Retention of ⁶⁴Cu-FLFLF, a Formyl Peptide Receptor 1-Specific PET Probe, Correlates with Macrophage and Neutrophil Abundance in Lung Granulomas from Cynomolgus Macaques

Abstract

Neutrophilic inflammation correlates with severe tuberculosis (TB), a disease caused by <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>). Granulomas are lesions that form in TB, and a PET probe for following neutrophil recruitment to granulomas could predict disease progression. We tested the formyl peptide receptor 1 (FPR1)-targeting peptide FLFLF in <i>Mtb</i>-infected macaques. Preliminary studies in mice demonstrated specificity for neutrophils. In macaques, ⁶⁴Cu-FLFLF was retained in lung granulomas and analysis of lung granulomas identified positive correlations between ⁶⁴Cu-FLFLF and neutrophil and macrophage numbers (R² = 0.8681 and 0.7643, respectively), and weaker correlations for T cells and B cells (R² = 0.5744 and 0.5908, respectively), suggesting that multiple cell types drive ⁶⁴Cu-FLFLF avidity. By PET/CT imaging, we found that granulomas retained ⁶⁴Cu-FLFLF but with less avidity than the glucose analog ¹⁸F-FDG. These studies suggest that neutrophil-specific probes have potential PET/CT applications in TB, but important issues need to be addressed before they can be used in nonhuman primates and humans.