Heart Uptake Research Articles

Induction of PDK4 in the heart muscle of JVS mice, an animal model of systemic carnitine deficiency, does not appear to reduce glucose utilization by the heart

Pyruvate dehydrogenase kinase 4 (PDK4) mRNA has been reported as an up-regulated gene in the heart and skeletal muscle of carnitine-deficient juvenile visceral steatosis (JVS) mice under fed conditions. PDK4 plays an important role in the inhibition of glucose oxidation via the phosphorylation of pyruvate dehydrogenase complex (PDC). This study evaluated the meaning of increased PDK4 mRNA in glucose metabolism by investigating PDK4 protein levels, PDC activity and glucose uptake by the heart and skeletal muscle of JVS mice. PDK4 protein levels in the heart and skeletal muscle of fed JVS mice were increased in accordance with mRNA levels, and protein was enriched in the mitochondria. PDK4 protein was co-fractionated with PDC in sucrose density gradient centrifugation, like PDK2 protein; however, the activities of the pyruvate dehydrogenase complex (PDC) active form in the heart and skeletal muscle of fed JVS mice were similar to those in fed control mice. Fed JVS mice showed significantly higher glucose uptake in the heart and similar uptake in the skeletal muscle compared with fed control mice. Thus, in carnitine deficiency under fed conditions, glucose was preferentially utilized in the heart as an energy source despite increased PDK4 protein levels in the mitochondria. The preferred glucose utilization may be involved in developing cardiac hypertrophy from carnitine deficiency in fatty acid oxidation abnormality.

The lung permeability index: A feasible measurement of pulmonary capillary permeability

We performed this study to determine the pulmonary capillary permeability (PCP) measuring radiolabeled human serum albumin leakage into the lung. The objective was to use PCP to differentiate between cardiogenic and non-cardiogenic pulmonary edema etiologies. We conducted this study in 10 patients admitted to the intensive care unit who had recently developed bilateral pulmonary infiltrates and required hemodynamic monitoring. In these patients we determined the association among the lung permeability index, cardiac output, pulmonary capillary wedge pressure, myocardial performance index, and the protein content of the bronchoalveolar lavage as expressed by bronchoalveolar lavage (BAL) total protein and BAL-to-serum protein ratio. Twenty mCi of technetium-labeled albumin was injected and measure in the heart and the lung at 10 and 180 min post-injection. Lung and heart uptake ratios as well as the lung permeability index were calculated. We found a good correlation between the lung permeability index and both the myocardial performance index (cardiac output/pulmonary capillary wedge pressure) and the total protein content of the bronchoalveolar lavage fluid. The lung permeability index is a feasible, noninvasive estimation of the pulmonary capillary permeability.

Synthesis and Evaluation of 15-(4-(2-[18F]Fluoroethoxy)phenyl)pentadecanoic Acid: A Potential PET Tracer for Studying Myocardial Fatty Acid Metabolism

15-(4-(2-[¹⁸F]fluoroethoxy)phenyl)pentadecanoic acid ([¹⁸F]7) was synthesized as a PET probe for assessing myocardial fatty acid metabolism. The radiosynthesis of [¹⁸F]7 was accomplished using a two-step reaction, starting with the corresponding tosylate ester, methyl 15-(4-(2-(tosyloxy)ethoxy)phenyl)pentadecanoate (5), and gave the radiolabeled fatty acid, [¹⁸F]7 in a radiolabeling yield of 55-60% and a specific activity of >2000 Ci/mmol (decay corrected to EOB). The biological evaluation of [¹⁸F]7 in rats displayed high uptake in heart (1.94%ID/g at 5 min), which was higher than the uptake (%ID/g) in blood, lung, muscle, pancreas, and brain. MicroPET studies of [¹⁸F]7 in Sprague-Dawley rats demonstrated excellent images of the myocardium when compared with [¹¹C]palmitate images in the same animal. Moreover, the tracer kinetics of [¹⁸F]7 paralleled those seen with [¹¹C]palmitate, with an early peak followed by biphasic washout. When compared to [¹¹C]palmitate, [¹⁸F]7 exhibited a slower early clearance (0.17 ± 0.01 vs 0.30 ± 0.02, P < 0.0001) and a significantly higher late clearance (0.0030 ± 0.0005 vs 0.0006 ± 0.00013, P < 0.01). These initial studies suggest that [¹⁸F]7 could be a potentially useful clinical PET tracer to assess abnormal myocardial fatty acid metabolism.

Technetium-99m Cysteine; A Novel Radiopharmaceutical for Detection of Experimental Myocardial Infarction in Rats

Infarct avid radiopharmaceuticals are necessary for rapid and timely diagnosis of acute myocardial infarction. None of the infarct avid radiopharmaceuticals so far developed fulfill all the required criteria like rapid localization at the infarct, high avidity and specificity, and reasonable duration of scan positivity. 99mTc Cysteine was already reported from this laboratory as a suitable radiopharmaceutical to determine both morphology and function of kidney. The chemical structure of this radiopharmaceutical was also established. The present study demonstrates the affinity of the same chelate for damaged myocardial mass. 99mTc-cysteine was first tested on isoproterenol induced damaged rat myocardium, when ECG and histological studies demonstrated significant damage of the heart muscle following isoproterenol injection. The results were compared to that of 99mTc-glucarate. The uptake of 99mTc-cysteine in damaged rat myocardium was maximum (0.45% ID/g) when the animals were treated with isoproterenol 18 hrs before radiopharmaceutical injection; under the same experimental protocol 99mTc glucarate exhibited maximum heart uptake (0.263% ID/g) when injected 8 hrs after isoproterenol treatment. Evaluation was also performed on rat models of reperfused and non reperfused acute myocardial infarction. Animals were sacrificed after radiopharmaceutical injection and the excised hearts were subjected to radionuclide imaging, TTC and H-E staining. 99mTc-Cysteine chelate localized predominantly in the damaged portion. The highest infarct/viable tissue activity ratio (12/1) was obtained in 90 min occlusion model (protocol-2).

ChemInform Abstract: Phosphine-Containing Ligands and the Search for a Tc-99m Based Myocardial Imaging Agent

A strategy used to develop several potential 99mTc-based myocardial imaging agents is described. Ether-substituted 1,2- and 1,3-diphosphine ligands were prepared and used to produce a range of cationic Tc-99m complexes for subsequent screening. Ligand/core combinations were optimised in several cases to produce agents showing good heart uptake and retention in both animals and humans. A range of phosphine-containing polydentate ligands has also been prepared and their potential for use in myocardial imaging agents assessed. A tridentate phosphine/amine/thiolate chelate system has been developed which gives a [99mTc(PNS)2]+ complex showing good heart uptake in the rat. Synthetic routes to ether-substituted derivatives of this PNS ligand system have also been developed.

VEGF-B: a thing of beauty

VEGF-B: a thing of beauty

Evaluation of 99 mTcN-MPO as a New Myocardial Perfusion Imaging Agent in Normal Dogs and in an Acute Myocardial Infarction Canine Model: Comparison with 99 mTc-Sestamibi

(99) (m)TcN-MPO ([(99) (m)TcN(mpo)(PNP5)](+): mpo = 2-mercaptopyridine oxide and PNP5 = N-ethoxyethyl-N,N-bis[2-(bis(3-methoxypropyl)phosphino)ethyl]amine) is a cationic (99) (m)Tc-nitrido complex, which has favorable biodistribution and myocardial uptake with rapid liver clearance in Sprague Dawley rats. The objective of this study was to compare the biodistribution and pharmacokinetics of (99) (m)TcN-MPO and (99) (m)Tc-Sestamibi in normal dogs, and to evaluate the potential of (99) (m)TcN-MPO as a myocardial perfusion agent in canines with acute myocardial infarction. Five normal mongrel dogs were injected intravenously with (99) (m)TcN-MPO. Venous blood samples were collected via a femoral vein catheter at 0.5, 1, 2, 3, 4, 5, 10, 20, 30, 40, 60, and 90 min post-injection (p.i.). Anterior-posterior planar images were acquired by γ-camera at 10, 20, 30, 60, 90, and 120 min p.i. Regions of interest (ROIs) were drawn around the heart, liver, and lungs. The heart/liver and heart/lung ratios were calculated by dividing the mean counts in heart ROI by the mean counts in the liver and lung ROI, respectively. For comparison, (99) (m)Tc-sestamibi was also evaluated in the same five dogs. The interval period between the two examinations was 1 week to eliminate possible interference between these two radiotracers. In addition, single positron emission computed tomography (SPECT) images in the canine infarct model were collected 24 h after myocardial infarction at 30 and 60 min after the administration of (99) (m)TcN-MPO (n = 4) or (99) (m)Tc-Sestamibi (n = 4). It was found that (99) (m)TcN-MPO and (99) (m)Tc-Sestamibi displayed very similar blood clearance characteristics during the first 90 min p.i. Both (99) (m)TcN-MPO and (99) (m)Tc-Sestamibi had a rapid blood clearance with less than 50% of initial radioactivity remaining at 1 min and less than 5% at 30 min p.i. (99) (m)TcN-MPO and (99) (m)Tc-Sestamibi both showed good heart/lung contrast. The heart/liver ratio of (99) (m)TcN-MPO increased with time (0.53 ± 0.06 at 10 min, 0.90 ± 0.062 at 30 min, and 1.22 ± 0.06 at 60 min p.i.), whereas the heart/liver ratio of (99) (m)Tc-Sestamibi remained low at all time points (0.50 ± 0.03 at 10 min, 0.64 ± 0.03 at 30 min, and 0.60 ± 0.02 at 60 min p.i.). SPECT imaging studies in canines with acute myocardial infarction indicated that good visualization of the left ventricular wall and perfusion defects could be achieved at 30 min after administration of (99) (m)TcN-MPO but not after (99) (m)Tc-Sestamibi. The combination of reasonable heart uptake with rapid hepatobiliary excretion makes (99) (m)TcN-MPO a promising new radiotracer for myocardial perfusion imaging.

Biological in Vitro and in Vivo Studies of a Series of New Asymmetrical Cationic [99mTc(N)(DTC-Ln)(PNP)]+ Complex (DTC-Ln = Alicyclic Dithiocarbamate and PNP = Diphosphinoamine)

(99m)Tc(N)-DBODC5 is a cationic mixed compound under clinical investigation as potential myocardial imaging agent. In spite of this, analogously to the other cationic (99m)Tc-agents, presents a relatively low first-pass extraction. Thus, modification of (99m)Tc(N)-DBODC(5) direct to increase its first-pass extraction keeping unaltered the favorable imaging properties would be desirable. This work describes the synthesis and biological evaluation of a series of novel cationic (99m)Tc-nitrido complexes, of general formula [(99m)TcN(DTC-Ln)(PNP)](+) (DTC-Ln= alicyclic dithiocarbamates; PNP = diphosphinoamine), as potential radiotracers for myocardial perfusion imaging. The synthesis of cationic (99m)Tc-(N)-complexes were accomplished in two steps. Biodistribution studies were performed in rats and compared with the distribution profiles of (99m)Tc(N)-DBODC5 and (99m)Tc-Sestamibi. The metabolisms of the most promising compounds were evaluated by HPLC methods. Biological studies revealed that most of the complexes have a high initial and persistent heart uptake with rapid clearance from nontarget tissues. Among tested compounds, 2 and 12 showed improved heart uptake with respect to the gold standard (99m)Tc-complexes with favorable heart-to-liver and slightly lower heart-to-lung ratios. Chromatographic profiles of (99m)Tc(N)-radioactivity extracted from tissues and fluids were coincident with the native compound evidencing remarkable in vivo stability of these agents. This study shows that the incorporation of alicyclic dithiocarbamate in the [(99m)Tc(N)(PNP)](+) building block yields to a significant increase of the heart uptake at early injection point suggesting that the first-pass extraction fraction of these novel complexes may be increased with respect to the other cationic (99m)Tc-agents keeping almost unaltered the favorable target/nontarget ratios.

Decreased apolipoprotein E and VLDL receptors cause lipidemia in nephrotic syndrome

Hyperlipidemia in nephrotic syndrome (NS) is due to decreased clearance of triglyceride rich lipoproteins (TGLs). Lipoprotein lipase (LPL) hydrolyzes plasma TG, promotes the binding and catabolism of TGLs. Apolipoprotein E (apo E) facilitates binding by TGLs both to their receptor and LPL. A reduced plasma LpL level and reduced VLDL apo E were found in nephrotic rats. It is unknown whether low levels of LPL and/or VLDL apoE may contribute to the defective clearance. Lipoprotein particle size measured by Microtrac, showed no significant difference in nephrotic VLDL compared with control one. This finding indicated that the increased lipids in NS are due to increased particles accumulation in plasma instead of defective TGLs lipolysis via LpL. To study whether this accumulation is from decreased clearance and/or uptake by cells and organs, heart perfusion study demonstrated a significant decrease of VLDL uptake in NS heart. Endothelial cell VLDL uptake using fluorescent labeling technique showed a significant decreased cell uptake VLDL in NS compared with control. However, two groups had a similar increase when adding exogenous LpL. ApoE significantly increased VLDL cell uptake in NS compared with control at low concentration, but not at high concentration. Further, Western showed a significant decreased VLDL receptor in NS heart. These findings indicate that decreased LpL in nephrotic is not the major cause of defective VLDL clearance, decreased apoE and VLDL receptor contribute to the defect. The study was supported by the Department of Veteran's Affairs.

Quantitative structure-activity relationship (QSAR) analysis of cationic complexes of heart perfusion imaging agents and subsequent proposition of two different uptake mechanisms.

Some physicochemical and quantum-chemical discriptors of two series of cationic complexes of heart perfusion imaging agents ([(99m)Tc(I)(NO)Cl(PL)(2)](+) and [(99m)Tc-Mine](+) series) have been obtained using a semi-empirical quantum mechanics method - ZINDO/1. Quantitative structure-activity relationships (QSARs) between these descriptors and heart uptake were investigated by multiple linear regression analysis method, as the result of which, several equations were obtained. Fairly complete new heart uptake mechanisms, redox mechanism for [(99m)Tc(I)(NO)Cl(PL)(2)](+) series and passively transport mechanism for [(99m)Tc-Mine](+) series are proposed based on the results shown in the equations.

Biodistribution and stability studies of [18F]Fluoroethylrhodamine B, a potential PET myocardial perfusion agent

Fluorine-18-labeled rhodamine B was developed as a potential positron emission tomography (PET) tracer for the evaluation of myocardial perfusion, but preliminary studies in mice showed no accumulation in the heart suggesting that it was rapidly hydrolyzed in vivo in mice. A study was therefore undertaken to further evaluate this hypothesis. [(18)F]Fluoroethylrhodamine B was equilibrated for 2 h at 37 degrees C in human, rat and mouse serum and in phosphate-buffered saline. Samples were removed periodically and assayed by high-performance liquid chromatography. Based on the results of the stability study, microPET imaging and a biodistribution study were carried out in rats. In vitro stability studies demonstrated that [(18)F]fluoroethylrhodamine B much more stable in rat and human sera than in mouse serum. After 2 h, the compound was >80% intact in rat serum but <30% intact in mouse serum. The microPET imaging and biodistribution studies in rats confirmed this result showing high and persistent tracer accumulation in the myocardium compared with the absence of uptake by the myocardium in mice thereby validating our original hypothesis that (18)F-labeled rhodamines should accumulate in the heart. [(18)F]Fluoroethylrhodamine B is more stable in rat and human sera than it is in mouse serum. This improved stability is demonstrated by the high uptake of the tracer in the rat heart in comparison to the absence of visible uptake in the mouse heart. These observations suggest that (18)F-labeled rhodamines are promising candidates for more extensive evaluation as PET tracers for the evaluation of myocardial perfusion.

Time-Dependent Migration of Systemically Delivered Bone Marrow Mesenchymal Stem Cells to the Infarcted Heart

In this study the time course of homing and the body distribution of systemically delivered bone marrow mesenchymal stem cells (BM-MSCs) after myocardial infarction (MI) were evaluated. BM-MSCs were isolated from Wistar rats, expanded in vitro, and their phenotypical characterization was performed by flow cytometer. Rats were randomly divided into three groups: control, sham MI, and MI. BM-MSCs (5 x 10(6)) were labeled with (99m)Tc-HMPAO and injected through the tail vein 7 days after MI. Gamma camera imaging was performed at 5, 15, 30, and 60 min after cell inoculation. Due to the (99m)Tc short half-life, cell migration and location were also evaluated in heart sections using DAPI-labeled cells 7 days after transplantation. Phenotypical characterization showed that BM-MSCs were CD90(+), CD73(+), CD54(+), and CD45(-). Five minutes after (99m)Tc-HMPAO-labeled cell injection, they were detected in various tissues. The cells migrated mainly to the lungs (approximately 70%) and, in small amounts, to the heart, kidneys, spleen, and bladder. The number of cells in the heart and lungs decreased after 60 min. MI markedly increased the amount of cells in the heart, but not in the lungs, during the period of observation (4.55 +/- 0.32 vs. 6.34 +/- 0.67% of uptake in infarcted hearts). No significant differences were observed between control and sham groups. Additionally, 7 days after DAPI-labeled cells injection, they were still detected in the heart but only in infarcted areas. These results suggest that the migration of systemically delivered BM-MSCs to the heart is time dependent and MI specifically increases BM-MSCs homing to injured hearts. However, the systemic delivery is limited by cell entrapment in the lungs.

Detecting Growing Mammary Tumors with Monoclonal Antibodies Against Vascular Endothelial Growth Factor Receptor – 3

Biodistribution of the monoclonal antibody (mAb 9d9f9) against the vascular endothelial growth factor receptor- 3 (VEGFR-3) is studied here in the rat. VEGFR-3 is expressed on endothelial cells of lymphatic endothelium during the tissue growth. The mAb9d9f9 is the first specific molecular marker to the endothelial cells of high venules. The specificity was detected with immunohistochemistry of tissue samples. Materials The affinity of 125I-mAb 9d9f9 was determined in HEL leukemia cells expressing the extracellular receptor and the biodistribution was detected both by external imaging and tissue sampling in the tumor model. The imaging result with subcutaneous injections was compared to the imaging after intravenous injections. Results Targeting to the induced mammary tumors in rat was detected with immunoscintigraphy of 125I-mAb. The imaging after subcutaneous administration showed lower uptake in liver, spleen, heart and stomach than the imaging after intravenous administration. The mAb 9d9f9 accumulated to the parasternal lymphatic vessels at 16 days after the subcutaneous injections. Conclusion The mAb 9d9f9 visualized the routes of lymphatic circulation probably based on binding to this transmembrane lymphatic endothelial receptor. Immunodetection of the tumors in rat was, however, possible with these antibodies targeting to the endothelial cells lining the vascular system.

Preparation and biodistribution of [ 18F]FP2OP as myocardial perfusion imaging agent for positron emission tomography

Myocardial extractions of pyridaben, a mitochondrial complex I (MC-I) inhibitor, is well correlated with blood flow. Based on the synthesis and characterization of pyridaben analogue 2- tert-butyl-5-[2-(2-[ 18F]fluroethoxy)ethoxy]benzyloxy]-4-chloro-2 H-pyridazin-3-one ([ 18F]FP2OP), this study assessed its potential to be developed as myocardial perfusion imaging (MPI) agent. Methods: The tosylate labeling precursor 2-(2-(4-( tert-butyl-5-chloro-6-oxo-1,6-dihydro-pyridazin-4-yloxymethyl)benzyloxy)ethoxy)ethyl ester (OTs-P2OP) and the nonradioactive 2- tert-butyl-5-[2-(2-[ 19F]fluroethoxy)ethoxy]benzyloxy]-4-chloro-2 H-pyridazin-3-one ([ 19F]FP2OP) were synthesized and characterized by IR, 1H NMR, 13C NMR and MS analysis. By substituting tosyl of precursor OTs-P2OP with 18F, the radiolabeled complex [ 18F]FP2OP was prepared and further evaluated for its in vitro physicochemical properties, in vivo biodistribution, the metabolic stability in mice, ex vivo autoradiography and cardiac PET/CT imaging. Results: Starting with [ 18F]F − Kryptofix 2.2.2./K 2CO 3 solution, the total reaction time for [ 18F]FP2OP was about 100 min, with final high-performance liquid chromatography purification included. Typical decay-corrected radiochemical yield stayed at 41 ± 5.3%, the radiochemical purity, 98% or more. Biodistribution in mice showed that the heart uptake of [ 18F]FP2OP was 41.90 ± 4.52%ID/g at 2 min post-injection time, when the ratio of heart/liver, heart/lung and heart/blood reached 6.83, 9.49 and 35.74, respectively. Lipophilic molecule was further produced by metabolized [ 18F]FP2OP in blood and urine at 30 min. Ex vivo autoradiography demonstrates that [ 18F]FP2OP may have high affinity with MC-I and that can be blocked by [ 19F]FP2OP or rotenone (a known MC-I inhibitor). Cardiac PET images were obtained in a Chinese mini-swine at 5, 15, 30 and 60 min post-injection time with high quality. Conclusion: [ 18F]FP2OP was synthesized with high radiochemical yield. The promising biological properties of [ 18F]FP2OP suggest high potential as MPI agent for positron emission tomography in the future.

Formulation of 68Ga BAPEN kit for myocardial positron emission tomography imaging and biodistribution study

Tris(4,6-dimethoxysalicylaldimine)-N,N'-bis(3-aminopropyl)-N,N'-ethylenediamine (BAPEN), a tris(salicylaldimine) derivative, is a heart positron emission tomography (PET) agent when labeled with (68)Ga. However, its labeling requires complicated and time-consuming procedures. In this study, the authors formulated a new BAPEN kit for convenient (68)Ga labeling. BAPEN (0.25 mg) kits were prepared by dispensing its solution in 1 M sodium acetate buffer (pH 5.5) into sterile vials and lyophilization. The prepared kits were labeled with generator-eluted (68)Ga in 0.1 N HCl. Stability in human serum was tested. Expiration date was determined by accelerated testing according to US Food and Drug Administration guidelines. A Biodistribution study was performed in normal mice after injection via tail vein. The prepared kits achieved radiolabeling efficiencies in excess of 95% and showed a shelf-life of 98 days at 25 degrees C and 64.3 months at 4 degrees C. (68)Ga-BAPEN was found to be stable in human serum at 37 degrees C for at least 1 h. Furthermore, a biodistribution study revealed high heart uptake (10.8% ID/g, 1 h). The authors developed a BAPEN kit for convenient labeling with (68)Ga. The (68)Ga-BAPEN showed high stability and excellent biodistribution results in normal mice, which is required for myocardial PET imaging.

Distinct Effects of Leptin and a Melanocortin Receptor Agonist Injected Into Medial Hypothalamic Nuclei on Glucose Uptake in Peripheral Tissues

OBJECTIVEThe medial hypothalamus mediates leptin-induced glucose uptake in peripheral tissues, and brain melanocortin receptors (MCRs) mediate certain central effects of leptin. However, the contributions of the leptin receptor and MCRs in individual medial hypothalamic nuclei to regulation of peripheral glucose uptake have remained unclear. We examined the effects of an injection of leptin and the MCR agonist MT-II into medial hypothalamic nuclei on glucose uptake in peripheral tissues.RESEARCH DESIGN AND METHODSLeptin or MT-II was injected into the ventromedial (VMH), dorsomedial (DMH), arcuate nucleus (ARC), or paraventricular (PVH) hypothalamus or the lateral ventricle (intracerebroventricularly) in freely moving mice. The MCR antagonist SHU9119 was injected intracerebroventricularly. Glucose uptake was measured by the 2-[3H]deoxy-d-glucose method.RESULTSLeptin injection into the VMH increased glucose uptake in skeletal muscle, brown adipose tissue (BAT), and heart, whereas that into the ARC increased glucose uptake in BAT, and that into the DMH or PVH had no effect. SHU9119 abolished these effects of leptin injected into the VMH. Injection of MT-II either into the VMH or intracerebroventricularly increased glucose uptake in skeletal muscle, BAT, and heart, whereas that into the PVH increased glucose uptake in BAT, and that into the DMH or ARC had no effect.CONCLUSIONSThe VMH mediates leptin- and MT-II–induced glucose uptake in skeletal muscle, BAT, and heart. These effects of leptin are dependent on MCR activation. The leptin receptor in the ARC and MCR in the PVH regulate glucose uptake in BAT. Medial hypothalamic nuclei thus play distinct roles in leptin- and MT-II–induced glucose uptake in peripheral tissues.

Chronic effects of dietary carbohydrate variation on [18F]-2-fluoro-2-deoxyglucose uptake in rodent heart

Measured cardiac [F]-2-fluoro-2-deoxyglucose (FDG) activity in human PET scans is variable despite efforts to standardize patient preparation. Heart uptake can obscure chest disease, and is of physiologic interest. Short-term carbohydrate (CHO) restriction can reduce FDG uptake, although unreliably, whereas long-term restriction of CHO has not been systematically studied. It would be valuable to understand FDG hearts' chronic dietary dependence. Fifteen Wistar rats (age 4 weeks) were randomized to three diet groups (n = 5) of low (0.1% of total energy), intermediate (52%), and high (78%) CHO content (LC, IC, and HC, respectively). After 4 weeks, blood for ketone bodies (KB), glucose, insulin, and glucagon was obtained, followed in 2 days by whole-body PET with 37 MBq FDG. Diet groups were switched every 4 weeks to control for the effects of dietary order. Heart maximal standardized uptake value was compared among animals. Heart mean maximal standardized uptake value was dramatically reduced for LC (3.4+/-0.4; P<0.001) compared with either IC (10.9+/-0.7) or HC (11.0+/-0.7) (P=NS, IC vs. HC). KB (mumol/l) differed widely (P<0.001) in LC (718.6+/-40.0) versus IC (120.3+/-34.0) and HC (99.2+/-32.1) (P=NS, IC vs. HC), whereas glucose, insulin, and glucagon did not differ among the groups. Sustained CHO-restriction results in marked, reproducibly reduced cardiac FDG uptake. Six-fold to seven-fold increased KB concentrations provide alternative substrate to glucose.

Accelerated Fatty Acid Oxidation in Muscle Averts Fasting-induced Hepatic Steatosis in SJL/J Mice

The accumulation of triglycerides (TG) in the liver, designated hepatic steatosis, is characteristically associated with obesity and insulin resistance, but it can also develop after fasting. Here, we show that fasting-induced hepatic steatosis is under genetic control in inbred mice. After a 24-h fast, C57BL/6J mice and SJL/J mice both lost more than 20% of body weight and approximately 60% of total body TG. In C57BL/6J mice, TG accumulated in liver, producing frank steatosis. In striking contrast, SJL/J mice failed to accumulate any hepatic TG even though they lost nearly as much adipose tissue mass as the C57BL/6J mice. Mice from five other inbred strains developed fasting-induced steatosis like the C57BL/6J mice. Measurements of the uptake of free fatty acids (FA) in vivo and in vitro demonstrated that SJL/J mice were protected from steatosis because their heart and skeletal muscle took up and oxidized twice as much FA as compared with C57BL/6J mice. As a result of this muscle diversion, serum-free FA and ketone bodies rose much less after fasting in SJL/J mice as compared with C57BL/6J mice. When livers of SJL/J and C57BL/6J mice were perfused with similar concentrations of FA, the livers took up and esterified similar amounts. We conclude that SJL/J mice express one or more variant genes that lead to enhanced FA uptake and oxidation in muscle, thereby sparing the liver from FA overload in the fasting state.

Effects of food intake and anesthetic on cardiac imaging and uptake of BMS747158-02 in comparison with FDG

BackgroundBMS747158-02 is an 18F-labeled agent being developed for PET myocardial perfusion imaging. This study examined impacts of feeding state and anesthetic on cardiac imaging and uptake of this agent in rats in comparison with 18F-fluorodeoxyglucose (FDG). Methods and resultsStudies were performed in rats either nonfasted or food deprived for 20 hours and anesthetized with either sodium pentobarbital (Pentob) or ketamine and xylazine (Ket/Xyl). Influences of the feeding state and anesthesia were examined by measurement of blood glucose levels, and tissue biodistribution and cardiac imaging of BMS747158-02 and FDG. The blood glucose levels were lower in fasted than nonfasted rats before anesthesia (91 ± 11 vs 122 ± 10 mg/dL) and the levels did not significantly change when anesthetized with Pentob. However, the levels increased markedly by 262 ± 64 mg/dL in nonfasted rats anesthetized with Ket/Xyl. At 60 minutes post-injection, the heart uptake of FDG was significantly lower in fasted than nonfasted rats (0.2 ± 0.1 vs 2.8 ± 1.5%ID/g). However, the heart uptake of BMS747158-02 did not differ under these conditions (3.3 ± 0.9 vs 3.6 ± 0.9%ID/g, respectively). In nonfasted rats, the heart uptake of FDG was markedly lower when anesthetized with Ket/Xyl than with Pentobl (0.2 ± 0.1 vs 2.8 ± 1.5%ID/g). In contrast, the heart uptake of BMS747158-02 was similar with both anesthetics (3.6 ± 0.5 vs 3.6 ± 0.9%ID/g). Consistent with the biodistribution studies, the myocardium was not visible following FDG imaging in fasted rats, but clearly seen with BMS747158-02 in both fasted and nonfasted rats anesthetized with either anesthetic. ConclusionsUnlike FDG, BMS747158-02 cardiac images are clear and not affected by the feeding state and anesthetics.

Automatisation and First Evaluation of [18F]FE@SUPPY:2, an Alternative PET-Tracer for the Adenosine A3 Receptor: A Comparison with [18F]FE@SUPPY

Introduction: Since the Adenosine-A3-receptor was identified in the late 1990´s, there is little data available de- scribing its distribution in vivo. Recently, we introduced ( 18 F)FE@SUPPY as the first PET-tracer for this receptor. In the present investigation we translated this fluoroethyl-ester into the fluoroethyl-thioester ( 18 F)FE@SUPPY:2 (5-ethyl 2,4- diethyl-3-((2-( 18 F)fluoroethyl) sulfanylcarbonyl)-6-phenylpyridine-5-carboxylate). Aims of the present study were the evaluation of (1) the automatized preparation of both ( 18 F)FE@SUPPY-derivatives, (2) the biodistribution of ( 18 F)FE@SUPPY:2, (3) the lipophilicity and (4) the comparison of the findings of ( 18 F)FE@SUPPY and ( 18 F)FE@SUPPY:2. Methods: The automated preparations of both ( 18 F)FE@SUPPY-analogs were performed on a GE TRACERlab FxFN syn- thesizer using suitable precursors. Biodistribution experiments were performed using Sprague-Dawley rats/Him:OFA. Lipophilicity of the compounds was determined using an HPLC assay. Results: 22 automated radiosyntheses were performed for both radiotracers. Specific radioactivity was 70 ± 26GBq/� mol for ( 18 F)FE@SUPPY and 340 ± 140GBq/� mol for ( 18 F)FE@SUPPY:2. Biodistribution experiments evinced bowels and liver as organs with highest uptake and intermediate uptake in kidney, lung and heart. LogP values of both molecules ranged from 3.99 to 4.12 at different pH. Conclusion: From a radiopharmaceutical perspective, drastically better specific radioactivities would militate in favour of ( 18 F)FE@SUPPY:2; preclinical evaluations, so far, do not permit the decision upon the selection of the optimum ( 18 F)FE@SUPPY-derivative. With ( 18 F)FE@SUPPY:2, we are able to provide a second potential tracer that could help to further characterize the still quite unexplored Adenosine-A3-receptor.