Image Quality of Cardiac Silicon Photomultiplier PET/CT Using an Infant Phantom of Extremely Low Birth Weight.

The lack of pediatrics-specific equipment for nuclear medicine imaging has resulted in insufficient diagnostic information for newborns, especially low-birth-weight infants. Although PET offers high spatial resolution and low radiation exposure, its use in newborns is limited. This study investigated the feasibility of cardiac PET imaging using the latest silicon photomultiplier (SiPM) PET technology in infants of extremely low birth weight (ELBW) using a phantom model. Methods: The study used a phantom model representing a 500-g ELBW infant with brain, cardiac, liver, and lung tissues. The cardiac tissue included a 3-mm-thick defect mimicking myocardial infarction. Organ tracer concentrations were calculated assuming 18F-FDG myocardial viability scans and 18F-flurpiridaz myocardial perfusion scans and were added to the phantom organs. Imaging was performed using an SiPM PET/CT scanner with a 5-min acquisition. The data acquired in list mode were reconstructed using 3-dimensional ordered-subsets expectation maximization with varying iterations. Image evaluation was based on the depiction of the myocardial defect compared with normal myocardial accumulation. Results: Increasing the number of iterations improved the contrast of the myocardial defect for both tracers, with 18F-flurpiridaz showing higher contrast than 18F-FDG. However, even at 50 iterations, both tracers overestimated the defect accumulation. A bull's-eye image can display the flow metabolism mismatch using images from both tracers. Conclusion: SiPM PET enabled cardiac PET imaging in a 500-g ELBW phantom with a 1-g heart. However, there were limitations in adequately depicting these defects. Considering the image quality and defect contrast,18F-flurpiridaz appears more desirable than 18F-FDG if only one of the two can be used.

Emerging PET Tracers in Cardiac Molecular Imaging.

18F-fluorodeoxyglucose (FDG) and 18F-sodium fluoride (NaF) represent emerging PET tracers used to assess atherosclerosis-related inflammation and molecular calcification, respectively. By localizing to sites with high glucose utilization, FDG has been used to assess myocardial viability for decades, and its role in evaluating cardiac sarcoidosis has come to represent a major application. In addition to determining late-stage changes such as loss of perfusion or viability, by targeting mechanisms present in atherosclerosis, PET-based techniques have the ability to characterize atherogenesis in the early stages to guide intervention. Although it was once thought that FDG would be a reliable indicator of ongoing plaque formation, micro-calcification as portrayed by NaF-PET/CT appears to be a superior method of monitoring disease progression. PET imaging with NaF has the additional advantage of being able to determine abnormal uptake due to coronary artery disease, which is obscured by physiologic myocardial activity on FDG-PET/CT. In this review, we discuss the evolving roles of FDG, NaF, and other PET tracers in cardiac molecular imaging.

Rest/stress myocardial perfusion imaging by positron emission tomography with 18F-Flurpiridaz: A feasibility study in mice.

BACKGROUND: Myocardial perfusion imaging by positron emission tomography (PET-MPI) is the current gold standard for quantification of myocardial blood flow. 18F-flurpiridaz was recently introduced as a valid alternative to currently used PET-MPI probes. Nonetheless, optimum scan duration and time interval for image analysis are currently unknown. Further, it is unclear whether rest/stress PET-MPI with 18F-flurpiridaz is feasible in mice. METHODS: Rest/stress PET-MPI was performed with 18F-flurpiridaz (0.6-3.0 MBq) in 27 mice aged 7-8 months. Regadenoson (0.1 µg/g) was used for induction of vasodilator stress. Kinetic modeling was performed using a metabolite-corrected arterial input function. Image-derived myocardial 18F-flurpiridaz uptake was assessed for different time intervals by placing a volume of interest in the left ventricular myocardium. RESULTS: Tracer kinetics were best described by a two-tissue compartment model. K1 ranged from 6.7 to 20.0 mL·cm-3·min-1, while myocardial volumes of distribution (VT) were between 34.6 and 83.6 mL·cm-3. Of note, myocardial 18F-flurpiridaz uptake (%ID/g) was significantly correlated with K1 at rest and following pharmacological vasodilation for all time intervals assessed. However, while Spearman's coefficients (rs) ranged between 0.478 and 0.681, R2 values were generally low. In contrast, an excellent correlation of myocardial 18F-flurpiridaz uptake with VT was obtained, particularly when employing the averaged myocardial uptake from 20 to 40 min post tracer injection (R2 ≥ 0.98). Notably, K1 and VT were similarly sensitive to pharmacological vasodilation induction. Further, mean stress-to-rest ratios of K1, VT, and %ID/g 18F-flurpiridaz were virtually identical, suggesting that %ID/g 18F-flurpiridaz can be used to estimate coronary flow reserve (CFR) in mice. CONCLUSION: Our findings suggest that a simplified assessment of relative myocardial perfusion and CFR, based on image-derived tracer uptake, is feasible with 18F-flurpiridaz in mice, enabling high-throughput mechanistic CFR studies in rodents.

A practical fully automated radiosynthesis of [18F]Flurpiridaz on the module modular lab-pharmtracer without external purification.

BACKGROUND: [18F]Flurpiridaz is a promising novel cardiac PET imaging tracer formed by the radiolabeling of pyridaben derivative with fluorine-18. Clinical studies on [18F]Flurpiridaz are currently at the phase III level for the assessment of MPI. Providing high image quality thanks to its relatively long half-life, F-18 is a high-potential radionuclide for the early detection of CAD. In this study, we aimed to develop a fully automated synthesis of [18F]Flurpiridaz without further preparative HPLC purification. RESULTS: Precursor 6 was obtained by multi-step synthesis starting from mucochloric acid (1) as a sole product with 35% yield and identified by spectroscopic measurement. Manually cold labeling experiments were performed using the stable isotope [19F]F, and TBA-HCO3 PTC provided desirable fluorinated compound with high yield. A fully automated [18F]Flurpiridaz synthesis on the ML-PT device provided 55-65% radiochemical yield with more than 98% radiochemical purity. The final product purification method demonstrated that [18F]Flurpiridaz could be obtained without an external preparative HPLC system as a pharmaceutical quality. CONCLUSION: A novel and fascinating strategy was developed for the fully automated synthesis of [18F]Flurpiridaz (7) on ML PT. Organic synthesis of precursor 6 was achieved with a desirable yield and characterized by NMR and HR-MS. A detailed set of cold experiments were completed for optimization conditions before hot trials and TBA-HCO3 increased molar activity with a minimum amount of side products. Radiolabeling showed that our self-designed automated synthesis method enables high radiochemical yield and radiochemical purity for the production of [18F]Flurpiridaz. The desirable radiopharmaceutical quality of the product was obtained without using an additional preparative HPLC system. [18F]Flurpiridaz (7) preserved its stability within 12 h and final specifications were consistent with the acceptance criteria in Ph. Eur. regulations.

Role of sex hormones in modulating myocardial perfusion and coronary flow reserve.

BACKGROUND: A growing body of evidence highlights sex differences in the diagnostic accuracy of cardiovascular imaging modalities. Nonetheless, the role of sex hormones in modulating myocardial perfusion and coronary flow reserve (CFR) is currently unclear. The aim of our study was to assess the impact of female and male sex hormones on myocardial perfusion and CFR. METHODS: Rest and stress myocardial perfusion imaging (MPI) was conducted by small animal positron emission tomography (PET) with [18F]flurpiridaz in a total of 56 mice (7-8 months old) including gonadectomized (Gx) and sham-operated males and females, respectively. Myocardial [18F]flurpiridaz uptake (% injected dose per mL, % ID/mL) was used as a surrogate for myocardial perfusion at rest and following intravenous regadenoson injection, as previously reported. Apparent coronary flow reserve (CFRApp) was calculated as the ratio of stress and rest myocardial perfusion. Left ventricular (LV) morphology and function were assessed by cardiac magnetic resonance (CMR) imaging. RESULTS: Orchiectomy resulted in a significant decrease of resting myocardial perfusion (Gx vs. sham, 19.4 ± 1.0 vs. 22.2 ± 0.7 % ID/mL, p = 0.034), while myocardial perfusion at stress remained unchanged (Gx vs. sham, 27.5 ± 1.2 vs. 27.3 ± 1.2 % ID/mL, p = 0.896). Accordingly, CFRApp was substantially higher in orchiectomized males (Gx vs. sham, 1.43 ± 0.04 vs. 1.23 ± 0.05, p = 0.004), and low serum testosterone levels were linked to a blunted resting myocardial perfusion (r = 0.438, p = 0.020) as well as an enhanced CFRApp (r = -0.500, p = 0.007). In contrast, oophorectomy did not affect myocardial perfusion in females. Of note, orchiectomized males showed a reduced LV mass, stroke volume, and left ventricular ejection fraction (LVEF) on CMR, while no such effects were observed in oophorectomized females. CONCLUSION: Our experimental data in mice indicate that sex differences in myocardial perfusion are primarily driven by testosterone. Given the diagnostic importance of PET-MPI in clinical routine, further studies are warranted to determine whether testosterone levels affect the interpretation of myocardial perfusion findings in patients.

Improved myocardial blood flow estimation with residual activity correction and motion correction in 18F-flurpiridaz PET myocardial perfusion imaging.

PURPOSE: We sought to evaluate the diagnostic performance for coronary artery disease (CAD) of myocardial blood flow (MBF) quantification with 18F-flurpiridaz PET using motion correction (MC) and residual activity correction (RAC). METHODS: In total, 231 patients undergoing same-day pharmacologic rest and stress 18F-flurpiridaz PET from Phase III Flurpiridaz trial (NCT01347710) were studied. Frame-by-frame MC was performed and RAC was accomplished by subtracting the rest residual counts from the dynamic stress polar maps. MBF and myocardial flow reserve (MFR) were derived with a two-compartment early kinetic model for the entire left ventricle (global), each coronary territory, and 17-segment. Global and minimal values of three territorial (minimal vessel) and segmental estimation (minimal segment) of stress MBF and MFR were evaluated in the prediction of CAD. MBF and MFR were evaluated with and without MC and RAC (1: no MC/no RAC, 2: no MC/RAC, 3: MC/RAC). RESULTS: The area-under the receiver operating characteristics curve (AUC [95% confidence interval]) of stress MBF with MC/RAC was higher for minimal segment (0.89 [0.85-0.94]) than for minimal vessel (0.86 [0.81-0.92], p = 0.03) or global estimation (0.81 [0.75-0.87], p < 0.0001). The AUC of MFR with MC/RAC was higher for minimal segment (0.87 [0.81-0.93]) than for minimal vessel (0.83 [0.76-0.90], p = 0.014) or global estimation (0.77 [0.69-0.84], p < 0.0001). The AUCs of minimal segment stress MBF and MFR with MC/RAC were higher compared to those with no MC/RAC (p < 0.001 for both) or no MC/no RAC (p < 0.0001 for both). CONCLUSIONS: Minimal segment MBF or MFR estimation with MC and RAC improves the diagnostic performance for obstructive CAD compared to global assessment.

Added value of myocardial blood flow using 18F-flurpiridaz PET to diagnose coronary artery disease: The flurpiridaz 301 trial.

BACKGROUND: 18F-Flurpiridaz is a promising investigational radiotracer for PET myocardial perfusion imaging with favorable properties for quantification of myocardial blood flow (MBF). We sought to validate the incremental diagnostic value of absolute MBF quantification in a large multicenter trial against quantitative coronary angiography. METHODS: We retrospectively analyzed a subset of patients (N = 231) from the first phase 3 flurpiridaz trial (NCT01347710). Dynamic PET data at rest and pharmacologic stress were fit to a previously validated 2-tissue-compartment model. Absolute MBF and myocardial flow reserve (MFR) were compared with coronary artery disease severity quantified by invasive coronary angiography on a per-patient and per-vessel basis. RESULTS: Stress MBF per-vessel accurately identified obstructive disease (c-index 0.79) and progressively declined with increasing stenosis severity (2.35 ± 0.71 in patients without CAD; 1.92 ± 0.49 in non-obstructed territories of CAD patients; and 1.54 ± 0.50 in diseased territories, P < 0.05). MFR similarly declined with increasing stenosis severity (3.03 ± 0.94; 2.69 ± 0.95; and 2.33 ± 0.86, respectively, P < 0.05). In multivariable logistic regression modeling, stress MBF and MFR provided incremental diagnostic value beyond patient characteristics and relative perfusion analysis. CONCLUSIONS: Clinical myocardial blood flow measurement with 18F-flurpiridaz cardiac PET shows promise for routine application.

Preliminary and Comparative Experiment Study Between 18F-Flurpiridaz and 13N-NH3·H2O Myocardial Perfusion Imaging With PET/CT in Miniature Pigs.

OBJECTVES: To comparatively explore the differences between 18F-Flurpiridaz and 13N-NH3·H2O PET/CT myocardial perfusion imaging in miniature pigs. METHODS: Ten Bama minipigs were divided into normal group and myocardial infarction group. The changes of the ratio of left ventricular myocardium to main organs with time were calculated and the best imaging time was confirmed for 18F-Flurpiridaz imaging in normal group. The image quality score, summed rest score(SRS), Extend, total perfusion deficit(TPD) and left ventricle ejection fraction(LVEF) were respectively compared for 18F-Flurpiridaz and 13N-NH3·H2O in infarction group. RESULTS: 18F-Flurpiridaz was rapid distributed in myocardium, and the background counts of cardiac cavity were very low, and no obvious interference extracardiac radioactivity was observed. The radioactive ratio of the left ventricular myocardium to cardiac blood pool and adjacent liver were high. Compared with 13N-NH3·H2O, there were no significant differences in functional parameters, including SRS, Extend, TPD and LVEF. CONCLUSION: The results preliminaryly show that 18F-FIurpiridaz is a promising positron MPI agent with good image quality, ability of accurately evaluating cardiac function, and also convenience for application.

Moving into the next era of PET myocardial perfusion imaging: introduction of novel 18F-labeled tracers.

The heart failure epidemic continues to rise with coronary artery disease as one of its main causes. Novel concepts for risk stratification to guide the referring cardiologist towards revascularization procedures are of significant value. Myocardial perfusion imaging using single-photon emission computed tomography (SPECT) agents has demonstrated high accuracy for the detection of clinically relevant stenoses. With positron emission tomography (PET) becoming more widely available, mainly due to its diagnostic performance in oncology, perfusion imaging with that modality is more practical than in the past and overcomes existing limitations of SPECT MPI. Advantages of PET include more reliable quantification of absolute myocardial blood flow, the routine use of computed tomography for attenuation correction, a higher spatiotemporal resolution and a higher count sensitivity. Current PET radiotracers such as rubidium-82 (half-life, 76 s), oxygen-15 water (2 min) or nitrogen-13 ammonia (10 min) are labeled with radionuclides with very short half-lives, necessitating that stress imaging is performed under pharmacological vasodilator stress instead of exercise testing. However, with the introduction of novel 18F-labeled MPI PET radiotracers (half-life, 110 min), the intrinsic advantages of PET can be combined with exercise testing. Additional advantages of those radiotracers include, but are not limited to: potentially improved cost-effectiveness due to the use of pre-existing delivery systems and superior imaging qualities, mainly due to the shortest positron range among available PET MPI probes. In the present review, widely used PET MPI radiotracers will be reviewed and potential novel 18F-labeled perfusion radiotracers will be discussed.

Optimization of imaging protocols for myocardial blood flow (MBF) quantification with 18F-flurpiridaz PET.

The new PET tracer, 18F-flurpiridaz, with high myocardial extraction allows quantitative myocardial blood flow (MBF) estimation from dynamic PET data and tracer kinetic modeling. The goal of this study is to determine the optimal imaging protocols and parameters using a realistic simulation study. The time activity curves (TACs) of different tissue organs from a 30-s infusion time (IT) of 18F-flurpiridaz in a dynamic PET study were extracted from a previous study. The TACs at different time points were incorporated in a series of realistic 3D XCAT phantoms from which the parameters of a 2-compartment model and the 'true' MBF of 18F-flurpiridaz were determined. The compartmental model was used to generate TACs from 7 additional ITs. PET projection data from the XCAT phantoms were generated using Monte Carlo simulation. They were reconstructed using an OS-EM reconstruction algorithm with different update number (N) to obtain dynamic PET images. The blood and myocardial TACs were derived from the dynamic images from which the MBF and %MBF error was estimated. The %MBF error decreases with increasing N of the OS-EM and levels off after ∼42. The 30-s IT gave the smallest %MBF error that decreases from ∼0.57% to ∼19.40%. The MBF for 2-min, 4-min, 8-min and 16-min IT were statistically significant different from the MBF for 30-s IT (P<0.05). Too fast or too slow infusion time gave higher %MBF error. The optimal imaging protocol in dynamic 18F-flurpiridaz PET for accurate quantitative MBF estimation was 30-s IT and N of ∼42 for the OS-EM.