An activatable PET imaging radioprobe is a dynamic reporter of myeloperoxidase activity in vivo

Abstract

Myeloperoxidase (MPO) is a critical proinflammatory enzyme implicated in cardiovascular, neurological, and rheumatological diseases. Emerging therapies targeting inflammation have raised interest in tracking MPO activity in patients. We describe ¹⁸F-MAPP, an activatable MPO activity radioprobe for positron emission tomography (PET) imaging. The activated radioprobe binds to proteins and accumulates at sites of MPO activity. The radioprobe ¹⁸F-MAPP has a short blood half-life, remains stable in plasma, does not demonstrate cytotoxicity, and crosses the intact blood–brain barrier. The ¹⁸F-MAPP imaging detected sites of elevated MPO activity in living mice embedded with human MPO and in mice induced with chemical inflammation or myocardial infarction. The ¹⁸F-MAPP PET imaging noninvasively differentiated varying amounts of MPO activity, competitive inhibition, and MPO deficiency in living animals, confirming specificity and showing that the radioprobe can quantify changes in in vivo MPO activity. The radiosynthesis has been optimized and automated, an important step in translation. These data indicate that ¹⁸F-MAPP is a promising translational candidate to noninvasively monitor MPO activity and inflammation in patients. Significance The innate immune response mediates tissue damage in many diseases, but available clinical imaging technologies do not distinguish between damaging and beneficial immune responses. We developed and validated a positron emission tomography radioprobe to noninvasively report on the activity of the damaging enzyme myeloperoxidase secreted by proinflammatory innate immune cells. The high sensitivity and specificity of the radioprobe enable the detection of damaging inflammation at an earlier stage than currently possible. Such early detection could lead to early treatment before irreversible damage occurs. With its properties characterized and synthesis automated, this radioprobe is a promising imaging biomarker ready for translation to track many diseases, including cardiovascular, neurological, and rheumatological diseases.