Radiopharmaceutical tracers for cardiac imaging

Abstract

Cardiovascular disease (CVD) is the leading cause of death and disease burden worldwide. Nuclear myocardial perfusion imaging with either single-photon emission computed tomography or positron emission tomography has been used extensively to perform diagnosis, monitor therapies, and predict cardiovascular events. Several radiopharmaceutical tracers have recently been developed to evaluate CVD by targeting myocardial perfusion, metabolism, innervation, and inflammation. This article reviews old and newer used in nuclear cardiac imaging.

Keywords: Cardiovascular disease; positron emission tomography; radiopharmaceutical; single-photon emission computed tomography.

Figure 1

Myocardial perfusion images Perfusion images of short-axis image at stress (A) and rest (B), vertical long-axis image at stress (C) and rest (D) using ^99mTc-product, and fused image of stress perfusion and CT coronary angiography (CTCA; E) are displayed. Severe perfusion reduction is detected in the inferior wall at stress (white arrows). Fill-in is seen at rest indicating stress-induced ischemia in the right coronary artery (RCA). CTCA revealed significant stenosis in the RCA (orange arrows)

Figure 2

Schematic representation of tracers for assessing myocardial perfusion ²⁰¹Tl and ⁸²Rb are potassium analogs and are transported into the myocyte by cell membrane Na⁺/K⁺ pumps. Injected uptake of ^99mTc-sestamibi, ^99mTc-tetrofosmin, and ¹⁸F-flurpiridaz in the myocardium is related to the presence of intact mitochondria. The uptake mechanism of ¹³N-NH₃ is unclear. After being taken into the myocyte, ¹³N-NH₃ underwent metabolic trapping with the conversion of NH₃ to glutamine, glutamic acid, and carbamoyl phosphate. ¹⁵O-H₂O is metabolically inert and freely diffusible tracer

Figure 3

Extraction fraction of each perfusion tracer The extraction fraction of ¹⁵O-H₂O is nearly 100% due to its exclusive property of being metabolically inert and freely diffusible. The extraction fraction of ⁸²Rb is lower than that of the other PET tracers. ²⁰¹Tl has a higher extraction fraction compared to that associated with ^99mTc-MIBI

Figure 4

Qualitative images of PET tracers ⁸²Rb PET has relatively low lesion contrast with low spatial resolution. ¹³N-NH₃ PET shows clear images due to rapid clearance from the blood pool. With ¹⁵O-H₂O PET, it is difficult to distinguish between myocardium and blood pool

Figure 5

Schematic representation of cardiac energy metabolism Substrates are transported across the extracellular membrane into the cytosol through GLUT for glucose and FAT for fatty acid. Metabolized intermediates such as pyruvate and acyl-CoA are transported across the inner mitochondrial membrane for oxidation. Then inside the mitochondrion, substrates are oxidized or carboxylated and fed into the TCA cycle and ETC to produce ATP. GLUT, glucose transporter; FAT, fatty acid transporter; G-6-P, glucose-6-phosphate; ATP, adenosine triphosphate; TCA, tricarboxylic acid; ETC, electron transport chain; CA I, carnitine acyltransferase I; CA II, carnitine acyltransferase II

Figure 6

Tracers for assessing cardiac energy metabolism ¹⁸F-FDG is a glucose analog in which the oxygen in position C-2 is replaced with ¹⁸F. ¹⁸F-FDG is actively transported into the cell mediated by GLUT in the same way as glucose. Once inside the cell, glucose and ¹⁸F-FDG are phosphorylated by hexokinase. Phosphorylated glucose (G-6-P) continues along the glycolytic pathway for energy production. However, ¹⁸F-FDG-6-phosphate cannot enter glycolysis and is trapped intracellularly in a condition known as “metabolic trapping.” GLUT, glucose transporter; G-6-P, glucose-6-phosphate; FDG, ¹⁸F-fluorodeoxyglucose; FDG-6-P, ¹⁸F-FDG-6-phosphate

Figure 7

Ischemic memory imaging Perfusion image of ^99mTc product shows slightly reduced perfusion (A, C), whereas moderately reduced ¹²³I-BMIPP uptake is seen in the anterior to septal wall (B, D), which indicates perfusion-metabolic mismatch. Coronary angiogram shows no significant stenosis (E); however, vasospastic angina in the left anterior descending artery due to the spasm is proved through intracoronary injection of acetylcholine (F)

Figure 8

Schema of myocardial adrenergic neuronal terminals Figure A shows the schematic representation of myocardial adrenergic neuronal terminals and Figure B shows the chemical structure of each tracer. MIBG is actively taken up into sympathetic nerves through the uptake-1 mechanism and then stored in the synaptic vesicle in a manner similar to that for norepinephrine (NE). Nerve stimulation releases MIBG and NE into the synaptic cleft through exocytosis. MIBG does not bind to the postsynaptic receptor and is not metabolized by monoamine oxidase (MAO) or catechol-O-methyltransferase (COMT). Most of the released MIBG undergoes reuptake through the uptake-1 mechanism, and the remaining MIBG goes into the blood (spillover). ¹²³ I-MIBG, m-[¹²³I]iodobenzylguanidine; ¹¹ C-HED, ¹¹C-hydroxyephedrine; DAG, diacylglycerol; AR, adrenergic receptor;Gq, phospholipase C-coupled Gq-protein; Gs, phospholipase C-coupled Gs-protein; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; IP ₂, inositol bisphosphate; PIP ₂, phosphatidylinositol biphosphate

Figure 9

Representative case of ¹²³I-MIBG scintigraphy and ¹¹C-hydroxyephedrine PET A male in his 40s suffered from dilated cardiomyopathy, with a left ventricular ejection fraction of approximately 30%. An early anterior planar image at 15 min after injection (A) and a late anterior planar image starting at 4 hours after injection (B) are acquired to calculate the heart-to-mediastinum ratio (HMR) and the washout ratio. Calculated early HMR, delayed HMR, and washout ratio were 1.7, 1.4, and 40.3%, respectively. Whole retention index from ¹¹C-hydroxyephedrine PET was calculated as 0.044. Distribution of sympathetic nerve system was lower especially in the lateral wall

Figure 10

Representative case of cardiac sarcoidosis Maximum intensity projection (MIP) image of ¹⁸F-FDG PET (A), PET/CT coronal image (B), short-axis image of ¹⁸F-FDG PET (C), late gadolinium enhancement (LGE)-MRI (D), and fused image of ¹⁸F-FDG PET and LGE-MRI (E) at pre-therapy, MIP image of ¹⁸F-FDG PET (F) and PET/CT coronal image (G) at post-therapy (steroid 30 mg/1 month) are displayed. ¹⁸F-FDG PET detected focal cardiac uptake and multiple lymph node disease in the supraclavicular, mediastinum, hilum, abdominal, and pelvis region at pre-therapy. ¹⁸F-FDG uptake is seen at the same site of LGE-MRI abnormal intensity. At post-therapy, ¹⁸F-FDG uptakes were markedly lower. ¹⁸F-FDG is useful not only for diagnosis but also to confirm the effectiveness of treatments

Figure 11

¹⁸F-FEDAC imaging a comparison between ¹⁸F-FEDAC imaging and double staining of translocator protein (TSPO) for neutrophils. Arrows indicate examples of cells doubly positive for TSPO (green) and chloroacetate esterase (red spots) staining. Control group showed no positive ¹⁸F-FEDAC uptake in either lung (A). No neutrophils were seen in the control. Lung injury model using lipopolysaccharide showed positive ¹⁸F-FEDAC uptake in both lungs (B)

Figure 12

Histology showed leukocyte infiltration in the lung injury model. Scale bar: 20 µm. ¹⁸F-FEDAC showed higher uptake ratios of heart/lung and heart/liver compared to those with ¹³N-NH₃ and similar to that with ¹⁸F-FDG. ¹⁸ F-FDG, ¹⁸F-fluorodeoxyglucose; ¹⁸ F-FEDAC, N-benzyl-N-methyl-2-[7,8-dihydro-7-(2-[¹⁸F]-fluoroethyl)-8-oxo-2-phenyl-9H-purin-9-yl] acetamide