[¹⁸F]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 in vitro and in vivo stability, rapid blood clearance, and minimal bone uptake in mice and rats. In vitro 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 in vivo stability, and target-specific binding support further development of [¹⁸F]-FNA-folate as a promising PET imaging agent for inflammatory diseases.