Folate receptor β-targeted Positron emission tomography imaging of activated macrophages in experimental myocardial infarction

Abstract

Background: Folate receptor β (FR-β) is expressed on activated macrophages in inflammatory conditions. In order to study FR-β in inflammatory response following myocardial infarction (MI), we evaluated FR-β-targeted PET imaging using aluminum fluoride-18-labeled NOTA-folate ([¹⁸F]FOL) in a rat model of MI.

Methods: Rats underwent [¹⁸F]FOL PET imaging on 3, 7, 15, and 90 days after induction of MI by permanent coronary artery ligation or sham operation. [¹⁸F]FDG PET was performed a day before [¹⁸F]FOL scans to localize the infarct area. A subset of rats underwent [¹⁸F]FOL PET on day 7 and serial echocardiography until 90 days post-surgery.

Results: The [¹⁸F]FOL uptake was significantly higher in the infarct area than in the myocardium of sham-operated rats on day 3 (SUV 1.97 ± 0.17 vs 0.74 ± 0.13), and remained higher on day 7 (SUV 1.35 ± 0.33 vs 0.70 ± 0.16), day 15 (SUV 1.24 ± 0.20 vs 0.59 ± 0.07), and day 90 (SUV 1.39 ± 0.25 vs 0.69 ± 0.11). Autoradiography of tissue sections confirmed tracer uptake in the infarct area, where immunofluorescence showed FR-β in CD68-positive macrophages. Uptake of [¹⁸F]FOL correlated with CD68-positive macrophage density (r = 0.669, P < 0.001) and was associated with decline in left ventricular ejection fraction between days 7 and 90 post-MI (r = -0.665, P = 0.007).

Conclusion: [¹⁸F]FOL PET detects expression of FR-β, a marker of activated macrophages after MI. FR-β expression peaks early and remains elevated up to 3 months post-MI. Early FR-β expression is associated with worsening of left ventricular systolic function.

Keywords: Ejection fraction; Folate receptor β; Macrophage; Myocardial infarction; PET; Rat.