Synthesis of iodine‐125 labelled analogues of metyrapone and metyrapol

Metyrapone (1) and metyrapol (2) are potent and reversible inhibitors of the 11β‐hydroxylase enzyme system of the adrenal cortex. Iodine‐125‐labelled derivatives of 1 and 2 were required for biodistribution studies. Utilizing a new exchange procedure these radioiodinated analogues were synthesized with radiochemical yields ranging from 24‐100% and specific activities as high as 1.72 Ci/mmol.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90279/1/2580201209_ftp.pd

Synthesis of (N‐[ 11 C]methyl)Y‐29794, a competitive inhibitor of prolyl endopeptidase

Prolyl endopeptidase (PEP: [E.C.3.4.21.26]) is a widely distributed serine peptidase that cleaves a variety of oligopeptides in the brain and peripheral tissues. Y‐29794 ((2‐(8‐dimethylaminooctylthio)‐6‐isopropyl‐3‐pyridyl‐2‐thienyl ketone) is a potent competitive reversible inhibitor of this enzyme. In order to study the biodistribution of PEP in vivo we have synthesized (N‐[ 11 C]methyl)Y‐29794, by [ 11 C]alkylation of the N‐desmethyl precursor. The radiotracer was purified by silica gel Sep‐Pak and was obtained in 10‐17% yields (EOB: synthesis times shorter than 45 min) with >98% radiochemical purities and specific activities >550 Ci/mmol (EOS).Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90219/1/2580340602_ftp.pd

Assessment of Oxidative Metabolism in Brown Fat Using PET Imaging

Objective: Although it has been believed that brown adipose tissue (BAT) depots disappear shortly after the perinatal period in humans, positron emission tomography (PET) imaging using the glucose analog 18F-deoxy-d-glucose (FDG) has shown unequivocally the existence of functional BAT in humans, suggesting that most humans have some functional BAT. The objective of this study was to determine, using dynamic oxygen-15 (15O) PET imaging, to what extent BAT thermogenesis is activated in adults during cold stress and to establish the relationship between BAT oxidative metabolism and FDG tracer uptake. Methods: Fourteen adult normal subjects (9F/5M, 30 ± 7 years) underwent triple oxygen scans (H215O, C15O, 15O2) as well as indirect calorimetric measurements at both rest and following exposure to mild cold (16°C). Subjects were divided into two groups (BAT+ and BAT−) based on the presence or absence of FDG tracer uptake (SUV > 2) in cervical–supraclavicular BAT. Blood flow and oxygen extraction fraction (OEF) was calculated from dynamic PET scans at the location of BAT, muscle, and white adipose tissue (WAT). The metabolic rate of oxygen (MRO2) in BAT was determined and used to calculate the contribution of activated BAT to daily energy expenditure (DEE). Results: The median mass of activated BAT in the BAT+ group (5F, age 31 ± 8) was 52.4 g (range 14–68 g) and was 1.7 g (range 0–6.3 g) in the BAT − group (5M/4F, age 29 ± 6). Corresponding SUV values were significantly higher in the BAT+ as compared to the BAT− group (7.4 ± 3.7 vs. 1.9 ± 0.9; p = 0.03). Blood flow values in BAT were significantly higher in the BAT+ group as compared to the BAT− group (13.1 ± 4.4 vs. 5.7 ± 1.1 ml/100 g/min, p = 0.03), but were similar in WAT (4.1 ± 1.6 vs. 4.2 ± 1.8 ml/100 g/min) and muscle (3.7 ± 0.8 vs. 3.3 ± 1.2 ml/100 g/min). Moreover, OEF in BAT was similar in the two groups (0.56 ± 0.18 in BAT+ vs. 0.46 ± 0.19 in BAT−, p = 0.39). Calculated MRO2 values in BAT increased from 0.95 ± 0.74 to 1.62 ± 0.82 ml/100 g/min in the BAT+ group and were significantly higher than those determined in the BAT− group (0.43 ± 0.27 vs. 0.56 ± 0.24, p = 0.67). The DEE associated with BAT oxidative metabolism was highly variable in the BAT+ group, with an average of 5.5 ± 6.4 kcal/day (range 0.57–15.3 kcal/day). Conclusion: BAT thermogenesis in humans accounts for less than 20 kcal/day during moderate cold stress, even in subjects with relatively large BAT depots. Furthermore, due to the large differences in blood flow and glucose metabolic rates in BAT between humans and rodents, the application of rodent data to humans is problematic and needs careful evaluation

Physical exercise training and coronary artery disease

Coronary artery disease (CAD) is a leading cause of death worldwide, despite improvements in medical and interventional therapies. Based on many studies in large cohorts, regular physical exercise training plays a central and indispensable role in both the primary and secondary prevention of CAD. Exercise training was shown to improve blood pressure control, lipid profile, glucose control, and enhance weight loss in obese patients. Moreover, exercise training not only affects clinical symptoms, it reduces CAD mortality and morbidity in addition to dietary, pharmacological and interventional treatments. Different kinds of exercise training (aerobic, interval, resistance training) have been studied and all are feasible, well tolerated, and beneficial in patients with CAD. Therefore, exercise training has the highest recommendation class (I) and level of evidence (A) in the European guidelines for patients with coronary artery disease. Nonetheless, exercise training is underutilized in patients with cardiac diseases and only a minority of eligible patients is referred to a cardiac rehabilitation or structured exercise training program by their physician

Synthesis of 2′‐[F‐18]fluoro‐2′‐DEOXY‐β‐D‐arabinofuranosyl nucleosides

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/91186/1/25804401320_ftp.pd

Radiopharmaceutical Tracers for Neural Progenitor Cells

The Technical Report summarizes the results of the synthesis and microPET animal scanning of several compounds labeled with positron-emitting isotopes in normal, neonatal and kainic acid treated (seizure induced) rats as potential PET tracers to image the process of neurogenesis using positron emission tomography (PET). The tracers tested were 3'-deoxy-3'-[F-18]fluorothymidine ([F-18]FLT) and 5'-benzoyl-FTL, 1-(2'-deoxy-2'-[F-18]fluoro-B-D-arabinofuranosyl)-5-bromouracil (FBAU) and 3',5'-dibenzoyl-FBAU, N-[F-18]fluoroacetyl-D-glucosamine (FLAG) and tetraacetyl-FLAG, and L-[1-C-11]leucine

Exercise Training Prevents Diaphragm Contractile Dysfunction in Heart Failure

Purpose: Patient studies have demonstrated the efficacy of exercise training in attenuating respiratory muscle weakness in chronic heart failure (HF), yet direct assessment of muscle fiber contractile function together with data on the underlying intracellular mechanisms remains elusive. The present study, therefore, used a mouse model of HF to assess whether exercise training could prevent diaphragm contractile fiber dysfunction by potentially mediating the complex interplay between intracellular oxidative stress and proteolysis. Methods: Mice underwent sham operation (n = 10) or a ligation of the left coronary artery and were randomized to sedentary HF (n = 10) or HF with aerobic exercise training (HF + AET; n = 10). Ten weeks later, echocardiography and histological analyses confirmed HF. Results: In vitro diaphragm fiber bundles demonstrated contractile dysfunction in sedentary HF compared with sham mice that was prevented by AET, with maximal force 21.0 ± 0.7 versus 26.7 ± 1.4 and 25.4 ± 1.4 N·cm−2, respectively (P < 0.05). Xanthine oxidase enzyme activity and MuRF1 protein expression, markers of oxidative stress and protein degradation, were ~20% and ~70% higher in sedentary HF compared with sham mice (P < 0.05) but were not different when compared with the HF + AET group. Oxidative modifications to numerous contractile proteins (i.e., actin and creatine kinase) and markers of proteolysis (i.e., proteasome and calpain activity) were elevated in sedentary HF compared with HF + AET mice (P < 0.05); however, these indices were not significantly different between sedentary HF and sham mice. Antioxidative enzyme activities were also not different between groups. Conclusion: Our findings demonstrate that AET can protect against diaphragm contractile fiber dysfunction induced by HF, but it remains unclear whether alterations in oxidative stress and/or protein degradation are primarily responsible

Imaging of cardiac neuronal function after cocaine exposure using Carbon-11 hydroxyephedrine and positron emission tomography

AbstractObjectives. The aim of the study was to define the effect of cocaine on the myocardial uptake and retention of C-11 hydroxyephedrine in the anesthetized dog model.Background. Cardiac toxcity of cocaine has been linked to its inhibitory effect on norepinephrine reuptake by the sympathetic nerve terminals of the heart. Carbon-11 hydroxyephedrine is a C-11-labled norepinephrine analog that has high specific affinity for uptake-1 and thus makes possible the assessment of the effect of cocaine on norepinephrine reuptake by cardiac sympathetic nerve terminals.Methods. The cardiac kinetics of C-11 hydroxyephedrine as assessed by dynamic positron emission tomographic imaging were used to characterize norepinephrine reuptake by the sympathetic nerve terminals. Carbon-11 hydroxyephedrine was injected intravenously before, as well as at 5 min and 2.5 h after, intravenous administration of 2 mg/kg body weight of cocaine in anesthetized dogs. Hemodynamic variables and microsphere-determined cardiac blood flow were also measured before and after cocaine exposure.Results. Intravenous injection of cocaine did not significantly affect hemodynamic variables and myocardial blood flow in the anesthetized animals. Compared with baseline, myocardial retention of C-11 hydroxyephedrine was significantly reduced by 78 ± 3% (mean ± SD) at 5 min and remained significantly reduced (28 ± 17%) at 2.5 h after cocaine injection. Cocaine administration after C-11 hydroxyephedrine injection (39 min) resulted in rapid biexponential clearance of C-11 hydroxyephedrine from myocardium.Conclusions. These results suggest prolonged effects of cocaine on the sympathetic nerve terminals of the heart. Positron emission tomography provides a noninvasive and sensitive means to objectively assess the cardiac pharmacokinetics of drugs such as cocaine

Synthesis of [11C]tetrabenazine, a vesicular monoamine uptake inhibitor, for PET imaging studies

Tetrabenazine (TBZ), a high affinity and specific inhibitor of the vesicular monoamine transporter, has been labeled with carbon-11 as a potential probe for in vivo positron emission tomographic imaging of monoaminergic neuronal losses in neurodegenerative diseases. [11C]TBZ was synthesized by O-[11C]methylation of the 9-O-desmethylTBZ using [11C]methyl iodide in the presence of tetrabutyl-ammonium hydroxide. The radiochemical yields were 35-55% (decay corrected) and the synthesis time 32-37 min from EOB. [11C]TBZ was obtained with specific activities of 2000-2500 Ci/mmol (EOS) and radiochemical and chemical purities were &gt;95%. [11C]Tetrabenazine is a promising new radioligand for the in vivo study of monoaminergic neurons using PET.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30889/1/0000558.pd

Effect of Aspartame-Derived Phenylalanine on Neutral Amino Acid Uptake in Human Brain: A Positron Emission Tomography Study

The possible effects of elevation of the plasma phe-nylalanine level secondary to the ingestion of aspartame on brain amino acid uptake in human subjects have been investigated by means of positron emission tomography (PET). 1-[ 11 C]Aminocyclohexanecarboxylate ([ 11 C]ACHC) is a poorly metabolized synthetic amino acid that crosses the blood-brain barrier by the same carrier that transports naturally occurring large neutral amino acids. Quantitative test-retest PET studies were performed on 15 individuals. Seven received two identical baseline scans, whereas eight received a baseline scan followed by a scan performed ∼40–45 min following ingestion of an orange-flavored beverage containing 34 mg/kg of body weight of the low-calorie sweetener aspartame, a dose equivalent to the amount in 5 L of diet soft drink consumed all at once by the study subjects, weighing an average of 76 kg. The 40–45-min interval was selected to maximize the detection of possible decreases in ACHC uptake resulting from increased competition for the carrier, because the plasma phenylalanine level is known to peak at this time. We observed an 11.5% decrease in the amino acid transport rate constant Kt and a smaller decrease in the tissue distribution volume of ACHC (6%). Under conditions of normal dietary use, aspartame is thus unlikely to cause changes in brain amino acid uptake that are measurable by PET.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65668/1/j.1471-4159.1991.tb02047.x.pd