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Review Article Searching for Novel PET Radiotracers: Imaging Cardiac Perfusion, Metabolism and Inflammation

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Review Article Searching for Novel PET Radiotracers: Imaging Cardiac Perfusion, Metabolism and Inflammation Am J Nucl Med Mol Imaging 2018;8(3):200-227 www.ajnmmi.us /ISSN:2160-8407/ajnmmi0079469 Review Article Searching for novel PET radiotracers: imaging cardiac perfusion, metabolism and inflammation Caitlund Q Davidson1, Christopher P Phenix2, TC Tai3, Neelam Khaper1,4, Simon J Lees1,4 1Department of Biology, Lakehead University, Thunder Bay, Ontario, Canada; 2Department of Chemistry, University of Saskatchewan, Saskatoon, Saskatchewan, Canada; 3Medical Sciences Division, Northern Ontario School of Medicine, Laurentian University, Sudbury, Ontario, Canada; 4Medical Sciences Division, Northern Ontario School of Medicine, Lakehead University, Thunder Bay, Ontario, Canada Received April 3, 2018; Accepted May 20, 2018; Epub June 5, 2018; Published June 15, 2018 Abstract: Advances in medical imaging technology have led to an increased demand for radiopharmaceuticals for early and accurate diagnosis of cardiac function and diseased states. Myocardial perfusion, metabolism, and hy- poxia positron emission tomography (PET) imaging radiotracers for detection of cardiac disease lack specificity for targeting inflammation that can be an early indicator of cardiac disease. Inflammation can occur at all stages of car- diac disease and currently, 18F-fluorodeoxyglucose (FDG), a glucose analog, is the standard for detecting myocardial inflammation. 18F-FDG has many ideal characteristics of a radiotracer but lacks the ability to differentiate between glucose uptake in normal cardiomyocytes and inflammatory cells. Developing a PET radiotracer that differentiates not only between inflammatory cells and normal cardiomyocytes, but between types of immune cells involved in inflammation would be ideal. This article reviews current PET radiotracers used in cardiac imaging, their limitations, and potential radiotracer candidates for imaging cardiac inflammation in early stages of development of acute and chronic cardiac diseases. The select radiotracers reviewed have been tested in animals and/or show potential to be developed as a radiotracer for the detection of cardiac inflammation by targeting the enzymatic activities or sub- populations of macrophages that are recruited to an injured or infected site. Keywords: Positron emission tomography (PET), radiotracer candidates, myocardial perfusion, metabolism, car- diac disease, cardiac inflammation, inflammatory cells, animal models, macrophages Introduction chemistry. PET has proven to be a superior technique for molecular imaging due to its Positron emission tomography (PET) is a nucle- accurate attenuation correction, higher spatial ar-based modality used for decades as an and temporal resolution, higher sensitivity, important clinical tool to non-invasively image quantitative abilities coupled with lower radia- blood flow [1, 2], cardiac tissue metabolism [3, tion risk due to the use of short-lived isotopes 4] and receptor expression [5, 6]. PET requires like carbon-11 (20 min), fluorine-18 (110 min) the injection of a radioactive tracer, labeled and rubidium-82 (76 secs) [7, 8]. Further, PET with a short-lived radioisotope, that upon decay appears to have improved diagnostic accuracy emits a positron that annihilates with an elec- compared to SPECT lowering the overall costs tron to release coincident photons that are of therapy and improved outcomes [9, 10]. detected by a PET camera. Although single- photon emission computed tomography (SP- Advances in medical imaging technology have ECT) is less expensive and more commonly led to an increased demand for radiopharma- used in nuclear medicine departments, a ceuticals for early and accurate diagnosis of recent expansion in the use of PET for cardiac organ function and diseased states. The use of imaging has resulted from the increasing avail- cyclotron produced PET tracers in clinical car- ability of new PET cameras, PET radiotracers diac imaging has been historically limited due and cyclotron facilities capable of producing to the requirement of a local cyclotron and the short-lived isotopes needed for labeling radiopharmacy and the challenges associated PET radiotracers for cardiac imaging Table 1. Half-lives of some PET radioisotopes PET radiotracers for cardiac imaging useful for cardiac imaging PET uses radiolabeled probes to measure the Radioisotope Half-life (minutes) expression of molecular markers, metabolic 18Fluorine 109.8 and physiological processes at different sta- 64 Copper 762 ges of disease [15]. Many radiotracers have 11 Carbon 20 been developed and evaluated in preclinical 68Gallium 68 imaging experiments but few have made it into 82Rubidium 1.27 routine human application for reasons includ- 15Oxygen 2.06 ing the cost of animal and clinical trials, com- 13Nitrogen 9.97 pany’s unwillingness to purchase diagnostic agents that will be used once or twice, and the tracers may lack one or more characteristics with the transportation of radiotracers labeled that make an ideal PET imaging probe [15]. A with short-lived PET isotopes to distant loca- PET radiotracer should have high specificity to tions. However, the International Atomic Energy a molecular target, for example a specific Agency published statistics in 2006, docu- enzyme, biomarker, or transport protein asso- menting 80 cyclotrons present in North Am- ciated with a particular cell population and erica. In the last decade, the number of cyclo- should have low non-specific uptake into other trons has doubled improving availability and tissues. Another ideal characteristic is high the ease of production of tracers for PET im- metabolic stability to prevent the probe from aging with an estimated 1200 cyclotron facili- being degraded by enzymes before imaging ties that produce medical imaging isotopes can be done. A radiotracer should have high world-wide. affinity for target tissue to achieve sufficient accumulation of the probe for quantitative Hybrid systems that combine PET with comput- imaging and analysis. High and rapid uptake ed tomography (CT) are now routinely found in of tracer into target tissues followed by long most nuclear medicine departments, although retention time is ideal for high contrast ratio systems that have PET combined with magnet- of target-to-background ensuring appropriate ic resonance imaging (MRI) are appearing at analysis of images. Quality of the images is select research intensive sites. The combina- also dependent on the positron range before tion of PET with CT allows for the visualization annihilation [16]. Shorter positron ranges pro- of biological processes facilitated by PET with duce higher resolution images [17]. Low pro- simultaneous anatomical imaging to identify duction cost and availability of the probes and determine localization of the tracer up- are also important characteristics of an ideal take in specific tissues and organs. PET/CT is probe. Finally, safety is a concern and there- widely used in clinical oncology but also incor- fore probes should have low toxicity and the porated into clinical cardiology for the detec- shortest feasible half-life to keep radiation tion of coronary artery disease [11, 12]. While exposure to a minimum [18, 19]. Table 1 there are benefits, including better image reso- shows the half-lives of some radioisotopes use- lution than with PET alone and reduced image ful for cardiac imaging. acquisition time resulting in high patient throughput, the addition of CT significantly In some cases, it is important for imaging to increases the amount of radiation exposure to be done under normal resting conditions, as the patient and in most cases, exceeds the well as, following a stress. Stress tests involve measured dose from the injected PET radio- cardiac imaging after the patient has per- tracer [13]. As a consequence, PET/MRI is formed physical exercise on a treadmill or becoming increasingly available since anatom- supine bicycle [20-23]. When exercise-induced ic detail and soft tissue contrast anatomical stress isn’t feasible because the length of the images are produced without the additional test exceeds the radiotracer half-life or patients radiation dose resulting from PET/CT. It impor- who cannot exercise, pharmacological stress is tant to acknowledge that PET/MRI cannot be induced by administering dipyridamole, ade- used on patients that have implanted devices nosine, regadenoson or dobutamine when the [14]. patient is ready to be imaged [23, 24]. Like 201 Am J Nucl Med Mol Imaging 2018;8(3):200-227 PET radiotracers for cardiac imaging Table 2. Hypoxia radiotracer targets, structures, and limitations Name Functional Target Structure Limitations 18F-fluoromisonidazole 18( F-FMISO) Thiol containing ● Slow blood clearance [37] intracellular ● Long uptake period macromolecules ● Low accumulation in target tissue [34] Copper(II)-diacetyl-bis(N(4)-methylthiosemicarbazone) (64Cu-ATSM) Intracellular copper ● Useful for detection of chaperone proteins extreme hypoxia [60] exercise, dobutamine increases blood pres- um-82 (82Rb), nitrogen-13 (13N) and oxygen-15 sure, heart rate and contractility whereas dipyr- (15O) are useful for perfusion imaging. A long idamole, adenosine, and regadenoson induce list of radiotracers has been developed for PET coronary vasodilation to increase myocardial imaging of hypoxia, metabolism, inflammation blood flow (MBF) [25-28]. Ideally, both stress and myocardial perfusion with several others and rest images can be obtained with one in development in attempt to create suitable administration of tracer and within the same PET probes for various physiological and dis- day.
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