[ ¹⁸ F]Fluoronicotinic-Acid-Conjugated Folate as a Novel Candidate Positron Emission Tomography Tracer for Inflammation

Folate receptors are clinically relevant targets, as evidenced by therapeutic agents, including mirvetuximab soravtansine-gynx, an antibody-drug conjugate recently approved for cancer treatment. In this study, we report the development of a novel positron emission tomography (PET) imaging agent, [¹⁸F]-fluoronicotinic-acid-conjugated folate ([¹⁸F]-FNA-folate), for the evaluation of folate receptor expression. The [¹⁸F]-FNA-folate was synthesized via the N-acylation of an amino-functionalized folate derivative with [¹⁸F]-FNA 4-nitrophenyl ester under mild reaction conditions. The resulting radiotracer exhibited excellent <i>in vitro</i> and <i>in vivo</i> stability, rapid blood clearance, and minimal bone uptake in mice and rats. <i>In vitro</i> tissue binding studies using heart sections from an experimental rat model of myocardial infarction demonstrated focal, intense, and heterogeneous uptake of [¹⁸F]-FNA-folate, and the binding specificity to macrophage folate receptors was confirmed. The straightforward radiosynthesis, excellent <i>in vivo</i> stability, and target-specific binding support further development of [¹⁸F]-FNA-folate as a promising PET imaging agent for inflammatory diseases.