Developing a new PET myocardial perfusion tracer

Abstract

Myocardial perfusion imaging is the most commonly used procedure in nuclear medicine. Availability of thallium-201 made it possible to study myocardial perfusion non-invasively at rest and with exercise in mid70s. Development of Tc-99m based perfusion tracers (Tc-sestamibi and Tc-ttrofosminin) in early 90s overcame many of the limitations of Tl-201 and is largely responsible for MPI becoming the centerpiece of non-invasive techniques for the evaluation of coronary artery disease. Despite the widespread use of Tc labeled myocardial perfusion tracers, artifacts due to attenuation and extra-cardiac activity continue to be important limitations of these agents. Furthermore, these agents do not provide quantitative information about myocardial blood flow. Therefore, the search for an ideal perfusion tracer is still on. Positron emission tomography (PET) offers several advantages over single photon emission computed tomography (SPECT): better imaging characteristics due to higher photon flux, more robust attenuation correction, shorter image acquisition time and possibility of obtaining quantitative information about myocardial perfusion. It is thought PET imaging may be able to overcome the limitations of currently used SPECT perfusion tracers. Whereas a number of PET tracers are currently available for myocardial perfusion imaging, they all suffer from significant limitations: N-ammonia and O-water require on-site cyclotron for their production, Rb is generator produced, but given an extremely short half-life this can only be used with pharmacological stress. Therefore, attention is turning toward developing ligands, which can be labeled with generator produced PET radionuclides, or with cyclotron-produced radionuclides with relatively longer halflife, which do not necessarily require on-site cyclotrons. In this respect, gallium-68 and copper-64 are potentially attractive PET tracers, which can be eluted from generators with long shelf life. However, so far no suitable ligands have been developed to exploit the use of Ga and Cu as myocardial perfusion tracers. Interestingly, Yu and colleagues have presented preliminary experimental data in this issue of the journal on BMS-74715802, a pyridazinone analog, which can be labeled with F-18 and used as a myocardial perfusion tracer. Any new potential myocardial perfusion imaging agent has to undergo a series of elaborate studies to characterize its biokinetics and behavior in in vitro and in vivo studies to detect any possible interaction with a multitude of physiological and pharmacological variables. Myocardial uptake of an ideal myocardial perfusion tracer should correlate directly and linearly with myocardial blood flow over a wide range and should not be affected by other metabolic and physiological variables. Yu and colleagues studied myocardial and other organ uptake of F-BMS747158-02 under fasting and non-fasting conditions and with the use of two different anesthetic agents (pentobarbital and ketamine/xylazine) to determine any effects of fed/fasting status or the choice of anesthetic agent on myocardial tracer uptake. As expected none of these conditions had any effect on myocardial tracer uptake, which remained approximately in the range of 3%ID/g. The tracer uptake by other organs was relatively low compared to the myocardial uptake and largely remained unchanged under different physiological conditions. They compared this with myocardial and other organ uptake of F-FDG. Interestingly, they found up to 14-fold variation in myocardial F-FDG uptake between fed and fasting conditions and between the two anesthetics used in this study (pentobarbital and ketamine/xylazine). The latter is known to interfere with insulin release from the From the Section of Cardiovascular Medicine and Cardiovascular Nuclear Imaging Laboratory, Drexel University College of Medicine, Philadelphia, PA; Department of Nuclear Medicine, Fu Wai Hospital, Chinese Academy of Medical Sciences, Beijing, China. Reprint requests: Diwakar Jain, MD, FACC, FASNC, Section of Cardiovascular Medicine and Cardiovascular Nuclear Imaging Laboratory, Drexel University College of Medicine, MS 470, 245 N. 15th Street, Philadelphia, PA 19102; Diwakar.Jain@Drexelmed.edu. J Nucl Cardiol 2009;16:689–90. 1071-3581/$34.00 Copyright 2009 by the American Society of Nuclear Cardiology. doi:10.1007/s12350-009-9113-x