Azcona Juan A, Wacker Anja S, Lee Chul-Hee, Fung Edward K, Jeitner Thomas M, Manzo Onorina L, Di Lorenzo Annarita, Babich John W, Amor-Coarasa Alejandro, Kelly James M
Department of Radiology, Weill Cornell Medicine, 413 E 69th Street, Room BB-1604, New York, NY, 10021, USA.
Citigroup Biomedical Imaging Center, Weill Cornell Medicine, New York, NY, USA.
Mol Imaging Biol. 2025 Feb;27(1):109-119. doi: 10.1007/s11307-024-01978-y. Epub 2025 Jan 14.
Treatment of pediatric cancers with doxorubicin is a common and predictable cause of cardiomyopathy. Early diagnosis of treatment-induced cardiotoxicity and intervention are major determinants for the prevention of advanced disease. The onset of cardiomyopathies is often accompanied by profound changes in lipid metabolism, including an enhanced uptake of short-chain fatty acids (SCFA). Therefore, we explored the utility of 2-[F]fluoropropionic acid ([F]FPA), an SCFA analog, as an imaging biomarker of cardiac injury in mice exposed to doxorubicin.
Cardiotoxicity and cardiac dysfunction were induced in mice by an 8-dose regimen of doxorubicin (cumulative dose 24 mg/kg) administered over 14 days. The effects of doxorubicin exposure were assessed by measurement of heart weights, left ventricular ejection fractions, and blood cardiac troponin levels. Whole body and cardiac [F]FPA uptakes were determined by PET and tissue gamma counting in the presence or absence of AZD3965, a pharmacological inhibitor of monocarboxylate transporter 1 (MCT1). Radiation absorbed doses were estimated using tissue time-activity concentrations.
Significantly higher cardiac [F]FPA uptake was observed in doxorubicin-treated animals. This uptake remained constant from 30 to 120 min post-injection. Pharmacological inhibition of MCT1-mediated transport by AZD3965 selectively decreased the uptake of [F]FPA in tissues other than the heart. Co-administration of [F]FPA and AZD3965 enhanced the imaging contrast of the diseased heart while reducing overall exposure to radioactivity.
[F]FPA, especially when co-administered with AZD3965, is a new tool for imaging changes in fatty acid metabolism occurring in response to doxorubicin-induced cardiomyopathy by PET.
用多柔比星治疗儿童癌症是导致心肌病的常见且可预测的原因。治疗诱导的心脏毒性的早期诊断和干预是预防晚期疾病的主要决定因素。心肌病的发作通常伴随着脂质代谢的深刻变化，包括短链脂肪酸（SCFA）摄取增加。因此，我们探讨了SCFA类似物2-[F]氟丙酸（[F]FPA）作为暴露于多柔比星的小鼠心脏损伤成像生物标志物的效用。
通过在14天内给予8剂多柔比星（累积剂量24mg/kg）诱导小鼠心脏毒性和心脏功能障碍。通过测量心脏重量、左心室射血分数和血中心肌肌钙蛋白水平评估多柔比星暴露的影响。在存在或不存在单羧酸转运蛋白1（MCT1）的药理学抑制剂AZD3965的情况下，通过PET和组织γ计数测定全身和心脏的[F]FPA摄取。使用组织时间-活性浓度估计辐射吸收剂量。
在多柔比星治疗的动物中观察到心脏[F]FPA摄取显著更高。该摄取在注射后30至120分钟保持恒定。AZD3965对MCT1介导的转运的药理学抑制选择性地降低了心脏以外组织中[F]FPA的摄取。[F]FPA与AZD3965共同给药增强了患病心脏的成像对比度，同时减少了总体放射性暴露。
[F]FPA，特别是与AZD3965共同给药时，是一种通过PET成像多柔比星诱导的心肌病引起的脂肪酸代谢变化的新工具。
