Myocardial perfusion imaging (MPI), a versatile tool for clinical diagnosis, plays an important role in the noninvasive measurement of coronary artery disease (CAD). Currently, common single-photon emission computed tomography (SPECT) MPI agents for determining myocardial blood flow (MBF) in patients comprise 201Tl or 99mTc-complexes, such as 99mTc‑sestamibi and 99mTc-tetrofosmin. However, SPECT imaging agents have inherent limitations, including the continuing threat of serious shortages of 99mMo/99mTc-generators. Additionally, current SPECT tracers also suffer from shortcomings in pharmacokinetics, low myocardial first-pass extraction, redistribution of the radiotracer to non-targeted tissues over time, and non-linearity of radiotracer uptake at elevated blood flow (the “roll-off” phenomenon). By comparison, positron emission tomography (PET) provides technical advantages, including higher spatial resolution, improved attenuation correction, and the capability to perform quantitative measurements at the peak of stress. Commonly employed PET MPI tracers are: 82RbCl, 13NH3, and H215O. However, the utility of these agents is limited due to their short physical half-life (less than 10 minutes), which pose difficulties for easy access to these agents. Additionally, a few promising 18F-labeled agents, such as mitochondrial membrane potential probe 18F-BnTP and mitochondrial complex I inhibitors 18F‑BMS-747158, 18F-10, 18F-RP1004, and 18F-MCI27, have also emerged as promising leads. However, aside from biochemical properties of various strengths and weaknesses, these agents also depend on an 18F-based radiopharmaceutical distribution model, which may not readily apply to all sites within the U.S. or other countries in the world. Thus, PET tracers demonstrating high myocardial first pass extraction, and rapid excretion from adjoining organs, while incorporating generator-produced, rather than cyclotron-produced, isotopes could potentially enable portable technologies, facilitating wide access to PET MPI agents.
Through structure-activity relationships (SAR), we have identified a lead PET agent that penetrates myocardium cells, localizes into mitochondria, and displays promising characteristics as a noninvasive MPI probe in vivo. Further validations and characterization in nonhuman primates are in progress.