Research ArticleContinuing Education

Radiotracers to Address Unmet Clinical Needs in Cardiovascular Imaging, Part 1: Technical Considerations and Perfusion and Neuronal Imaging

John C. Stendahl, Jennifer M. Kwan, Darko Pucar and Mehran M. Sadeghi
Journal of Nuclear Medicine May 2022, 63 (5) 649-658; DOI: https://doi.org/10.2967/jnumed.121.263506

Abstract

The development of new radiotracers for PET and SPECT is central to addressing unmet diagnostic needs related to systemwide trends toward molecular characterization and personalized therapies in cardiovascular medicine. In the following 2-part review, we discuss select emerging radiotracers that may help address important unmet diagnostic needs in central areas of cardiovascular medicine, such as heart failure, arrhythmias, valvular disease, atherosclerosis, and thrombosis. Part 1 examines key technical considerations pertaining to cardiovascular radiotracer development and reviews emerging radiotracers for perfusion and neuronal imaging. Highlights of this work include discussions on the development of 18F-flurpiridaz, an emerging PET perfusion tracer, and the development of 18F-based radiotracers for cardiovascular neuronal imaging, such as 18F-flubrobenguane. Part 2 of this review covers emerging radiotracers for the imaging of inflammation, fibrosis, thrombosis, calcification, and cardiac amyloidosis.

Despite considerable progress in patient care, cardiovascular disease remains a major cause of morbidity and mortality. Improved diagnostics, treatments, and risk factor management have altered the landscape of patient care and have likely contributed to the increasing prevalence of chronic cardiovascular disease. For example, the number of patients living with heart failure is expected to increase from 5.8 million in 2012 to 8.5 million in 2030 (1). This evolution of patient demographics and an improved understanding of cardiovascular pathophysiology underpin many current diagnostic and risk stratification gaps in cardiovascular medicine. Emerging molecular imaging techniques have the potential to address many of these unmet needs (Table 1).

View this table:
TABLE 1

Unmet Diagnostic Needs in Cardiovascular Medicine

Myocardial perfusion imaging, myocardial viability imaging, and equilibrium radionuclide angiocardiography have traditionally constituted most nuclear cardiology procedures. However, use patterns in nuclear cardiology laboratories have been changing because of advances in molecular imaging, the emergence of alternative diagnostic techniques, and evolving evidence questioning established approaches to diagnose and risk-stratify coronary artery disease. PET and SPECT have several advantages for physiologic and precision molecular applications in cardiovascular imaging, including their sensitivity, versatility, and quantitative nature. This is evident in the fact that PET- and SPECT-based molecular imaging techniques are now routinely performed clinically for the diagnosis of cardiac sarcoidosis and amyloidosis. Moreover, the feasibilities of neurohormonal and device infection imaging have been demonstrated, although their specific roles in patient management remain to be established. Many additional cardiovascular applications of PET and SPECT are in earlier stages of preclinical and clinical development, and their advancement to mainstream clinical use is critically dependent on the physical, chemical, and biologic properties of their radiotracers.

In the following 2-part review, we discuss select emerging radiotracers that may help address key unmet clinical diagnostic needs in cardiovascular medicine. For simplicity, these tracers are organized by general pathobiologic processes rather than specific diseases. Part 1 of the review examines key technical considerations pertaining to cardiovascular radiotracer development and reviews the development of radiotracers for perfusion and neuronal imaging (Table 2). Part 2 covers emerging radiotracers for the imaging of inflammation, fibrosis, thrombosis, calcification, and cardiac amyloidosis.

View this table:
TABLE 2

Select Perfusion and Neuronal Signaling Radiotracers in Cardiovascular Medicine

TECHNICAL CONSIDERATIONS FOR OPTIMAL NUCLEAR CARDIOVASCULAR IMAGING

Multiple variables related to radiotracers, instrumentation, and image analysis contribute to the generation of useful nuclear imaging data. PET offers several distinct advantages over SPECT for cardiovascular imaging, including greater spatial resolution and more established quantification methods (2). However, SPECT is usually less expensive and more widely available in clinical nuclear cardiology laboratories. With recent improvements in SPECT technology such as cardiorespiratory gating and cadmium-zinc-telluride (CZT) detectors (3–5), differences between the 2 modalities may be less significant. One potential advantage of SPECT over PET in cardiovascular molecular imaging is its capability for simultaneous multitracer imaging (Fig. 1) (4,6–8). CZT SPECT cameras facilitate multitracer imaging by providing greater spatial and energy resolution than traditional Anger cameras (5).

FIGURE 1.
FIGURE 1.

Dual-tracer SPECT imaging of postmyocardial infarction angiogenesis in a canine model using 111I-RP748, an αvβ3 integrin–targeted agent. Shown are in vivo 111In-RP748 SPECT images acquired at 20 and 45min after tracer administration (top 2 rows), 99mTc-sestamibi images (third row), and fused 99mTc-sestamibi (green) and 45-min 11In-RP748 (red) images (bottom row) in a dog 3 wk after left anterior descending coronary artery occlusion. 99mTc-sestamibi perfusion images demonstrate anterior perfusion deficit (yellow arrows). 111In-RP748 images demonstrate corresponding increased uptake in hypoperfused region (white arrows). Authors demonstrate that 4-fold increase in 111In-RP748 uptake in infarct region corresponds to increased αvβ3 expression and histologic evidence of angiogenesis. LV = left ventricle; MIBI = sestamibi; RV = right ventricle; VLA = vertical long axis; HLA = horizontal long axis. (Reprinted with permission of (8).)

Cardiac imaging with PET and SPECT is facilitated by the large size of the organ, although motion remains a challenge. Vascular imaging presents additional challenges, including the small size of vessels. This may be addressed by hybrid imaging with CT or MRI, which provides anatomic definition and helps to correct partial-volume effects. Cardiovascular molecular imaging applications would benefit from improved quantitation tools, as the semiquantitative techniques developed for perfusion imaging to assess relative radiotracer uptake are not suitable for hot-spot imaging, which is common in molecular imaging applications.

Radiotracer kinetics govern acquisition protocols and greatly influence data quality. Fast blood pool clearance is desirable for most non–blood pool cardiovascular applications because it improves target-to-background ratios. For perfusion imaging, it is desirable to have high levels of target tissue extraction and retention, with lesser uptake or greater washout in surrounding organs. For molecular imaging, high levels of specific target binding relative to the background are critical for achieving useful data. In this regard, radiotracer uptake depends on delivery of the tracer as well as target expression and binding affinity, thus raising challenges for comparing uptake values, such as in areas of myocardium with differing levels of perfusion. The incorporation of regional perfusion data from kinetic modeling could potentially improve the accuracy of molecular imaging techniques.

The chemical and physical properties of radionuclides also influence synthesis and acquisition protocols and affect data quality (Table 3). Radionuclide chemical properties impact their incorporation into organic tracer molecules or, in the case of inorganic radiotracers (e.g., 82Rb), their biologic uptake (9). Radionuclides with shorter half-lives are ideally suited for applications with faster pharmacokinetics and favorable count statistics. Shorter half-lives reduce radiation exposure to both patients and staff and typically permit greater imaging throughput. This advantage is especially useful in perfusion imaging to minimize delays between stress and rest scans. However, radionuclides with shorter half-lives are not always practical. For example, radiolabeled antibodies have slower pharmacokinetics than small molecules, and their binding to target molecules with low levels of expression can require hours to produce high-quality signals. As such, molecular imaging with antibodies often necessitates the use of radionuclides with a longer half-life, such as 64Cu (half-life, 12.7 h) or 89Zr (half-life, 78.4 h). Radionuclides with longer half-lives can also provide considerable procedural flexibility. For example, radionuclides with a longer half-life facilitate unit dose delivery in place of on-site generators and cyclotrons, which may not be cost-effective in lower-volume centers (10). Longer–half-life radionuclides also expand options for chemical modifications to radiotracers before administration. For myocardial perfusion imaging, longer–half-life radionuclides permit exercise stress (10) and may be favorable for nontraditional applications such as image-guided interventions (11). However, greater radiation exposure associated with these longer–half-life radionuclides and practical workflow considerations remain major limiting factors for cardiovascular applications, where risk–benefit considerations may be different from, for example, imaging in patients with malignancies. In PET imaging, radionuclide positron energy influences image resolution. Lower-energy β-emitters such as 18F and 64Cu have shorter positron ranges in tissue and thus tend to produce images with spatial resolution superior to that of higher-energy positron emitters such as 82Rb and 68Ga (12). The benefits of high-resolution imaging are the greatest in small targets that are more susceptible to partial-volume effects, such as vessel walls. With anticipated improvements in resolution related to PET camera technology and motion correction, the effects of radionuclide positron range will likely become increasingly significant.

View this table:
TABLE 3

Properties of SPECT and PET Radionuclides with Existing or Potential Applications in Cardiovascular Imaging (9,12,70)

The mode of decay of radionuclides also affects their imaging properties. PET radionuclides such as 11C, 13N, 15O, and 18F are pure β+-emitters and do not directly produce γ- or β−-emissions (9,12). Prompt γ-emissions from nonpure PET radionuclides such as 68Ga, 82Rb, and 124I have traditionally been considered unfavorable because they increase radiation exposure and create spurious coincidences that degrade image quality (12). However, the presence of smaller levels of prompt γ-emissions in radionuclides with other favorable properties is not considered prohibitive, and image quality can potentially be improved by instituting corrections (12). Moreover, it has been proposed that radionuclides emitting prompt γ-emissions provide distinct emission signatures that could be harnessed for multitracer PET imaging (12).

RADIOTRACERS FOR PERFUSION IMAGING

There has been longstanding interest in the development of 18F-based perfusion tracers given the intrinsic advantages of PET imaging and the limitations of current clinical perfusion tracers such as 99mTc sestamibi, 99mTc tetrofosmin, 82Rb, and 13N-NH3 (13). 18F is advantageous because it has a shorter mean positron range (0.6 mm, in water) than 82Rb (7.1 mm) and 13N (1.8 mm) and thus provides superior spatial resolution (12). In addition, 18F has a longer half-life (109 min) than 82Rb (76 s) and 13N (10 min). Although this characteristic can be unfavorable from a dosimetric standpoint and may necessitate greater delays between rest and stress acquisitions, it also provides several distinct advantages. Most importantly, the longer half-life of 18F permits unit dose delivery. In addition, the longer half-life of 18F permits both exercise and pharmacologic stress protocols and makes repeat image acquisition possible in cases of motion or extracardiac radiotracer uptake.

18F-flurpirdaz is a perfusion tracer that binds to mitochondrial complex 1 and is currently undergoing evaluation in clinical trials (10,13–17). In addition to the features listed above, 18F-flurpiridaz has greater myocardial extraction at higher blood flow rates than traditional PET and SPECT perfusion radiotracers; thus, its uptake demonstrates a smaller deviation from linearity over the physiologic range of blood flow (Fig. 2) (18). This property potentially improves its sensitivity for detection of ischemia and is advantageous for quantification of absolute blood flow. In a recent phase 3 clinical evaluation, 18F-flurpiridaz PET demonstrated increased sensitivity for the detection of obstructive coronary artery disease (as defined by >50% coronary stenosis by invasive angiography) in comparison to 99mTc-SPECT (71.9% vs. 53.7%, P < 0.001) but did not meet the predetermined noninferiority criterion pertaining to specificity (76.2% vs 86.6%, P = not significant) (10). Overall, on the basis of area under the receiver-operating-characteristic curve, 18F-flurpiridaz PET demonstrated superior discrimination of obstructive coronary disease in comparison to 99mTc-SPECT myocardial perfusion imaging (0.78 vs. 0.72, P < 0.001). 18F-flurpiridaz also exhibited better image quality than 99mTc-SPECT at lower radiation doses (6.1 ± 0.4 vs. 13.4 ± 3.2 mSv; P < 0.001) (10). Of note, this comparison was based solely on retention scans and did not incorporate 18F-flurpiridaz myocardial blood flow quantification (19). It is also worth noting that this study did not compare 18F-flurpiridaz with other PET perfusion tracers and that at least some of the differences likely represent intrinsic differences between SPECT and PET techniques, including a lack of attenuation correction for SPECT images. The effects of spatial resolution in 18F-flurpiridaz PET were further illustrated in a subsequent analysis of the trial data that compared diagnostic performance in large and small ventricles. The diagnostic performance of 18F-flurpiridaz PET for the detection of ischemia was similar in large and small left ventricles (area under the curve, 0.79 vs. 0.77, P = 0.49), but 99mTc-SPECT performance was reduced in smaller left ventricles (area under the curve, 0.75 vs. 0.67, P = 0.03), likely because of its lower spatial resolution (Fig. 3) (17). Other 18F-based PET perfusion tracers that are undergoing initial characterization and evaluation in humans include 18F-rhodamine 6G (NCT04528758) (20) and 18F-fluorophenyltriphenylphosphonium (NCT02252783) (21).

FIGURE 2.
FIGURE 2.

Schematic representation of myocardial uptake of various PET and SPECT perfusion radiotracers in relation to coronary blood flow. Background colors in figure show typical ranges of myocardial blood flow during rest (peach), exercise stress (blue), and pharmacologic vasodilator stress (green). 15O-H2O displays nearly linear uptake over physiologic range of blood flow but has limited clinical utility because of suboptimal imaging characteristics. 18F-flurpiridaz maintains high levels of myocardial extraction at stress-level blood flows, and its uptake-flow curve thus demonstrates only minimal deviation from linearity. By contrast, 99mTc-sestamibi and 99mTc-tetrofosmin have more significant reductions in myocardial extraction at moderate and high blood flow rates, and their uptake-flow curves demonstrate significant deviations from linearity. 201Tl, 13N-NH3, and 82Rb have intermediate uptake-flow properties. (Reprinted from (18).)

FIGURE 3.
FIGURE 3.

Representative rest–stress 99mTc-SPECT and 18F-flurpiridaz PET images in patient with small heart. Images were acquired in 66-y-old woman with left ventricular end diastolic volume of 82 mL. Reversible anterior perfusion defect is more evident in 18F-flurpiridaz PET images (B) than 99mTc-SPECT images (A) and is consistent with 82% stenosis of left anterior descending coronary artery that was found on invasive coronary angiography. Greater sensitivity of 18F-flurpiridaz PET for detection of myocardial ischemia partially relates to its greater spatial resolution and more linear uptake over physiologic range of blood flow. (Reprinted from (17).)

Several new SPECT perfusion agents are also in development, including the 123I-labeled rotenone derivatives 123I-CMICE-013 (22) and 123I-ZIROT (23). These agents target mitochondrial complex 1 in a similar fashion to 18F-flurpiridaz and are intended to address the shortcomings of existing SPECT perfusion agents by potentially combining the benefits of greater myocardial extraction across the physiologic range of blood flow, with favorable imaging characteristics and dosimetry. Moreover, as these agents are labeled with 123I rather than 99mTc, they could also address ongoing concerns about the stability of the 99mTc supply. In initial preclinical studies on pigs, 123I-CMICE-013 demonstrated greater myocardial uptake than the conventional SPECT tracers 201Tl, 99mTc-tetrofosmin, and 99mTc-sestamibi at blood flows exceeding 1.5 mL/min/g (P < 0.05) (Fig. 4) (22). Similarly, 123I-ZIROT demonstrated greater myocardial uptake than 201Tl and 99mTc-sestamibi at blood flows greater than 1.5 mL/min/g, with linear uptake extending to greater flow values (23). 123I-CMICE-013 recently completed a phase 1 clinical evaluation (NCT01558362). One potential technical issue with 123I-based perfusion agents is that 123I emits small proportions of high-energy photons (>400 keV) in addition to its primary emission at 159 keV. These high-energy photons can degrade image quality and impair quantitative analyses by penetrating septa on standard low-energy, high-resolution collimators. Collimators with thicker septa may be used in 123I SPECT imaging to decrease septal photon penetration, although thicker septa tend to decrease spatial resolution (24).

FIGURE 4.
FIGURE 4.

Representative 123I-CMICE-013 SPECT perfusion images in a porcine model with left anterior descending coronary artery occlusion during dipyridamole stress. Images were acquired 15 min after injection and provide clear definition of occluded region. (Reprinted from (22).)

Despite the trend toward greater use of PET for perfusion imaging, improved SPECT radiotracers may still have a significant clinical impact, as SPECT myocardial perfusion imaging is expected to continue being the most common perfusion modality for years to come because of advantages in cost and availability. Moreover, with technologic advances such as attenuation correction (25) and CZT detectors (5), modern SPECT imaging systems provide substantially better image quality at a more favorable dosimetry than prior-generation instruments. The combination of advances in instrumentation and the development of perfusion tracers with better myocardial extraction characteristics also raises the possibility of applying SPECT-based quantitative blood flow assessments in clinical settings (26).

A potentially significant area for growth and possible application for these new perfusion agents is skeletal muscle perfusion imaging. Peripheral artery disease affects more than 200 million people worldwide (27) and presents significant challenges for clinical assessment and treatment. SPECT and PET perfusion imaging with traditional radiotracers has been applied to help diagnose peripheral artery disease, stratify risk, and evaluate responses to treatment (28–31). Although not currently part of mainstream clinical peripheral artery disease management, radiotracer imaging techniques may provide supplemental information to better assess risk for acute limb ischemia and potential for wound healing, as well as to direct optimal approaches for revascularization. The high spatial resolution, quantitative potential, and ability to accommodate exercise stress protocols are features of the new 18F-based tracers that make them attractive for peripheral perfusion applications.

RADIOTRACERS FOR CARDIOVASCULAR NEURONAL IMAGING

Neuronal signaling in the myocardium plays a critical role in maintaining cardiac function and homeostasis by modulating electromechanical behavior, vasoreactivity, metabolism, and remodeling (32). Neuronal signals are transmitted to the heart via the sympathetic and parasympathetic branches of the autonomic nervous system. Sympathetic activation of the heart has mainly stimulatory effects, including increased inotropy and chronotropy (32). Preganglionic sympathetic neurons originate in the spinal cord and transmit signals to postganglionic fibers that innervate the atria, ventricles, and coronary arteries. On stimulation, the termini of these postganglionic neurons release stored norepinephrine into the synaptic cleft. Sympathetic effects are mediated by binding of norepinephrine to postsynaptic α- and β-adrenergic receptors in the cardiac tissue. In contrast, parasympathetic activation tends to be inhibitory, with negative chronotropic and, to a lesser extent, negative inotropic effects (32). Parasympathetic signals are transmitted from the medulla oblongata to the heart by way of the vagus nerve. The termini of postganglionic vagal efferents are concentrated in the atria and conduction nodes and release acetylcholine when stimulated. Signal transmission is completed by binding of acetylcholine to muscarinic and nicotinic receptors. Muscarinic acetylcholine receptors are present in cardiomyocytes and intracardiac ganglia, and their stimulation decreases both inotropy and chronotropy (33). Nicotinic acetylcholine receptors are present in the myocardium and vasculature, although their roles are less well defined (33). In addition to efferent sympathetic and parasympathetic innervation of the heart, there are numerous afferent sympathetic and vagal nerve fibers that travel from the heart for sensory purposes and to mediate cardiac reflexes.

Alterations to cardiac neuronal activity play important roles in the pathophysiology of arrythmias, myocardial infarction, and heart failure related to various types of cardiomyopathy (34–42). In the case of heart failure, it is postulated that chronically elevated sympathetic activity drives desensitization or downregulation of both presynaptic norepinephrine reuptake transporters and postsynaptic β-adrenergic receptors, which leads to progressive dysfunction and remodeling and creates substrates for arrhythmias (43). The development of radiotracers for targeted noninvasive imaging of various aspects of cardiac innervation has improved our understanding of complex cardiovascular diseases and has helped to guide treatments. Recent efforts in the field have focused on developing new tracers and improving image acquisition and analysis techniques to expand diagnostic capabilities and provide more accurate and reproduceable assessments (44).

Presynaptic Sympathetic Imaging

123I-metaiodobenzylguanidine (123I-MIBG) targets the norepinephrine transporter and was the first neuronal radiotracer to be extensively studied in hearts and Food and Drug Administration–approved for cardiac applications. Myocardial 123I-MIBG uptake can be imaged by both planar scintigraphy and SPECT/CT, although quantification has traditionally been performed with heart-to-mediastinum ratios in planar images. Reduced myocardial uptake of 123I-MIBG has been associated with various cardiac diseases and has demonstrated clinical predictive value. In the ADMIRE-HF trial (AdreView Myocardial Imaging for Risk Evaluation in Heart Failure) of patients with heart failure with reduced ejection fraction, a 123I-MIBG heart-to-mediastinum ratio of at least 1.6 was predictive of decreased adverse outcomes such as heart failure progression (hazard ratio, 0.49; P = 0.002), serious arrhythmic events (hazard ratio, 0.37; P = 0.020), and cardiac death (hazard ratio, 0.14; P = 0.006) as compared with a heart-to-mediastinum ratio of less than 1.6 (35). Although 123I-MIBG has been criticized because assessments are often global and semiquantitative (45), improved SPECT technology such as cardiorespiratory gating and CZT detectors have renewed interest by improving spatial resolution and sensitivity. Recent examples of new applications generated by these technical improvements include the localization of left atrial ganglionic plexi, which could aid in the development of more effective catheter ablation procedures for treating atrial fibrillation (39), and detailed assessments of innervation–perfusion mismatch in patients with ischemic heart disease, which could provide valuable insight into patient risk for developing potentially lethal ventricular arrhythmias (38).

Despite the proven utility of 123I-MIBG SPECT imaging, PET neuronal imaging has gained popularity because of greater tracer variety, superior sensitivity and spatiotemporal resolution, and more developed means of quantification (46,47). PET offers several radiotracers that target predominantly the norepinephrine transporter to image presynaptic sympathetic activity. The earliest norepinephrine transporter–targeted PET radiotracers were 11C-labeled agents, including 11C-hydroxyephedrine (11C-HED), 11C-epinephrine, and 11C-phenylephrine (48). Alterations in the presynaptic uptake of these radiotracers have been demonstrated in numerous cardiac diseases, including heart failure, ischemic heart disease, and arrhythmias (37,48–50).

11C-HED, a nonmetabolized analog of norepinephrine, is the most extensively studied radiotracer among the group of 11C-labeled norepinephrine transporter–targeted radiotracers. Reduced retention of 11C-HED corresponding to myocardial denervation has been demonstrated in the settings of acute myocardial infarction (42), ischemic (34,37,49,51) and nonischemic cardiomyopathies (51,52), hypertrophic cardiomyopathy (36), and heart failure with preserved ejection fraction (53). In the PAREPET trial (Prediction of Arrhythmic Events with PET) of individuals with ischemic cardiomyopathy, patients who experienced sudden cardiac arrest had greater volumes of denervated myocardium by 11C-HED PET than did those without cardiac arrest (33% ± 10% vs. 26% ± 11% of the left ventricle; P = 0.001) (34). Interestingly, patients with sudden cardiac arrest did not have statistically greater infarct volumes (22% ± 7% vs. 19% ± 9% of the left ventricle; P = 0.18) or lower left ventricular ejection fractions (24% ± 8% vs. 28% ± 9% of the left ventricle; P = 0.053). In addition, work with 11C-HED PET in patients with heart failure with a preserved ejection fraction demonstrated that a lower global retention index of 11C-HED was independently associated with the presence of advanced diastolic dysfunction (grades 2 and 3) in a multivariate logistic regression analysis (odds ratio, 0.66 per 0.01 min−1, P = 0.044) (53). Despite the established clinical relevance of 11C-based radiotracers, their popularity has been limited by a relatively short half-life (20 min) that necessitates on-site cyclotron production.

As a result of the intrinsic limitations of 11C-based radiotracers, 18F-based radiotracers targeting the norepinephrine transporter have generated significant interest. 18F-flubrobenguane (18F-FBBG, also known as 18F-LMI1195) is a benzylguanidine that is similar in structure to 123I-MIBG (54,55). First-in-humans studies of 18F-FBBG demonstrated favorable characteristics for imaging, including rapid blood pool clearance, moderate rates of liver and lung clearance, and stable myocardial uptake, with a myocardium-to-liver ratio of more than 2 at 4 h (Fig. 5) (55). Preliminary results of subsequent clinical evaluations demonstrated that 18F-FBBG yields estimates of myocardial sympathetic innervation similar to those of 11C-HED but has more favorable kinetics (54). Given the advantages of 18F-FBBG for quantifying regional myocardial innervation, it was selected for evaluation in the PAREPET II trial to determine the risk of sudden cardiac death in patients with ischemic cardiomyopathy (NCT03493516). In addition to 18F-FBBG, there are several other 18F-labeled norepinephrine transporter–targeted radiotracers that are currently in development. 18F-meta-fluorobenzylguanidine (18F-MFBG) is another benzylguanidine with potential for use in cardiac applications; it has demonstrated rapid and sustained myocardial uptake with fast blood pool clearance in initial clinical evaluations (56,57) (NCT02348749). 4-18F-fluoro-meta-hydroxyphenethylguanidine and its structural isomer 3-18F-fluoro-para-hydroxyphenethylguanidine are phenethylguanidines that were designed for slow neuronal uptake and irreversible presynaptic retention, features thought to be favorable for accurate detection and quantification of cardiac sympathetic denervation (58). First-in-humans studies with these radiotracers demonstrated high-quality images with reproducible measurements of regional cardiac sympathetic nerve density (NCT02669563) (58).

FIGURE 5.
FIGURE 5.

Presynaptic sympathetic imaging with 18F-FBBG PET. Figure shows representative sequence of whole-body 18F-FBBG coronal PET images in healthy volunteer. Myocardial signal persists after clearance from liver and surrounding organs. (Reprinted from (55).)

Postsynaptic Sympathetic Imaging

11C-CGP-12177 (4-(3-tert-butylamino-2-hydroxypropoxy)-2H-benzimidazol-2-11C-one) (37,49) and 11C-CGP-12388 ((S)-4-(3-(2′-11C-isopropylamino)-2-hydroxypropoxy)-2H-benzimidazol-2-one) (59,60) are nonselective β-receptor antagonists that have been used for postsynaptic adrenergic imaging. 11C-CGP-12177 has been paired with presynaptic sympathetic tracers such as 123I-MIBG (61) and 11C-HED (36,37,49) to help elucidate the complex relationships between pre- and postsynaptic sympathetic function (Fig. 6). The studies show significant alterations in both pre- and postsynaptic sympathetic function in patients with various types of cardiomyopathies. Chronically increased sympathetic tone in the setting of heart failure is reflected in the decreased uptake or increased washout of presynaptic catecholamines and leads to the observed downregulation of postsynaptic β-adrenergic receptors (61). Although α-adrenergic signaling is less intensively investigated, it also plays a fundamental role in cardiovascular physiology (62) and is an intriguing target for therapeutics and molecular imaging. 11C-labeled N-[6-[(4-amino-6,7-dimethoxyquinazolin-2-yl)-methylamino]hexyl]-N-methylfuran-2-carboxamide;hydrochloride (11C-GB67) is a prazosin analog and α1-adrenergic antagonist that has demonstrated myocardial uptake in preclinical and initial human studies, although its clinical role has yet to be established (63,64).

FIGURE 6.
FIGURE 6.

Pre- and postsynaptic sympathetic imaging with 11C-HED and 11C-CGP 12177 PET. Short axis 11C-HED and 11C-CGP 12177 PET images of patient with congestive heart failure. Significant pre- and postsynaptic mismatch are noted by arrows. (Reprinted from (49).)

Parasympathetic Imaging

Techniques for radioligand imaging of cardiac parasympathetic activity remain far less developed than those for sympathetic imaging despite the central role that parasympathetic innervation plays in cardiovascular physiology. 11C-donepezil is a reversible, noncompetitive antagonist of acetylcholinesterase that has been investigated in humans as a potential surrogate marker of cardiac parasympathetic innervation (65), although its utility is hindered by donepezil’s significant affinity for σ1-receptors, which are also plentiful in the heart (66). 11C-methylquinuclidinyl benzilate is a specific hydrophobic antagonist of muscarinic acetylcholine receptors that has demonstrated significantly greater uptake in patients with dilated cardiomyopathy than in healthy controls (34.5 ± 8.9 vs. 25.0 ± 7.7 pmol/mL, P < 0.005) (40). In addition, 2-deoxy-2-18F-fluoro-d-glucose-A85380 is a selective agonist of the α4β2 nicotinic receptor that was developed for central nervous system imaging and has demonstrated feasibility in humans for imaging nicotinic receptors in the heart (67) and vasculature (68). More recently, the vesicular acetylcholine transporter has been investigated as a potential target for radioligand imaging of cardiovascular cholinergic activity. 18F-fluoroethoxybenzovesamicol is a noncompetitive inhibitor of the vesicular acetylcholine transporter that, in contrast to 11C-donepezil, has low affinity for σ1-receptors (69). 18F-fluoroethoxybenzovesamicol has been extensively studied in the central nervous system and recently demonstrated favorable properties for quantitative cardiac imaging (69).

Overall, neuronal radiotracers have thus far not gained widespread use in cardiovascular medicine despite some intriguing preclinical and clinical findings. Multiple technical, clinical, and economic factors likely contribute to the slow advancement of neuronal imaging techniques, including incomplete definitions of their clinical roles and potential added value over established imaging techniques. Given the advantages of PET over SPECT, the field of cardiovascular neuronal imaging will likely continue to shift toward quantitative PET techniques, likely with 18F-labeled tracers. This will require further development of 18F-based radiotracers and related quantitative analysis techniques.

CONCLUSION

Cardiovascular imaging is evolving in response to systemwide trends toward molecular characterization and personalized therapies. The development of new radiotracers for PET and SPECT imaging is central to addressing the numerous unmet diagnostic needs that relate to these changes. Overall, there is a trend toward greater use of PET in cardiovascular medicine given its beneficial imaging properties and established methods for quantification, although SPECT remains highly used because of its favorable cost and availability and the numerous benefits of recent technical improvements. The development of radiotracers for improved characterization of cardiovascular neuronal activity as well as perfusion in both the myocardium and periphery has been discussed in part 1 of this review. Part 2 will present a detailed overview of emerging radiotracers for the imaging of cardiovascular inflammation, fibrosis, thrombosis, calcification, and cardiac amyloidosis.

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  • Revision received February 22, 2022.
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