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Background To characterize regional kidney sodium response by MRI following NKCC2 inhibition. Methods Regional renal sodium signals were monitored noninvasively using 23Na-MRI at 9.4T with a temporal resolution of 1.5 min in anesthetized rats (N = 14). A mild NKCC2 inhibition was induced using a slow intravenous furosemide infusion. Time course of sodium signal was modeled as an exponential transient with a single characteristic time constant. Results Under normal physiological conditions, the renal sodium signals in medullary and cortical regions were stable and found to respond differently to furosemide challenge. Furosemide infusion at 1.2 mg/kg/h (N = 7) increased sodium signal in the cortex by 40 ± 6% ( P < 7 × 10−5) whereas decreased in the medulla by 29 ± 2% ( P < 3 × 10−6) with different temporal kinetics. The characteristic time constants of the change were determined to be: 8 ± 2 and 70 ± 10 min for medulla and cortex. Also, the medullary change occurred 9(±3) times faster than cortical independent of furosemide infusion rate up to 35 mg/kg/h. Conclusion The pharmacological effects in terms of regional kidney sodium signal changes induced by NKCC2 inhibition are region-specific and highly predictable. Using noninvasive sodium MRI, we obtained regional renal sodium kinetics data sets in response to a low dose furosemide infusion in normal rats. J. Magn. Reson. Imaging 2015;41:1622-1628. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Objectives: This study hypothesized that 1H magnetic resonance spectroscopy (1H-MRS) can identify carotid plaque cholesteryl ester in vivo in humans. Background: Liquid phase cholesteryl ester comprises a major fraction of atherosclerotic plaque, and its abundance is associated with plaque rupture and atherothrombosis. A noninvasive imaging technique to detect liquid cholesteryl ester that has been applied ex vivo is now demonstrated in vivo. Methods: 1H-MRS scans were obtained of carotid plaques of 35 subjects at 3.0 T. Turbo spin echo, black blood, T1-weighted images were acquired for localization. Spectra were acquired using a 2-dimensional point resolved spectroscopy sequence: repetition time/echo time = 1,100/30 ms, 5-mm slice thickness, 8 × 8-cm field of view, 16 × 16 matrix size, and 13-min acquisition time. Saturation bands were placed around the artery. Resonance of methylene protons and allylic methylene protons were assigned to 1.2 ppm and 2.0 ppm. The 2.0:1.2 ppm ratio was calculated to reflect the ratio of the fatty acid composition of plaque cholesteryl ester to that of triglycerides of perivascular tissue. We obtained spectra of lipid standards as a reference. Results: Our 1H-MRS data showed typical spectra of cholesteryl ester mixed with triglycerides, with intense resonance from methylene (1.2 ppm) and allylic methylene (2.0 ppm) protons. The average 2.0:1.2 ppm ratio was 0.10 ± 0.03. The 2.0:1.2 ppm ratio correlated with the plaque tissue volume to perivascular tissue volume ratio (Spearman rho = 0.55, p = 0.02), suggesting that more 1H-MRS signal was obtained from cholesteryl ester when the 1H-MRS voxel comprised more plaque tissue. Repeat 1H-MRS scans in 4 subjects showed an intraclass correlation coefficient of 0.92 (95% prediction intervals: 0.40 to 0.99), indicating good reproducibility. Seventeen of the 35 1H-MRS spectra were of adequate quality for analysis. Conclusions: In vivo image-guided 1H-MRS for detection of liquid phase cholesteryl ester in carotid atherosclerotic plaques in humans is feasible. [Copyright &y& Elsevier]

The renin-angiotensin system (RAS) is well studied for its regulation of blood pressure and fluid homeostasis, as well as for increased activity associated with a variety of diseases and conditions, including cardiovascular disease, diabetes, and kidney disease. The enzyme renin cleaves angiotensinogen to form angiotensin I (ANG I), which is further cleaved by angiotensin-converting enzyme to produce ANG II. Although ANG II is the main effector molecule of the RAS, renin is the rate-limiting enzyme, thus playing a pivotal role in regulating RAS activity in hypertension and organ injury processes. Our objective was to develop a near-infrared fluorescent (NIRF) renin-imaging agent for noninvasive in vivo detection of renin activity as a measure of tissue RAS and in vitro plasma renin activity. We synthesized a reninactivatable agent, ReninSense 680 FAST (ReninSense), using a NIRF-quenched substrate derived from angiotensinogen that is cleaved specifically by purified mouse and rat renin enzymes to generate a fluorescent signal. This agent was assessed in vitro, in vivo, and ex vivo to detect and quantify increases in plasma and kidney renin activity in sodium-sensitive inbred C57BL/6 mice maintained on a low dietary sodium and diuretic regimen. Noninvasive in vivo fluorescence molecular tomographic imaging of the ReninSense signal in the kidney detected increased renin activity in the kidneys of hyperreninemic C57BL/6 mice. The agent also effectively detected renin activity in ex vivo kidneys, kidney tissue sections, and plasma samples. This approach could provide a new tool for assessing disorders linked to altered tissue and plasma renin activity and to monitor the efficacy of therapeutic treatments. [ABSTRACT FROM AUTHOR]

Inflammation as a core pathological event of atherosclerotic lesions is associated with the secretion of cathepsin proteases and the expression of αvβ3 integrin. We employed fluorescence molecular tomographic (FMT) noninvasive imaging of these molecular activities using cathepsin sensing (Pro Sense, CatB FAST) and αvβ3 integrin (Integri Sense) near-infrared fluorescence (NIRF) agents. A statistically significant increase in the ProSense and Integri Sense signal was observed within the chest region of apoE-/- mice (P < 0.05) versus C57BL/6 mice starting 25 and 22 weeks on high cholesterol diet, respectively. In a treatment study using ezetimibe (7mg/kg), there was a statistically significant reduction in the ProSense and CatB FAST chest signal of treated (P < 0.05) versus untreated apoE-/- mice at 31 and 21 weeks on high cholesterol diet, respectively. The signal of ProSense and CatB FAST correlated with macrophage counts and was found associated with inflammatory cells by fluorescence microscopy and flow cytometry of cells dissociated from aortas. This report demonstrates that cathepsin and αvβ3 integrin NIRF agents can be used as molecular imaging biomarkers for longitudinal detection of atherosclerosis, and cathepsin agents can monitor anti-inflammatory effects of ezetimibe with applications in preclinical testing of therapeutics and potentially for early diagnosis of atherosclerosis in patients [ABSTRACT FROM AUTHOR]

Programmed death ligand 1 (PD-L1) is an immune regulatory ligand that binds to the T-cell immune check point programmed death 1. Tumor expression of PD-L1 is correlated with immune suppression and poor prognosis. It is also correlated with therapeutic efficacy of programmed death 1 and PD-L1 inhibitors. In vivo imaging may enable real-time follow-up of changing PD-L1 expression and heterogeneity evaluation of PD-L1 expression across tumors in the same subject. We have radiolabeled the PD-L1-binding Affibody molecule NOTA-Z PD-L1&#95;1 with 18 F and evaluated its in vitro and in vivo binding affinity, targeting, and specificity. Methods: The affinity of the PD-L1-binding Affibody ligand Z PD-L1&#95;1 was evaluated by surface plasmon resonance. Labeling was accomplished by maleimide coupling of NOTA to a unique cysteine residue and chelation of 18 F-AlF. In vivo studies were performed in PD-L1-positive, PD-L1-negative, and mixed tumor-bearing severe combined immunodeficiency mice. Tracer was injected via the tail vein, and dynamic PET scans were acquired for 90 min, followed by γ-counting biodistribution. Immunohistochemical staining with an antibody specific for anti-PD-L1 (22C3) was used to evaluate the tumor distribution of PD-L1. Immunohistochemistry results were then compared with ex vivo autoradiographic images obtained from adjacent tissue sections. Results: NOTA-Z PD-L1&#95;1 was labeled, with a radiochemical yield of 15.1% ± 5.6%, radiochemical purity of 96.7% ± 2.0%, and specific activity of 14.6 ± 6.5 GBq/μmol. Surface plasmon resonance showed a NOTA-conjugated ligand binding affinity of 1 nM. PET imaging demonstrated rapid uptake of tracer in the PD-L1-positive tumor, whereas the PD-L1-negative control tumor showed little tracer retention. Tracer clearance from most organs and blood was quick, with biodistribution showing prominent kidney retention, low liver uptake, and a significant difference between PD-L1-positive (percentage injected dose per gram [%ID/g] = 2.56 ± 0.33) and -negative (%ID/g = 0.32 ± 0.05) tumors ( P = 0.0006). Ex vivo autoradiography showed excellent spatial correlation with immunohistochemistry in mixed tumors. Conclusion: Our results show that Affibody ligands can be effective at targeting tumor PD-L1 in vivo, with good specificity and rapid clearance. Future studies will explore methods to reduce kidney activity retention and further increase tumor uptake., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: To characterize regional kidney sodium response by MRI following NKCC2 inhibition., Methods: Regional renal sodium signals were monitored noninvasively using (23) Na-MRI at 9.4T with a temporal resolution of 1.5 min in anesthetized rats (N = 14). A mild NKCC2 inhibition was induced using a slow intravenous furosemide infusion. Time course of sodium signal was modeled as an exponential transient with a single characteristic time constant., Results: Under normal physiological conditions, the renal sodium signals in medullary and cortical regions were stable and found to respond differently to furosemide challenge. Furosemide infusion at 1.2 mg/kg/h (N = 7) increased sodium signal in the cortex by 40 ± 6% (P < 7 × 10(-5) ) whereas decreased in the medulla by 29 ± 2% (P < 3 × 10(-6) ) with different temporal kinetics. The characteristic time constants of the change were determined to be: 8 ± 2 and 70 ± 10 min for medulla and cortex. Also, the medullary change occurred 9(±3) times faster than cortical independent of furosemide infusion rate up to 35 mg/kg/h., Conclusion: The pharmacological effects in terms of regional kidney sodium signal changes induced by NKCC2 inhibition are region-specific and highly predictable. Using noninvasive sodium MRI, we obtained regional renal sodium kinetics data sets in response to a low dose furosemide infusion in normal rats., (© 2014 Wiley Periodicals, Inc.)