度>99%，并将其配制成用于小鼠临床前PET/CT成像。稳定性分析表明没有显著的代谢物形成。生物分布研究显示血池活性高且肝胆清除缓慢。注射后2小时（pi）在肺部检测到显著活性（11.0±1.5%ID/g），而在注射后6小时未观察到肺部本底。注射后6小时的放射自显影显示，[F]在动脉粥样硬化小鼠的主动脉弓区域和头臂动脉中有显著高摄取，而在对照小鼠中无摄取，这与脂质染色所见的斑块分布以及免疫荧光染色所见的PFKFB3表达相匹配。PET扫描显示，动脉粥样硬化ApoE基因敲除小鼠的主动脉区域对[F]的摄取高于对照小鼠（0.78±0.05 vs 0.44±0.09%ID/g）。在载脂蛋白E（中度动脉粥样硬化）和ApoE基因敲除小鼠（重度、晚期动脉粥样硬化）的主动脉弓和头臂动脉中检测到[F]，表明该示踪剂可能有助于动脉粥样硬化斑块的无创检测。
