Purpose <p>Inflammation affects cardiac remodelling following myocardial infarction (MI), and can be imaged using Positron Emission Tomography (PET) targeting the 18 kDa translocator protein (TSPO). We utilised a rat reperfusion MI model to assess whether longitudinal [¹⁸F]LW223 could accurately measure macrophage-driven inflammation using outcome measures amenable to clinical translation, in addition to assessing the prognostic potential of [¹⁸F]LW223 for cardiac dysfunction.</p> Methods <p>Adult male Sprague–Dawley rats underwent coronary artery ligation and reperfusion to induce MI. [¹⁸F]LW223 PET/Computed Tomography was performed longitudinally on day 2, 7, 14 and 28 post-MI. On day 28, cardiac function was assessed by ultrasound. Naïve and sham rat controls were compared to the MI cohort. A separate cohort of rats were produced for histological validation and proteomic analysis.</p> Results <p>[¹⁸F]LW223 standard uptake value corrected for myocardial blood flow (<i>SUV</i>_<i>MBF</i>) was highest within the MI cohort and localised to the infarct. This peaked at day 2 and remained elevated versus naïve and sham controls out to day 28. These patterns were validated by histology, revealing that the majority of TSPO expressing cells within the infarct at day 2 were also CD68⁺ (55.2%). Proteomics confirmed upregulation of several proinflammatory processes at day 2, and a commonality in upregulated inflammatory response proteins at both day 2 and day 28, indicting ongoing inflammation. Infarct [¹⁸F]LW223 uptake at day 2 correlated with infarct size (<i>p = </i>0.0016, R² = 0.73) and cardiac dysfunction at day 28 (<i>p = </i>0.0020, R² = 0.82).</p> Conclusion <p>[¹⁸F]LW223 identifies a persistent and predominantly macrophage-driven inflammatory response with early [¹⁸F]LW223 infarct binding associated with later cardiac dysfunction.</p>