The Next Generation of Cardiac Positron Emission Tomography Imaging Agents: Discovery of Flurpiridaz F-18 for Detection of Coronary Disease

Myocardial perfusion imaging (MPI) with thallium 201 (201Tl) or 99mTc based imaging agents has become a major tool for noninvasive identification of coronary artery disease (CAD). However, single photon emission computed tomography (SPECT) imaging with the current agents is vulnerable to artifacts associated with soft tissue attenuation, proximal gastrointestinal activity, image quality, and suboptimal sensitivity and is limited by the degree of first-pass myocardial extraction. The development of 18F-based flurpiridaz F-18 takes advantage of positron emission tomography (PET) to overcome many of the imaging issues and structural design to achieve an ideal MPI agent profile. Flurpiridaz F-18 was designed to bind to mitochondrial complex I with high affinity and demonstrates high heart uptake in multiple species with clear delineation of perfusion deficits. It exhibits rapid uptake in the myocardium, prolonged retention, and superior extraction versus flow profiles compared with 201Tl and 99mTc-sestamibi. A first in man study has established the safety and dosimetry of flurpiridaz F-18 and confirmed high sustained cardiac uptake. Subsequent studies performed in CAD patients established the dose and timing needed to detect perfusion deficits when the agent is administered under rest and stress conditions. This review compares the current preclinical and clinical data with an ideal MPI agent profile. The assessment indicates flurpiridaz F-18 represents a new generation of PET MPI agents and demonstrates significantly improved molecular and imaging characteristics.