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Purpose: To validate a new T(2) -prepared method for the quantification of regional myocardial O(2) consumption during pharmacologic stress with positron emission tomography (PET).Materials and Methods: A T(2) prepared gradient-echo sequence was modified to measure myocardial T(2) within a single breath-hold. Six beagle dogs were randomly selected for the induction of coronary artery stenosis. Magnetic resonance imaging (MRI) experiments were performed with the T(2) imaging and first-pass perfusion imaging at rest and during either dobutamine- or dipyridamole-induced hyperemia. Myocardial blood flow (MBF) was quantified using a previously developed model-free algorithm. Hyperemic myocardial O(2) extraction fraction (OEF) and consumption (MVO(2) ) were calculated using a two-compartment model developed previously. PET imaging using (11) C-acetate and (15) O-water was performed in the same day to validate OEF, MBF, and MVO(2) measurements.Results: The T(2) -prepared mapping sequence measured regional myocardial T(2) with a repeatability of 2.3%. By myocardial segment-basis analysis, MBF measured by MRI is closely correlated with that measured by PET (R(2) = 0.85, n = 22). Similar correlation coefficients were observed for hyperemic OEF (R(2) = 0.90, n = 9, mean difference of PET - MRI = -2.4%) and MVO(2) (R(2) = 0.83, n = 7, mean difference = 4.2%).Conclusion: The T(2) -prepared imaging method may allow quantitative estimation of regional myocardial oxygenation with relatively good accuracy. The precision of the method remains to be improved. [ABSTRACT FROM AUTHOR]

Objective: To validate fast perfusion mapping techniques in a setting of coronary artery stenosis, and to further assess the relationship of absolute myocardial blood volume (MBV) and blood flow (MBF) to global myocardial oxygen demand.Methods: A group of 27 mongrel dogs were divided into 10 controls and 17 with acute coronary stenosis. On 1.5-T MRI, first-pass perfusion imaging with a bolus injection of a blood-pool contrast agent was performed to determine myocardial perfusion both at rest and during either dipyridamole-induced vasodilation or dobutamine-induced stress. Regional values of MBF and MBV were quantified by using a fast mapping technique. Color microspheres and (99m)Tc-labeled red blood cells were injected to obtain respective gold standards.Results: Microsphere-measured MBF and (99m)Tc-measured MBV reference values correlated well with the MR results. Given the same changes in MBF, changes in MBV are twofold greater with dobutamine than with dipyridamole. Under dobutamine stress, MBV shows better association with total myocardial oxygen demand than MBF. Coronary stenosis progressively reduced this association in the presence of increased stenosis severity.Conclusions: MR first-pass perfusion can rapidly estimate regional MBF and MBV. Absolute quantification of MBV may add additional information on stenosis severity and myocardial viability compared with standard qualitative clinical evaluations of myocardial perfusion. [ABSTRACT FROM AUTHOR]

Background: The purpose of the present study was to assess the accuracy of rates of myocardial fatty acid esterification (MFAE) obtained using positron emission tomography (PET).Methods and Results: Sixteen dogs were studied after an overnight fast (FAST), during a euglycemic hyperinsulinemic clamp (CLAMP), or during infusion of intralipid (IL) or IL plus dobutamine (IL/DOB). MFAE was quantified using [1-(11)C]palmitate and PET and compared to the rate of triglyceride (TG) synthesis measured using [1-(13)C]palmitate and tissue sampling. Plasma free fatty acid (FFA) concentration varied approximately 20-fold across groups, with this variation in FFA availability accompanied by a approximately 20-fold range in TG synthesis. MFAE varied approximately 12-fold across groups, and was significantly correlated with TG synthesis (R = 0.80, P < .001). MFAE, however, was 3- to 4-fold higher than TG synthesis in FAST, CLAMP, and IL, but only approximately 50% higher when cardiac work was increased in IL/DOB, suggesting that MFAE reflects, in part, the incorporation of label into amino acids via TCA cycle exchange reactions.Conclusions: Changes in MFAE parallel changes in TG synthesis, at least in the basal state. Although the data need to be interpreted cautiously, such measurements should be useful for quantifying acute changes in FFA storage by the heart in various pathophysiological states. [ABSTRACT FROM AUTHOR]

Background: The goal of this study was to test whether myocardial triglyceride (TG) turnover including oxidation of TG-derived fatty acids (FA) could be assessed with PET and (11)C-palmitate.Methods and Results: A total of 26 dogs were studied fasted (FAST), during Intralipid infusion (IL), during a hyperinsulinemic-euglycemic clamp without (HIEG), or with Intralipid infusion (HIEG + IL). (11)C-palmitate was injected, and 45 minutes were allowed for labeling of myocardial TG pool. 3D PET data were then acquired for 60 minutes, with first 15 minutes at baseline followed by 45 minutes during cardiac work stimulated with constant infusion of either phenylephrine (FAST, n = 6; IL, n = 6; HIEG + IL, n = 6) or dobutamine (FAST, n = 4; HIEG, n = 4). Myocardial (11)C washout during adrenergic stimulation (AS) was fitted to a mono-exponential function (Km(PET)). To determine the source of this (11)C clearance, Km(PET) was compared to direct coronary sinus-arterial measurements of total (11)C activity, (11)C-palmitate, and (11)CO(2). Before AS, PET curves in all groups were flat indicating absence of net clearance of (11)C activity from heart. In both FAST groups, AS resulted in negligible net (11)C activity and (11)CO(2) production higher than net (11)C-palmitate uptake. AS with phenylephrine resulted in net myocardial uptake of total (11)C activity and (11)C-palmitate in IL and HIEG + IL, and (11)CO(2) production lower than (11)C-palmitate uptake. In contrast, AS with dobutamine in HIEG resulted in net clearance of all (11)C metabolites (total (11)C activity, (11)C-palmitate and (11)CO(2)) with (11)CO(2) contributing 66% to endogenous FA oxidation. The AS resulted in significant Km(PET) in all the groups, except HIEG + IL. However, positive correlation between Km(PET) and (11)CO(2) was observed only in HIEG (R (2) = 0.83, P = .09).Conclusions: This is the first study to demonstrate that using PET and pre-labeling of intracardiac TG pool with (11)C-palmitate, noninvasive assessment of myocardial TG use is feasible under metabolic conditions that favor endogenous TG use such as increased metabolic demand (beta-adrenergic stimulation of cardiac work) with limited availability of exogenous substrate (HIEG). [ABSTRACT FROM AUTHOR]

Here we report our design and synthesis of 28 new fluorine-containing compounds as potential F-18 radiotracers for CNS imaging of sphingosine-1-phosphate receptor 1 (S1PR1), and determination of their in vitro binding potency and selectivity toward S1PR1 over other S1PR subtypes. Nine potent and selective compounds, 7c&d, 9a&c, 12b, 15b, and 18a-c with IC 50 values ranging from 0.6-12.3 nM for S1PR1 and weak binding toward S1PR2, 3, 4, and 5, were further 18 F-radiolabeled to produce [ 18 F]7c&d, [ 18 F]9a&c, [ 18 F]12b, [ 18 F]15b, and [ 18 F]18a-c. Multi-step F-18 radiochemistry procedures were investigated for radiosynthesis of [ 18 F]7c&d and [ 18 F]9a&c, and the presumed intermediates were synthesized and authenticated by analytic HPLC. We then performed nonhuman primate (NHP) PET brain imaging studies for eight radiotracers: [ 18 F]7c&d, [ 18 F]9a, [ 18 F]12b, [ 18 F]15b, and [ 18 F]18a-c. Three radiotracers, [ 18 F]7c, [ 18 F]7d, and [ 18 F]15b, had high NHP brain uptake with standardized uptake values (SUVs) at 2 h post-injection of 2.42, 2.84, and 2.00, respectively, and good brain retention. Our ex vivo biodistribution study in rats confirmed [ 18 F]7d had a high brain uptake with no in vivo defluorination. Radiometabolic analysis of [ 18 F]7c and [ 18 F]7d in rat plasma and brain samples found that [ 18 F]7c has a more favorable metabolic profile than [ 18 F]7d. However, the trend of increased brain uptake precludes [ 18 F]7c as a suitable PET radiotracer for imaging S1PR1 in the brain. Further structural optmization is warranted to identify a highly S1PR1-specific radiotracer with rapid brain uptake kinetics.

Purpose: The sphingosine-1-phosphate receptor-1 (S1PR 1 ) is involved in regulating responses to neuroimmune stimuli. There is a need for S1PR 1 -specific radioligands with clinically suitable brain pharmcokinetic properties to complement existing radiotracers. This work evaluated a promising S1PR 1 radiotracer, [ 18 F]TZ4877, in nonhuman primates., Procedures: [ 18 F]TZ4877 was produced via nucleophilic substitution of tosylate precursor with K[ 18 F]/F - followed by deprotection. Brain PET imaging data were acquired with a Focus220 scanner in two Macaca mulatta (6, 13 years old) for 120-180 min following bolus injection of 118-163 MBq [ 18 F]TZ4877, with arterial blood sampling and metabolite analysis to measure the parent input function and plasma free fraction ( f P ). Each animal was scanned at baseline, 15-18 min after 0.047-0.063 mg/kg of the S1PR 1 inhibitor ponesimod, 33 min after 0.4-0.8 mg/kg of the S1PR 1 -specific compound TZ82112, and 167-195 min after 1 ng/kg of the immune stimulus endotoxin. Kinetic analysis with metabolite-corrected input function was performed to estimate the free fraction corrected total distribution volume ( V T / f P ). Whole-body dosimetry scans were acquired in 2 animals (1M, 1F) with a Biograph Vision PET/CT System, and absorbed radiation dose estimates were calculated with OLINDA., Results: [ 18 F]TZ4877 exhibited fast kinetics that were described by the reversible 2-tissue compartment model. Baseline [ 18 F]TZ4877 f P was low (< 1%), and [ 18 F]TZ4877 V T / f P values were 233-866 mL/cm 3 . TZ82112 dose-dependently reduced [ 18 F]TZ4877 V T / f P , while ponesimod and endotoxin exhibited negligible effects on V T / f P , possibly due to scan timing relative to dosing. Dosimetry studies identified the critical organs of gallbladder (0.42 (M) and 0.31 (F) mSv/MBq) for anesthetized nonhuman primate., Conclusions: [ 18 F]TZ4877 exhibits reversible kinetic properties, but the low f P value limits quantification with this radiotracer. S1PR 1 is a compelling PET imaging target, and these data support pursuing alternative F-18 labeled radiotracers for potential future human studies., Competing Interests: Conflict of Interest: The authors declare that they have no conflict of interest.

The sphingosine-1-phosphate receptor 1 (S1PR1) radiotracer [ 11 C] CS1P1 has shown promise in proof-of-concept PET imaging of neuroinflammation in multiple sclerosis (MS). Our HPLC radiometabolite analysis of human plasma samples collected during PET scans with [ 11 C] CS1P1 detected a radiometabolite peak that is more lipophilic than [ 11 C] CS1P1 . Radiolabeled metabolites that cross the blood-brain barrier complicate quantitative modeling of neuroimaging tracers; thus, characterizing such radiometabolites is important. Here, we report our detailed investigation of the metabolite profile of [ 11 C] CS1P1 in rats, nonhuman primates, and humans. CS1P1 is a fluorine-containing ligand that we labeled with C-11 or F-18 for preclinical studies; the brain uptake was similar for both radiotracers. The same lipophilic radiometabolite found in human studies also was observed in plasma samples of rats and NHPs for CS1P1 labeled with either C-11 or F-18. We characterized the metabolite in detail using rats after injection of the nonradioactive CS1P1 . To authenticate the molecular structure of this radiometabolite, we injected rats with 8 mg/kg of CS1P1 to collect plasma for solvent extraction and HPLC injection, followed by LC/MS analysis of the same metabolite. The LC/MS data indicated in vivo mono-oxidation of CS1P1 produces the metabolite. Subsequently, we synthesized three different mono-oxidized derivatives of CS1P1 for further investigation. Comparing the retention times of the mono-oxidized derivatives with the metabolite observed in rats injected with CS1P1 identified the metabolite as N -oxide 1 , also named TZ82121 . The MS fragmentation pattern of N -oxide 1 also matched that of the major metabolite in rat plasma. To confirm that metabolite TZ82121 does not enter the brain, we radiosynthesized [ 18 F] TZ82121 by the oxidation of [ 18 F] FS1P1 . Radio-HPLC analysis confirmed that [ 18 F] TZ82121 matched the radiometabolite observed in rat plasma post injection of [ 18 F] FS1P1 . Furthermore, the acute biodistribution study in SD rats and PET brain imaging in a nonhuman primate showed that [ 18 F] TZ82121 does not enter the rat or nonhuman primate brain. Consequently, we concluded that the major lipophilic radiometabolite N -oxide [ 11 C] TZ82121 , detected in human plasma post injection of [ 11 C] CS1P1 , does not enter the brain to confound quantitative PET data analysis. [ 11 C] CS1P1 is a promising S1PR1 radiotracer for detecting S1PR1 expression in the CNS.

Tissue-resident macrophages are complementary to proinflammatory macrophages to promote the progression of atherosclerosis. The noninvasive detection of their presence and dynamic variation will be important to the understanding of their role in the pathogenesis of atherosclerosis. The goal of this study was to develop a targeted PET radiotracer for imaging CD163-positive (CD163+) macrophages in multiple mouse atherosclerosis models and assess the potential of CD163 as a biomarker for atherosclerosis in humans. Methods: CD163-binding peptide was identified using phage display and conjugated with a NODAGA chelator for 64 Cu radiolabeling ([ 64 Cu]Cu-ICT-01). CD163-overexpressing U87 cells were used to measure the binding affinity of [ 64 Cu]Cu-ICT-01. Biodistribution studies were performed on wild-type C57BL/6 mice at multiple time points after tail vein injection. The sensitivity and specificity of [ 64 Cu]Cu-ICT-01 in imaging CD163+ macrophages upregulated on the surface of atherosclerotic plaques were assessed in multiple mouse atherosclerosis models. Immunostaining, flow cytometry, and single-cell RNA sequencing were performed to characterize the expression of CD163 on tissue-resident macrophages. Human carotid atherosclerotic plaques were used to measure the expression of CD163+ resident macrophages and test the binding specificity of [ 64 Cu]Cu-ICT-01. Results: [ 64 Cu]Cu-ICT-01 showed high binding affinity to U87 cells. The biodistribution study showed rapid blood and renal clearance with low retention in all major organs at 1, 2, and 4 h after injection. In an ApoE -/- mouse model, [ 64 Cu]Cu-ICT-01 demonstrated sensitive and specific detection of CD163+ macrophages and capability for tracking the progression of atherosclerotic lesions; these findings were further confirmed in Ldlr -/- and PCSK9 mouse models. Immunostaining showed elevated expression of CD163+ macrophages across the plaques. Flow cytometry and single-cell RNA sequencing confirmed the specific expression of CD163 on tissue-resident macrophages. Human tissue characterization demonstrated high expression of CD163+ macrophages on atherosclerotic lesions, and ex vivo autoradiography revealed specific binding of [ 64 Cu]Cu-ICT-01 to human CD163. Conclusion: This work reported the development of a PET radiotracer binding CD163+ macrophages. The elevated expression of CD163+ resident macrophages on human plaques indicated the potential of CD163 as a biomarker for vulnerable plaques. The sensitivity and specificity of [ 64 Cu]Cu-ICT-01 in imaging CD163+ macrophages warrant further investigation in translational settings., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

The immune-fibrosis axis plays a critical role in cardiac remodeling after acute myocardial infarction. Imaging approaches to monitor temporal inflammation and fibroblast activation in mice have seen wide application in recent years. However, the repeatability of quantitative measurements remains challenging, particularly across multiple imaging centers. We aimed to determine reproducibility of quantitative inflammation and fibroblast activation images acquired at 2 facilities after myocardial infarction in mice. Methods: Mice underwent coronary artery ligation and sequential imaging with 68 Ga-DOTA-ECL1i to assess chemokine receptor type 2 expression at 3 d after myocardial infarction and 68 Ga-FAPI-46 to assess fibroblast activation protein expression at 7 d after myocardial infarction. Images were acquired at 1 center using either a local or a consensus protocol developed with the second center; the protocols differed in the duration of isoflurane anesthesia and the injected tracer dose. A second group of animals were scanned at the second site using the consensus protocol. Image analyses performed by each site and just by 1 site were also compared. Results: The uptake of 68 Ga-DOTA-ECL1i in the infarct territory tended to be higher when the consensus protocol was used ( P = 0.03). No difference was observed between protocol acquisitions for 68 Ga-FAPI-46. Compared with the local protocol, the consensus protocol decreased variability between individual animals. When a matched consensus protocol was used, the 68 Ga-DOTA-ECL1i infarct territory percentage injected dose per gram of tissue was higher on images acquired at site B than on those acquired at site A ( P = 0.006). When normalized to body weight as SUV, this difference was mitigated. Both the percentage injected dose per gram of tissue and the SUV were comparable between sites for 68 Ga-FAPI-46. Image analyses at the sites differed significantly, but this difference was mitigated when all images were analyzed at site A. Conclusion: The application of a standardized acquisition protocol may lower variability within datasets and facilitate comparison of molecular radiotracer distribution between preclinical imaging centers. Like clinical studies, multicenter preclinical studies should use centralized core-based image analysis to maximize reproducibility across sites., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Multiple sclerosis (MS) is an immune-mediated disease that is characterized by demyelination and inflammation in the central nervous system (CNS). Previous studies demonstrated that sphingosine-1-phosphate receptor (S1PR) modulators effectively inhibit S1PR1 in immune cell trafficking and reduce entry of pathogenic cells into the CNS. Studies have also implicated a nonimmune, inflammatory role of S1PR1 within the CNS in MS. In this study, we explored the expression of S1PR1 in the development and progression of demyelinating pathology of MS by quantitative assessment of S1PR1 expression using our S1PR1-specific radioligand, [ 3 H]CS1P1, in the postmortem human CNS tissues including cortex, cerebellum, and spinal cord of MS cases and age- and sex-matched healthy cases. Immunohistochemistry with whole slide scanning for S1PR1 and various myelin proteins was also performed. Autoradiographic analysis using [ 3 H]CS1P1 showed that the expression of S1PR1 was statistically significantly elevated in lesions compared to nonlesion regions in the MS cases, as well as normal healthy controls. The uptake of [ 3 H]CS1P1 in the gray matter and nonlesion white matter did not significantly differ between healthy and MS CNS tissues. Saturation autoradiography analysis showed an increased binding affinity ( K d ) of [ 3 H]CS1P1 to S1PR1 in both gray matter and white matter of MS brains compared to healthy brains. Our blocking study using NIBR-0213, a S1PR1 antagonist, indicated [ 3 H]CS1P1 is highly specific to S1PR1. Our findings demonstrated the activation of S1PR1 and an increased uptake of [ 3 H]CS1P1 in the lesions of MS CNS. In summary, our quantitative autoradiography analysis using [ 3 H]CS1P1 on human postmortem tissues shows the feasibility of novel imaging strategies for MS by targeting S1PR1.

Infiltrative cardiomyopathies comprise a broad spectrum of inherited or acquired conditions caused by deposition of abnormal substances within the myocardium. Increased wall thickness, inflammation, microvascular dysfunction, and fibrosis are the common pathological processes that lead to abnormal myocardial filling, chamber dilation, and disruption of conduction system. Advanced disease presents as heart failure and cardiac arrhythmias conferring poor prognosis. Infiltrative cardiomyopathies are often diagnosed late or misclassified as other more common conditions, such as hypertrophic cardiomyopathy, hypertensive heart disease, ischemic or other forms of nonischemic cardiomyopathies. Accurate diagnosis is also critical because clinical features, testing methodologies, and approach to treatment vary significantly even within the different types of infiltrative cardiomyopathies on the basis of the type of substance deposited. Substantial advances in noninvasive cardiac imaging have enabled accurate and early diagnosis. thereby eliminating the need for endomyocardial biopsy in most cases. This scientific statement discusses the role of contemporary multimodality imaging of infiltrative cardiomyopathies, including echocardiography, nuclear and cardiac magnetic resonance imaging in the diagnosis, prognostication, and assessment of response to treatment.

Among the diverse populations of myeloid cells that reside within the healthy and diseased heart, C-C chemokine receptor 2 (CCR2) is specifically expressed on inflammatory populations of monocytes and macrophages that contribute to the development and progression of heart failure 1-4 . Here, we evaluated a peptide-based imaging probe ( 64 Cu-DOTA-ECL1i) that specifically recognizes CCR2 + monocytes and macrophages for human cardiac imaging. Compared to healthy controls, 64 Cu-DOTA-ECL1i heart uptake was increased in subjects following acute myocardial infarction, predominately localized within the infarct area, and was associated with impaired myocardial wall motion. These findings establish the feasibility of molecular imaging of CCR2 expression to visualize inflammatory monocytes and macrophages in the injured human heart., Competing Interests: Competing interests K.J.L. serves as a consultant for Implicit Biosciences and Medtronic and is the recipient of sponsored research agreements with Amgen and Novartis. K.J.L., D.K., S.L.B., R.J.G., and Y.L. have a pending patent entitled “Methods for detecting CCR2 receptors” (application number: US17/001,857). The remaining authors declare no competing interests

Background: Artificial intelligence-based methods have generated substantial interest in nuclear medicine. An area of significant interest has been the use of deep-learning (DL)-based approaches for denoising images acquired with lower doses, shorter acquisition times, or both. Objective evaluation of these approaches is essential for clinical application., Purpose: DL-based approaches for denoising nuclear-medicine images have typically been evaluated using fidelity-based figures of merit (FoMs) such as root mean squared error (RMSE) and structural similarity index measure (SSIM). However, these images are acquired for clinical tasks and thus should be evaluated based on their performance in these tasks. Our objectives were to: (1) investigate whether evaluation with these FoMs is consistent with objective clinical-task-based evaluation; (2) provide a theoretical analysis for determining the impact of denoising on signal-detection tasks; and (3) demonstrate the utility of virtual imaging trials (VITs) to evaluate DL-based methods., Methods: A VIT to evaluate a DL-based method for denoising myocardial perfusion SPECT (MPS) images was conducted. To conduct this evaluation study, we followed the recently published best practices for the evaluation of AI algorithms for nuclear medicine (the RELAINCE guidelines). An anthropomorphic patient population modeling clinically relevant variability was simulated. Projection data for this patient population at normal and low-dose count levels (20%, 15%, 10%, 5%) were generated using well-validated Monte Carlo-based simulations. The images were reconstructed using a 3-D ordered-subsets expectation maximization-based approach. Next, the low-dose images were denoised using a commonly used convolutional neural network-based approach. The impact of DL-based denoising was evaluated using both fidelity-based FoMs and area under the receiver operating characteristic curve (AUC), which quantified performance on the clinical task of detecting perfusion defects in MPS images as obtained using a model observer with anthropomorphic channels. We then provide a mathematical treatment to probe the impact of post-processing operations on signal-detection tasks and use this treatment to analyze the findings of this study., Results: Based on fidelity-based FoMs, denoising using the considered DL-based method led to significantly superior performance. However, based on ROC analysis, denoising did not improve, and in fact, often degraded detection-task performance. This discordance between fidelity-based FoMs and task-based evaluation was observed at all the low-dose levels and for different cardiac-defect types. Our theoretical analysis revealed that the major reason for this degraded performance was that the denoising method reduced the difference in the means of the reconstructed images and of the channel operator-extracted feature vectors between the defect-absent and defect-present cases., Conclusions: The results show the discrepancy between the evaluation of DL-based methods with fidelity-based metrics versus the evaluation on clinical tasks. This motivates the need for objective task-based evaluation of DL-based denoising approaches. Further, this study shows how VITs provide a mechanism to conduct such evaluations computationally, in a time and resource-efficient setting, and avoid risks such as radiation dose to the patient. Finally, our theoretical treatment reveals insights into the reasons for the limited performance of the denoising approach and may be used to probe the effect of other post-processing operations on signal-detection tasks., (© 2023 American Association of Physicists in Medicine.)

Background: Diabetes mellitus is a chronic progressive metabolic disorder that affects millions of people worldwide. Emerging evidence suggests the important roles of sphingolipid metabolism in diabetes. In particular, sphingosine-1-phosphate (S1P) and S1P receptor 2 (S1PR2) have important metabolic functions and are involved in several metabolic diseases. In diabetes, S1PR2 can effectively preserve β cells and improve glucose/insulin tolerance in high-fat diet induced and streptozotocin (STZ)-induced diabetic mouse models. We previously developed a group of potent and selective S1PR2 ligands and radioligands., Methods: In this study, we continued our efforts and characterized our leading S1PR2 radioligand, [ 11 C]TZ34125, in a STZ-induced diabetic mouse model. [ 11 C]TZ34125 was radiosynthesized in an automated synthesis module and in vitro saturation binding assay was performed using recombinant human S1PR2 membrane. In vitro saturation autoradiography analysis was also performed to determine the binding affinity of [ 11 C]TZ34125 against mouse tissues. Type-1 diabetic mouse model was developed following a single high dose of STZ in C57BL/6 mice. Ex vivo biodistribution was performed to evaluate the distribution and amount of [ 11 C]TZ34125 in tissues. In vitro autoradiography analysis was performed to compare the uptake of [ 11 C]TZ34125 between diabetic and control animals in mouse spleen and pancreas., Results: Our in vitro saturation binding assay using [ 11 C]TZ34125 confirmed [ 11 C]TZ34125 is a potent radioligand to recombinant human S1PR2 membrane with a K d value of 0.9 nM. Saturation autoradiographic analysis showed [ 11 C]TZ34125 has a K d of 67.5, 45.9, and 25.0 nM to mouse kidney, spleen, and liver tissues respectively. Biodistribution study in STZ-induced diabetic mice showed the uptake of [ 11 C]TZ34125 was significantly elevated in the spleen (~2 fold higher) and pancreas (~1.4 fold higher) compared to normal controls. The increased uptake of [ 11 C]TZ34125 was further confirmed using autoradiographic analysis in the spleen and pancreases of STZ-induced diabetic mice, indicating S1PR2 can potentially act as a biomarker of diabetes in pancreases and inflammation in spleen. Future mechanistic analysis and in vivo quantitative assessment using non-invasive PET imaging in large animal model of diabetes is worthwhile., Conclusions: Overall, our data showed an increased uptake of our lead S1PR2-specific radioligand, [ 11 C]TZ34125, in the spleen and pancreases of STZ-induced diabetic mice, and demonstrated [ 11 C]TZ34125 has a great potential for preclinical and clinical usage for assessment of S1PR2 in diabetes and inflammation., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

In the past 2 decades, research on atherosclerotic cardiovascular disease has uncovered inflammation to be a key driver of the pathophysiological process. A pressing need therefore exists to quantitatively and longitudinally probe inflammation, in preclinical models and in cardiovascular disease patients, ideally using non-invasive methods and at multiple levels. Here, we developed and employed in vivo multiparametric imaging approaches to investigate the immune response following myocardial infarction. The myocardial infarction models encompassed either transient or permanent left anterior descending coronary artery occlusion in C57BL/6 and Apoe -/- mice. We performed nanotracer-based fluorine magnetic resonance imaging and positron emission tomography (PET) imaging using a CD11b-specific nanobody and a C-C motif chemokine receptor 2-binding probe. We found that immune cell influx in the infarct was more pronounced in the permanent occlusion model. Further, using 18 F-fluorothymidine and 18 F-fluorodeoxyglucose PET, we detected increased hematopoietic activity after myocardial infarction, with no difference between the models. Finally, we observed persistent systemic inflammation and exacerbated atherosclerosis in Apoe -/- mice, regardless of which infarction model was used. Taken together, we showed the strengths and capabilities of multiparametric imaging in detecting inflammatory activity in cardiovascular disease, which augments the development of clinical readouts., Competing Interests: This work was supported by National Institute of Health grants R01HL143814 (to Dr Fayad), P01HL131478 (Drs Fayad and Mulder), P41EB025815 (Drs Liu and Gropler ), R35HL145212 (Dr Liu), and R35HL139598 (Dr Nahrendorf) and award K22CA226040 (Dr Rashidian). This work was also supported by an Innovation Research Fund Basic Research Award from the Dana-Farber Cancer Institute (Dr Rashidian). Dr Maier was supported by Deutsche Forschungsgemeinschaft grants (MA 7059/1 and MA 7059/3-1) and is part of SFB1425 funded by the Deutsche Forschungsgemeinschaft (project no. 422681845). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2023 The Authors.)

Angina pectoris and dyspnea in patients with normal or nonobstructive coronary vessels remains a diagnostic challenge. Invasive coronary angiography may identify up to 60% of patients with nonobstructive coronary artery disease (CAD), of whom nearly two-thirds may, in fact, have coronary microvascular dysfunction (CMD) that may account for their symptoms. Positron emission tomography (PET) determined absolute quantitative myocardial blood flow (MBF) at rest and during hyperemic vasodilation with subsequent derivation of myocardial flow reserve (MFR) affords the noninvasive detection and delineation of CMD. Individualized or intensified medical therapies with nitrates, calcium-channel blockers, statins, angiotensin-converting enzyme inhibitors, angiotensin II type 1-receptor blockers, beta-blockers, ivabradine, or ranolazine may improve symptoms, quality of life, and outcome in these patients. Standardized diagnosis and reporting criteria for ischemic symptoms caused by CMD are critical for optimized and individualized treatment decisions in such patients. In this respect, it was proposed by the cardiovascular council leadership of the Society of Nuclear Medicine and Molecular Imaging to convene thoughtful leaders from around the world to serve as an independent expert panel to develop standardized diagnosis, nomenclature and nosology, and cardiac PET reporting criteria for CMD. This consensus document aims to provide an overview of the pathophysiology and clinical evidence of CMD, its invasive and noninvasive assessment, standardization of PET-determined MBFs and MFR into "classical" (predominantly related to hyperemic MBFs) and "endogen" (predominantly related to resting MBF) normal coronary microvascular function or CMD that may be critical for diagnosis of microvascular angina, subsequent patient care, and outcome of clinical CMD trials., Competing Interests: Funding Support and Author Disclosures Dr Schindler has received institutional research grant support from GE Healthcare and National Institutes of Health/NHLBI (1RO1HL142297-01A1). Dr Fearon has received institutional research grant support from Abbott, Boston Scientific, and Medtronic; consulting fees from CathWorks and Siemens; and stock options from HeartFlow. Dr Pelletier-Galarneau is supported by a Junior 1 Research Award from the Fonds de Recherche du Québec–Santé (FRQS), and he has received consultant fees and research funds from Jubilant Radiopharma. Dr Bhatt has served on the advisory boards of AngioWave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, and Stasys; has served on the board of directors for AngioWave (stock options), Boston VA Research Institute, Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock), Society of Cardiovascular Patient Care, and TobeSoft; has served as chair for the American Heart Association Quality Oversight Committee (Inaugural Chair); consultant for Broadview Ventures; and on data-monitoring committees for Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial funded by St. Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial), Cleveland Clinic (including for the ExCEED trial, funded by Edwards Lifesciences), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo, and for the ABILITY-DM trial, funded by Concept Medical), Novartis, Population Health Research Institute, Rutgers University (for the National Institutes of Health–funded MINT trial); has received honoraria from American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol-Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute); RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor, Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary-Treasurer), WebMD (CME steering committees), Wiley (steering committee); has served as Deputy Editor for Clinical Cardiology, Chair for NCDR-ACTION Registry Steering Committee and VA CART Research and Publications Committee; he has received a patent for sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women's Hospital who assigned to Lexicon; neither he nor Brigham and Women's Hospital have received income from this patent); has received research funding from Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, 89Bio; and royalties from Elsevier (Editor, Braunwald’s Heart Disease); Site Co-Investigator for Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, Vascular Solutions; Trustee: American College of Cardiology; and unfunded research for FlowCo and Takeda. Dr Ruddy has received institutional research grant support from GE Healthcare and Advanced Accelerator Applications International. Dr Bateman has received institutional research grant support from Bracco, GEHC, and Spectrum Dynamics; has served as consultant for GEHC and has received royalties from SPECT and PET software products and equity interest from CVIT. Dr Knuuti has received consultancy fees from GE Healthcare and AstraZeneca and speaker fees from GE Healthcare, Bayer, Lundbeck, Boehringer-Ingelheim, Pfizer, and Merck, outside of the submitted work. Dr Slart has received institutional research grant support from Pfizer and Siemens Healthineers. Dr Windecker has received research and educational grants to the institution from Abbott, Abiomed, Amgen, AstraZeneca, Bayer, Biotronik, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardinal Health, CardioValve, Corflow Therapeutics, CSL Behring, Daiichi Sankyo, Edwards Lifesciences, Guerbet, InfraRedx, Janssen-Cilag, Johnson & Johnson, Medicure, Medtronic, Merck Sharp & Dohme, Miracor Medical, Novartis, Novo Nordisk, Organon, OrPha Suisse, Pfizer, Polares, Regeneron, Sanofi-Aventis, Servier, Sinomed, Terumo, Vifor, and V-Wave; has served as an unpaid advisory board member or unpaid member of the steering-executive group of trials funded by Abbott, Abiomed, Amgen, AstraZeneca, Bayer, Boston Scientific, Biotronik, Bristol Myers Squibb, Edwards Lifesciences, Janssen, MedAlliance, Medtronic, Novartis, Polares, Recardio, Sinomed, Terumo, V-Wave, and Xeltis but has not received personal payments by pharmaceutical companies or device manufacturers; and is also a member of the steering-executive committee group of several investigator-initiated trials that receive funding by industry without impact on his personal remuneration. Dr Taqueti has received research support from National Institutes of Health K23HL135438. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Matrix metalloproteinases (MMPs) play a key role in the pathogenesis of abdominal aortic aneurysm (AAA). Imaging aortic MMP activity, especially using positron emission tomography to access high sensitivity, quantitative data, could potentially improve AAA risk stratification. Here, we describe the design, synthesis, characterization, and evaluation in murine AAA and human aortic tissue of a first-in-class MMP-targeted positron emission tomography radioligand, 64 Cu-RYM2., Methods: The broad spectrum MMP inhibitor, RYM2 was synthetized, and its potency as an MMP inhibitor was evaluated by a competitive inhibition assay. Toxicology studies were performed. Tracer biodistribution was evaluated in a murine model of AAA induced by angiotensin II infusion in Apolipoprotein E-deficient mice. 64 Cu-RYM2 binding to normal and aneurysmal human aortic tissues was assessed by autoradiography., Results: RYM2 functioned as an MMP inhibitor with nanomolar affinities. Toxicology studies showed no adverse reaction in mice. Upon radiolabeling with Cu-64, the resulting tracer was stable in murine and human blood in vitro. Biodistribution and metabolite analysis in mice showed rapid renal clearance and acceptable in vivo stability. In vivo positron emission tomography/computed tomography in a murine model of AAA showed a specific aortic signal, which correlated with ex vivo measured MMP activity and Cd68 gene expression. 64 Cu-RYM2 specifically bound to normal and aneurysmal human aortic tissues in correlation with MMP activity., Conclusions: 64 Cu-RYM2 is a first-in-class MMP-targeted positron emission tomography tracer with favorable stability, biodistribution, performance in preclinical AAA, and importantly, specific binding to human tissues. These data set the stage for 64 Cu-RYM2-based translational imaging studies of vessel wall MMP activity, and indirectly, inflammation, in AAA.

Aims: The aim of this study is to evaluate whether post-acute sequelae of COVID-19 cardiovascular syndrome (PASC-CVS) is associated with alterations in coronary circulatory function., Materials and Methods: In individuals with PASC-CVS but without known cardiovascular risk factors (n = 23) and in healthy controls (CON, n = 23), myocardial blood flow (MBF) was assessed with 13 N-ammonia and PET/CT in mL/g/min during regadenoson-stimulated hyperemia, at rest, and the global myocardial flow reserve (MFR) was calculated. MBF was also measured in the mid and mid-distal myocardium of the left ventricle (LV). The Δ longitudinal MBF gradient (hyperemia minus rest) as a reflection of an impairment of flow-mediated epicardial vasodilation, was calculated., Results: Resting MBF was significantly higher in PASC-CVS than in CON (1.29 ± 0.27 vs. 1.08 ± 0.20 ml/g/min, p ≤ .024), while hyperemic MBFs did not differ significantly among groups (2.46 ± 0.53 and 2.40 ± 0.34 ml/g/min, p = .621). The MFR was significantly less in PASC-CVS than in CON (1.97 ± 0.54 vs. 2.27 ± 0.43, p ≤ .031). In addition, there was a Δ longitudinal MBF gradient in PASC-CVS, not observed in CON (-0.17 ± 0.18 vs. 0.04 ± 0.11 ml/g/min, p < .0001)., Conclusions: Post-acute sequelae of COVID-19 cardiovascular syndrome may be associated with an impairment of flow-mediated epicardial vasodilation, while reductions in coronary vasodilator capacity appear predominantly related to increases in resting flow in women deserving further investigations., (© 2022 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

This study evaluated the safety, dosimetry, and characteristics of 3-((2-fluoro-4-(5-(2'-methyl-2-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)(methyl- 11 C)amino)propanoic acid ( 11 C-CS1P1), a radiotracer targeting sphingosine-1-phosphate receptor (S1PR) 1 (S1PR1). S1PR1 is of clinical interest because of its role in multiple sclerosis (and other conditions), with an expanding class of S1PR modulators approved for relapsing multiple sclerosis. 11 C-CS1P1 binds S1PR1 with high specificity and has shown promise in animal models of inflammatory diseases. Methods: 11 C-CS1P1 was injected into 5 male and 6 female healthy participants. Ten participants were imaged with PET using a multipass whole-body continuous-bed-motion acquisition, and one had dedicated head and neck PET and MRI. Participants were continuously monitored for safety events. Organ time-activity curve data were collected, integrated, and normalized to the injected activity. Organ radiation doses and effective dose were computed using the adult male and female models in OLINDA, version 2.2. SUV images were evaluated for qualitative biodistribution. Results: No adverse events were observed after the dose, including no bradycardia. The liver was the critical organ from dosimetry analysis (mean ± SD: female, 23.12 ± 5.19 μSv/MBq; male, 21.06 ± 1.63 μSv/MBq). The whole-body effective dose (as defined by International Commission on Radiological Protection publication 103) was 4.18 ± 0.30 μSv/MBq in women and 3.54 ± 0.14 μSv/MBq in men. Using a maximum delivered dose of 740 MBq (20 mCi), the effective dose for women would be 3.1 mSv (0.31 rem), with a liver dose of 17.1 mSv (1.7 rem); the effective dose for men would be 2.6 mSv (0.26 rem), with a liver dose of 15.6 mSv (1.56 rem). Brain uptake was seen predominantly in gray matter and correlated with regional S1PR1 RNA expression ( r = 0.84). Conclusion: These results support the safety of 11 C-CS1P1 for evaluation of inflammation in human clinical populations. Dosimetry permits repeated measures in the same participants. Brain uptake correlates well with known target topography., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

CD36 mediates the uptake of long-chain fatty acids (FAs), a major energy substrate for the myocardium. Under excessive FA supply, CD36 can cause cardiac lipid accumulation and inflammation while its deletion reduces heart FA uptake and lipid content and increases glucose utilization. As a result, CD36 was proposed as a therapeutic target for obesity-associated heart disease. However, more recent reports have shown that CD36 deficiency suppresses myocardial flexibility in fuel preference between glucose and FAs, impairing tissue energy balance, while CD36 absence in tissue macrophages reduces efferocytosis and myocardial repair after injury. In line with the latter homeostatic functions, we had previously reported that CD36 -/- mice have chronic subclinical inflammation. Lipids are important for the maintenance of tissue homeostasis and there is limited information on heart lipid metabolism in CD36 deficiency. Here, we document in the hearts of unchallenged CD36 -/- mice abnormalities in the metabolism of triglycerides, plasmalogens, cardiolipins, acylcarnitines, and arachidonic acid, and the altered remodeling of these lipids in response to an overnight fast. The hearts were examined for evidence of inflammation by monitoring the presence of neutrophils and pro-inflammatory monocytes/macrophages using the respective positron emission tomography (PET) tracers, 64 Cu-AMD3100 and 68 Ga-DOTA-ECL1i. We detected significant immune cell infiltration in unchallenged CD36 -/- hearts as compared with controls and immune infiltration was also observed in hearts of mice with cardiomyocyte-specific CD36 deficiency. Together, the data show that the CD36 -/- heart is in a non-homeostatic state that could compromise its stress response. Non-invasive immune cell monitoring in humans with partial or total CD36 deficiency could help evaluate the risk of impaired heart remodeling and disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Cifarelli, Kuda, Yang, Liu, Gross, Pietka, Heo, Sultan, Luehmann, Lesser, Ross, Goldberg, Gropler, Liu and Abumrad.)

Background: Although it is well-accepted that increased plasma free fatty acid (FFA) concentration causes lipid overload and muscle insulin resistance in people with obesity, plasma FFA concentration poorly predicts insulin-resistant glucose metabolism. It has been proposed that hyperinsulinemia in people with obesity sufficiently inhibits adipose tissue triglyceride lipolysis to prevent FFA-induced insulin resistance. However, we hypothesized enhanced FFA clearance in people with obesity, compared with lean people, prevents a marked increase in plasma FFA even when FFA appearance is high., Methods: We assessed FFA kinetics during basal conditions and during a hyperinsulinemic-euglycemic clamp procedure in 14 lean people and 46 people with obesity by using [ 13 C]palmitate tracer infusion. Insulin-stimulated muscle glucose uptake rate was evaluated by dynamic PET-imaging of skeletal muscles after [ 18 F]fluorodeoxyglucose injection., Results: Plasma FFA clearance was accelerated in participants with obesity and correlated negatively with muscle insulin sensitivity without a difference between lean and obese participants. Furthermore, insulin infusion increased FFA clearance and the increase was greater in obese than lean participants., Conclusions: Our findings suggest plasma FFA extraction efficiency, not just plasma FFA concentration, is an important determinant of the cellular fatty acid load and the stimulatory effect of insulin on FFA clearance counteracts some of its antilipolytic effect., (Copyright © 2022. Published by Elsevier Inc.)

Aims: The aim of this investigation was to explore and characterize alterations in coronary circulatory function in function of increasing body weight with medically controlled cardiovascular risk factors and, thus, "metabolically" unhealthy obesity., Materials and Methods: We prospectively enrolled 106 patients with suspected CAD but with normal stress-rest myocardial perfusion on 13 N-ammonia PET/CT and with medically controlled or no cardiovascular risk factors. 13 N-ammonia PET/CT concurrently determined myocardial blood flow (MBF) during pharmacologically induced hyperaemia and at rest. Based on body mass index (BMI), patients were grouped into normal weight (BMI: 20.0-24.9 kg/m 2 , n = 22), overweight (BMI: 25.0-29.9 kg/m 2 , n = 27), obese (BMI: 30.0-39.9 kg/m 2 , n = 31), and morbidly obese (BMI ≥ 40kg/m 2 , n = 26)., Results: Resting MBF was comparable among groups (1.09 ± 0.18 vs. 1.00 ± 0.15 vs. 0.96 ± 0.18 vs.. 1.06 ± 0.31 ml/g/min; p = .279 by ANOVA). Compared to normal weight individuals, the hyperaemic MBF progressively decreased in in overweight and obese groups, respectively (2.54 ± 0.48 vs. 2.02 ± 0.27 and 1.75 ± 0.39 ml/g/min; p < .0001), while it increased again in the group of morbidly obese individuals comparable to normal weight (2.44 ± 0.41 vs. 2.54 ± 0.48 ml/g/min, p = .192). The BMI of the study population correlated with the hyperaemic MBF in a quadratic or U-turn fashion (r = .34, SEE = 0.46; p ≤ .002)., Conclusions: The U-turn of hyperaemic MBF from obesity to morbid obesity is likely to reflect contrasting effects of abdominal versus subcutaneous adipose tissue on coronary circulatory function indicative of two different disease entities, but needing further investigations., (© 2022 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

We assessed image quality using a practical and time-efficient protocol for intravenous glucose loading and insulin injection before administration of 18 F-FDG for PET myocardial viability evaluation in patients with ischemic cardiomyopathy (ICM), with and without type 2 diabetes mellitus. Methods: The metabolic preparation period (MPP) or optimal cardiac 18 F-FDG uptake was determined from the time of intravenous infusion of 12.5 or 25 g of 50% dextrose to the time of 18 F-FDG injection. Cardiac 18 F-FDG image quality was evaluated according to a 5-point scoring system (from 5, excellent, to 1, nondiagnostic) by 2 independent observers. In cases of disagreement, consensus was achieved in a joint reading. Fifteen patients with ICM who underwent oral glucose loading and intravenous insulin administration served as a reference for MPP comparisons. Results: Fifty-nine consecutive patients (age, 63 ± 10 y; 48 men and 11 women) underwent rest 99m Tc-tetrofosmin SPECT/CT and 18 F-FDG PET/CT for the evaluation of myocardial viability. 18 F-FDG image quality was scored as excellent in 42%, very good in 36%, good in 17%, fair in 3%, and nondiagnostic in 2%. When diabetic and nondiabetic patients were compared, the quality scores were excellent in 29% versus 76%, very good in 41% versus 18%, good in 24% versus 6%, fair in 4% versus 0%, and nondiagnostic in 2% versus 0%. The mean (±SD) quality score was 4.12 ± 0.95, and overall it was better in nondiabetic than in diabetic patients (4.71 ± 0.59 vs. 3.88 ± 0.96; P < 0.0001). Notably, the average MPP was significantly less with intravenous glucose loading than with oral glucose loading (51 ± 15 min vs. 132 ± 29 min; P < 0.0001), paralleled by higher insulin doses (6.3 ± 2.2 U vs. 2.0 ± 1.69 U; P < 0.001). Conclusion: Using a practical and time-efficient protocol for intravenous glucose loading and insulin administration before 18 F-FDG injection reduces the MPP by 61% as compared with an oral glucose challenge and affords good-to-excellent image quality in 95% of ICM patients., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: Obstructive sleep apnea (OSA) is prevalent in people with obesity and is a major risk factor for type 2 diabetes (T2D). The effect of OSA on metabolic function and the precise mechanisms (insulin resistance, β-cell dysfunction, or both) responsible for the increased T2D risk in people with OSA are unknown., Design and Methods: We used a two-stage hyperinsulinemic-euglycemic clamp procedure in conjunction with stable isotopically labeled glucose and palmitate tracer infusions and 18F-fluorodeoxyglucose injection and positron emission tomography to quantify multi-organ insulin action and oral and intravenous tolerance tests to evaluate glucose-stimulated insulin secretion in fifteen people with obesity and OSA and thirteen people with obesity without OSA., Results: OSA was associated with marked insulin resistance of adipose tissue triglyceride lipolysis and glucose uptake into both skeletal muscles and adipose tissue, whereas there was no significant difference between the OSA and control groups in insulin action on endogenous glucose production, basal insulin secretion, and glucose-stimulated insulin secretion during both intravenous and oral glucose tolerance tests., Conclusions: These data demonstrate that OSA is a key determinant of insulin sensitivity in people with obesity and underscore the importance of taking OSA status into account when evaluating metabolic function in people with obesity. These findings may also have important clinical implications because disease progression and the risk of diabetes-related complications vary by T2D subtype (i.e. severe insulin resistance vs insulin deficiency). People with OSA may benefit most from the targeted treatment of peripheral insulin resistance and early screening for complications associated with peripheral insulin resistance.

Assessment of sphingosine-1-phosphate receptor 1 (S1PR1) expression could be a unique tool to determine the neuroinflammatory status for central nervous system (CNS) disorders. Our preclinical results indicate that PET imaging with [ 11 C]CS1P1 radiotracer can quantitatively measure S1PR1 expression changes in different animal models of inflammatory diseases. Here we developed a multiple step F-18 labeling strategy to synthesize the radiotracer [ 18 F]FS1P1, sharing the same structure with [ 11 C]CS1P1. We explored a wide range of reaction conditions for the nucleophilic radiofluorination starting with the key ortho -nitrobenzaldehyde precursor 10. The tertiary amine additive TMEDA proved crucial to achieve high radiochemical yield of ortho -[ 18 F]fluorobenzaldehyde [ 18 F]12 starting with a small amount of precursor. Based on [ 18 F]12, a further four-step modification was applied in one-pot to generate the target radiotracer [ 18 F]FS1P1 with 30-50% radiochemical yield, >95% chemical and radiochemical purity, and a high molar activity (37-166.5 GBq μmol -1 , decay corrected to end of synthesis, EOS). Subsequently, tissue distribution of [ 18 F]FS1P1 in rats showed a high brain uptake (ID% g -1 ) of 0.48 ± 0.06 at 5 min, and bone uptake of 0.27 ± 0.03, 0.11 ± 0.02 at 5, and 120 min respectively, suggesting no in vivo defluorination. MicroPET studies showed [ 18 F]FS1P1 has high macaque brain uptake with a standard uptake value (SUV) of ∼2.3 at 120 min. Radiometabolite analysis of macaque plasma samples indicated that [ 18 F]FS1P1 has good metabolic stability, and no major radiometabolite confounded PET measurements of S1PR1 in nonhuman primate brain. Overall, [ 18 F]FS1P1 is a promising F-18 S1PR1 radiotracer worthy of further clinical investigation for human use.

A series of twenty-nine new quinazoline-2,4-dione compounds were synthesized and their IC 50 values for binding toward sphingosine-1-phosphate receptor 2 (S1PR2) were determined using a [ 32 P]S1P binding assay. Seven compounds 2a, 2g, 2h, 2i, 2j, 2k, and 5h exhibit high S1PR2 binding potencies (IC 50 values < 50 nM) and four of these new compounds 2g, 2i, 2j, and 2k have IC 50 values (<10 nM) of 6.3, 5.7, 4.8, and 2.6 nM, and are highly selective for S1PR2 over other S1PR subtypes, S1PR1, 3, 4, and 5. Compounds 2a and 2i were chosen for C-11 radiosynthesis through O -[ 11 C]methylation of precursors 13 and 2k with good radiochemical yields (35-40%), high chemical and radiochemical purity (>98%), and high molar activity (153-222 GBq μmol -1 , at the end of bombardment). [ 11 C]2a and [ 11 C]2i were further evaluated by the ex vivo biodistribution study. The results showed that both tracers have low brain uptake, preventing their potential for neuroimaging application. Further explorations of this class of S1PR2 PET tracers in peripheral tissue diseases are underway., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Sphingosine-1-phosphate receptor 1 (S1PR1) is ubiquitously expressed among all tissues and plays key roles in many physiological and cellular processes. In the central nervous system (CNS), S1PR1 is expressed in different types of cells including neurons, astrocytes, and oligodendrocyte precursor cells. S1PR1 has been recognized as a novel therapeutic target in multiple sclerosis and other diseases. We previously reported a promising S1PR1-specific radioligand, [ 11 C]CS1P1 (previously named [ 11 C]TZ3321), which is under clinical investigation for human use. In the current study, we performed a detailed characterization of [ 3 H]CS1P1 for its binding specificity to S1PR1 in CNS using autoradiography and immunohistochemistry in human and rat CNS tissues. Our data indicate that [ 3 H]CS1P1 binds to S1PR1 in human frontal cortex tissue with a K d of 3.98 nM and a B max of 172.5 nM. The distribution of [ 3 H]CS1P1 in human and rat CNS tissues is consistent with the distribution of S1PR1 detected by immunohistochemistry studies. Our microPET studies of [ 11 C]CS1P1 in a nonhuman primate (NHP) show a standardized uptake value of 2.4 in the NHP brain, with test-retest variability of 0.23% among six different NHPs. Radiometabolite analysis in the plasma samples of NHP and rat, as well as in rat brain samples, showed that [ 11 C]CS1P1 was stable in vivo . Kinetic modeling studies using a two-compartment tissue model showed that the positron emission tomography (PET) data fit the model well. Overall, our study provides a detailed characterization of [ 3 H]CS1P1 binding to S1PR1 in the CNS. Combined with our microPET studies in the NHP brain, our data suggest that [ 11 C]CS1P1 is a promising radioligand for PET imaging of S1PR1 in the CNS.

Sphingosine-1-phosphate receptor 1 (S1PR1) plays a crucial role in infectious diseases. Targeting S1PR1 provides protection against pathogens, such as influenza viruses. This study is aimed at investigating S1PR1 in response to bacterial infection by assessing S1PR1 expression in S. aureus -infected mice. A rodent local muscle bacterial infection model was developed by injecting S. aureus to the lower hind limb of Balb/c mice. The changes of S1PR1 expression in response to bacterial infection and blocking treatment were assessed using ex vivo biodistribution and in vivo positron emission tomography (PET) after intravenous injection of an S1PR1-specific radiotracer [ 18 F]TZ4877. The specificity of [ 18 F]TZ4877 was assessed using S1PR1-specific antagonist, NIBR-0213, and S1PR1-specific DsiRNA pretreated the animals. Immunohistochemical studies were performed to confirm the increase of S1PR1 expression in response to infection. Ex vivo biodistribution data showed that the uptake of [ 18 F]TZ4877 was increased 30.6%, 54.3%, 74.3%, and 115.3% in the liver, kidney, pancreas, and thymus of the infected mice, respectively, compared to that in normal control mice, indicating that S1PR1 is involved in the early immune response to bacterial infection. NIBR-0213 or S1PR1-specific DsiRNA pretreatment reduced the tissue uptake of [ 18 F]TZ4877, suggesting that uptake of [ 18 F]TZ4877 is specific. Our PET/CT study data also confirmed that infected mice have increased [ 18 F]TZ4877 uptake in several organs comparing to that in normal control mice. Particularly, compared to control mice, a 39% increase of [ 18 F]TZ4877 uptake was observed in the infected muscle of S. aureus mice, indicating that S1PR1 expression was directly involved in the inflammatory response to infection. Overall, our study suggested that S1PR1 plays an important role in the early immune response to bacterial infection. The uptake of [ 18 F]TZ4877 is tightly correlated with the S1R1 expression in response to S. aureus infection. PET with S1PR1-specific radiotracer [ 18 F]TZ4877 could provide a noninvasive tool for detecting the early S1PR1 immune response to infectious diseases., Competing Interests: The authors have no conflict of interest to declare., (Copyright © 2021 Hao Jiang et al.)

We used stable isotope-labeled glucose and palmitate tracer infusions, a hyperinsulinemic-euglycemic clamp, positron emission tomography of muscles and adipose tissue after [ 18 F]fluorodeoxyglucose and [ 15 O]water injections, and subcutaneous adipose tissue (SAT) biopsy to test the hypotheses that 1 ) increased glucose uptake in SAT is responsible for high insulin-stimulated whole-body glucose uptake in people with obesity who are insulin sensitive and 2 ) putative SAT factors thought to cause insulin resistance are present in people with obesity who are insulin resistant but not in those who are insulin sensitive. We found that high insulin-stimulated whole-body glucose uptake in insulin-sensitive participants with obesity was not due to channeling of glucose into SAT but, rather, was due to high insulin-stimulated muscle glucose uptake. Furthermore, insulin-stimulated muscle glucose uptake was not different between insulin-sensitive obese and lean participants even though adipocytes were larger, SAT perfusion and oxygenation were lower, and markers of SAT inflammation, fatty acid appearance in plasma in relation to fat-free mass, and plasma fatty acid concentration were higher in the insulin-sensitive obese than in lean participants. In addition, we observed only marginal or no differences in adipocyte size, SAT perfusion and oxygenation, and markers of SAT inflammation between insulin-resistant and insulin-sensitive obese participants. Plasma fatty acid concentration was also not different between insulin-sensitive and insulin-resistant obese participants, even though SAT was resistant to the inhibitory effect of insulin on lipolysis in the insulin-resistant obese group. These data suggest that several putative SAT factors commonly implicated in causing insulin resistance are normal consequences of SAT expansion unrelated to insulin resistance., (© 2021 by the American Diabetes Association.)

Purpose: Recent studies have shown that standard compartmental models using plasma input or the cerebellum reference tissue input are generally not reliable for quantifying tau burden in dynamic 18 F-flortaucipir PET studies of Alzheimer disease. So far, the optimal reference region for estimating 18 F-flortaucipir delivery and specific tau binding has yet to be determined. The objective of the study is to improve 18 F-flortaucipir brain tau PET quantification using a spatially constrained kinetic model with dual reference tissues., Methods: Participants were classified as either cognitively normal (CN) or cognitively impaired (CI) based on clinical assessment. T1-weighted structural MRI and 105-min dynamic 18 F-flortaucipir PET scans were acquired for each participant. Using both a simplified reference tissue model (SRTM2) and Logan plot with either cerebellum gray matter or centrum semiovale (CS) white matter as the reference tissue, we estimated distribution volume ratios (DVRs) and the relative transport rate constant R 1 for region of interest-based (ROI) and voxelwise-based analyses. Conventional linear regression (LR) and LR with spatially constrained (LRSC) parametric imaging algorithms were then evaluated. Noise-induced bias in the parametric images was compared to estimates from ROI time activity curve-based kinetic modeling. We finally evaluated standardized uptake value ratios at early phase (SUVR EP , 0.7-2.9 min) and late phase (SUVR LP , 80-105 min) to approximate R 1 and DVR, respectively., Results: The percent coefficients of variation of R 1 and DVR estimates from SRTM2 with spatially constrained modeling were comparable to those from the Logan plot and SUVRs. The SRTM2 using CS reference tissue with LRSC reduced noise-induced underestimation in the LR generated DVR images to negligible levels (< 1%). Inconsistent overestimation of DVR in the SUVR LP only occurred using the cerebellum reference tissue-based measurements. The CS reference tissue-based DVR and SUVR LP , and cerebellum-based SUVR EP and R 1 provided higher Cohen's effect size d to detect increased tau deposition and reduced relative tracer transport rate in CI individuals., Conclusion: Using a spatially constrained kinetic model with dual reference tissues significantly improved quantification of relative perfusion and tau binding. Cerebellum and CS are the suggested reference tissues to estimate R 1 and DVR, respectively, for dynamic 18 F-flortaucipir PET studies. Cerebellum-based SUVR EP and CS-based SUVR LP may be used to simplify 18 F-flortaucipir PET study., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Barth syndrome (BTHS) is a rare X-linked condition resulting in cardiomyopathy, however; the effects of BTHS on myocardial substrate metabolism and its relationships with cardiac high-energy phosphate metabolism and left ventricular (LV) function are unknown. We sought to characterize myocardial glucose, fatty acid (FA), and leucine metabolism in BTHS and unaffected controls and examine their relationships with cardiac high-energy phosphate metabolism and LV function., Methods/results: Young adults with BTHS (n = 14) and unaffected controls (n = 11, Control, total n = 25) underwent bolus injections of 15 O-water and 1- 11 C-glucose, palmitate, and leucine and concurrent positron emission tomography imaging. LV function and cardiac high-energy phosphate metabolism were examined via echocardiography and 31 P magnetic resonance spectroscopy, respectively. Myocardial glucose extraction fraction (21 ± 14% vs 10 ± 8%, P = .03) and glucose utilization (828.0 ± 470.0 vs 393.2 ± 361.0 μmol·g -1 ·min -1 , P = .02) were significantly higher in BTHS vs Control. Myocardial FA extraction fraction (31 ± 7% vs 41 ± 6%, P < .002) and uptake (0.25 ± 0.04 vs 0.29 ± 0.03 mL·g -1 ·min -1 , P < .002) were significantly lower in BTHS vs Control. Altered myocardial metabolism was associated with lower cardiac function in BTHS., Conclusions: Myocardial substrate metabolism is altered and may contribute to LV dysfunction in BTHS. Clinical Trials #: NCT01625663., (© 2019. American Society of Nuclear Cardiology.)

Aims/hypothesis: It has been proposed that muscle fibre type composition and perfusion are key determinants of insulin-stimulated muscle glucose uptake, and alterations in muscle fibre type composition and perfusion contribute to muscle, and consequently whole-body, insulin resistance in people with obesity. The goal of the study was to evaluate the relationships among muscle fibre type composition, perfusion and insulin-stimulated glucose uptake rates in healthy, lean people and people with obesity., Methods: We measured insulin-stimulated whole-body glucose disposal and glucose uptake and perfusion rates in five major muscle groups (erector spinae, obliques, rectus abdominis, hamstrings, quadriceps) in 15 healthy lean people and 37 people with obesity by using the hyperinsulinaemic-euglycaemic clamp procedure in conjunction with [ 2 H]glucose tracer infusion (to assess whole-body glucose disposal) and positron emission tomography after injections of [ 15 O]H 2 O (to assess muscle perfusion) and [ 18 F]fluorodeoxyglucose (to assess muscle glucose uptake). A biopsy from the vastus lateralis was obtained to assess fibre type composition., Results: We found: (1) a twofold difference in glucose uptake rates among muscles in both the lean and obese groups (rectus abdominis: 67 [51, 78] and 32 [21, 55] μmol kg -1  min -1 in the lean and obese groups, respectively; erector spinae: 134 [103, 160] and 66 [24, 129] μmol kg -1  min -1 , respectively; median [IQR]) that was unrelated to perfusion or fibre type composition (assessed in the vastus only); (2) the impairment in insulin action in the obese compared with the lean group was not different among muscle groups; and (3) insulin-stimulated whole-body glucose disposal expressed per kg fat-free mass was linearly related with muscle glucose uptake rate (r 2  = 0.65, p < 0.05)., Conclusions/interpretation: Obesity-associated insulin resistance is generalised across all major muscles, and is not caused by alterations in muscle fibre type composition or perfusion. In addition, insulin-stimulated whole-body glucose disposal relative to fat-free mass provides a reliable index of muscle glucose uptake rate.

Chemokines and chemokine receptors play an important role in the initiation and progression of atherosclerosis by mediating the trafficking of inflammatory cells. Chemokine receptor 5 (CCR5) has major implications in promoting the development of plaques to advanced stage and related vulnerability. CCR5 antagonist has demonstrated the effective inhibition of atherosclerotic progression in mice, making it a potential biomarker for atherosclerosis management. To accurately determine CCR5 in vivo , we synthesized CCR5 targeted Comb nanoparticles through a modular design and construction strategy with control over the physiochemical properties and functionalization of CCR5 targeting peptide d-Ala-peptide T-amide (DAPTA-Comb). In vivo pharmacokinetic evaluation through 64 Cu radiolabeling showed extended blood circulation of 64 Cu-DAPTA-Combs conjugated with 10%, 25%, and 40% DAPTA. The different organ distribution profiles of the three nanoparticles demonstrated the effect of DAPTA on not only physicochemical properties but also targeting efficiency. In vivo positron emission tomography/computed tomography (PET/CT) imaging in an apolipoprotein E knockout mouse atherosclerosis model (ApoE -/- ) showed that the three 64 Cu-DAPTA-Combs could sensitively and specifically detect CCR5 along the progression of atherosclerotic lesions. In an ApoE-encoding adenoviral vector (AAV) induced plaque regression ApoE -/- mouse model, decreased monocyte recruitment, CD68+ macrophages, CCR5 expression, and plaque size were all associated with reduced PET signals, which not only further confirmed the targeting efficiency of 64 Cu-DAPTA-Combs but also highlighted the potential of these targeted nanoparticles for atherosclerosis imaging. Moreover, the up-regulation of CCR5 and colocalization with CD68+ macrophages in the necrotic core of ex vivo human plaque specimens warrant further investigation for atherosclerosis prognosis.

Proinflammatory macrophages are important mediators of inflammation after myocardial infarction and of allograft injury after heart transplantation. The aim of this study was to image the recruitment of proinflammatory chemokine receptor 2-positive (CCR2+) cells in multiple heart injury models. Methods: 64 Cu-DOTA-extracellular loop 1 inverso (ECL1i) PET was used to image CCR2+ monocytes and macrophages in a heart transplantation mouse model. Flow cytometry was performed to characterize CCR2+ cells. Autoradiography on a human heart specimen was conducted to confirm binding specificity. 64 Cu- and 68 Ga-DOTA-ECL1i were compared in an ischemia-reperfusion injury mouse model. Results: 64 Cu-DOTA-ECL1i showed sensitive and specific detection of CCR2+ cells in all tested mouse models, with efficacy comparable to that of 68 Ga-DOTA-ECL1i. Flow cytometry demonstrated specific expression of CCR2 on monocytes and macrophages. The tracer binds to human CCR2. Conclusion: This work establishes the utility of 64 Cu-DOTA-ECL1i to image CCR2+ monocytes and macrophages in mouse models and provides the requisite preclinical information to translate the targeted clinical-grade CCR2 imaging probe for clinical investigation of heart diseases., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

Rationale: Idiopathic pulmonary fibrosis (IPF) is a progressive inflammatory lung disease without effective molecular markers of disease activity or treatment responses. Monocyte and interstitial macrophages that express the C-C motif CCR2 (chemokine receptor 2) are active in IPF and central to fibrosis. Objectives: To phenotype patients with IPF for potential targeted therapy, we developed 64 Cu-DOTA-ECL1i, a radiotracer to noninvasively track CCR2 + monocytes and macrophages using positron emission tomography (PET). Methods: CCR2 + cells were investigated in mice with bleomycin- or radiation-induced fibrosis and in human subjects with IPF. The CCR2 + cell populations were localized relative to fibrotic regions in lung tissue and characterized using immunolocalization, single-cell mass cytometry, and Ccr2 RNA in situ hybridization and then correlated with parallel quantitation of lung uptake by 64 Cu-DOTA-ECL1i PET. Measurements and Main Results: Mouse models established that increased 64 Cu-DOTA-ECL1i PET uptake in the lung correlates with CCR2 + cell infiltration associated with fibrosis ( n  = 72). As therapeutic models, the inhibition of fibrosis by IL-1β blockade ( n  = 19) or antifibrotic pirfenidone ( n  = 18) reduced CCR2 + macrophage accumulation and uptake of the radiotracer in mouse lungs. In lung tissues from patients with IPF, CCR2 + cells concentrated in perifibrotic regions and correlated with radiotracer localization ( n  = 21). Human imaging revealed little lung uptake in healthy volunteers ( n  = 7), whereas subjects with IPF ( n  = 4) exhibited intensive signals in fibrotic zones. Conclusions: These findings support a role for imaging CCR2 + cells within the fibrogenic niche in IPF to provide a molecular target for personalized therapy and monitoring.Clinical trial registered with www.clinicaltrials.gov (NCT03492762).