Long-term effects of the angiotensin-converting enzyme inhibitor enalapril on chronic heart failure. Examination by 123I-MIBG imaging

To examine the long-term effects of the angiotensin-converting enzyme (ACE) inhibitor enalapril on chronic heart failure, 10 patients (7 men and 3 women, mean age: 62 +/- 11 years) with chronic stable heart failure, classified as New York Heart Association (NYHA) functional class 2-3 for more than 3 months, and a left ventricular ejection fraction less than 45% were treated with 2.5-5.0 mg of enalapril once a day for 3-15 months (mean 7 months). The causes of heart failure were old myocardial infarction (n = 7), hypertension (n = 2), and atrial fibrillation (n = 1). Radioiodinated metaiodobenzyl guanidine (123I-MIBG) imaging, radionuclide angiography, and treadmill exercise test were performed before and after the treatment. With enalapril treatment, (1) left ventricular ejection fraction (LVEF) increased significantly from 38.3 +/- 6.9% to 47.5 +/- 14.7%; (2) sub-maximal exercise time increased significantly from 205 +/- 112 to 272 +/- 120 seconds; (3) the heart to mediastinum (H/M) ratio of 123I-MIBG increased significantly (early image: 1.99 +/- 0.38 versus 2.20 +/- 0.50; delayed image: 1.86 +/- 0.44 versus 2.09 +/- 0.51); and (4) the washout rate of 123I-MIBG decreased slightly from 29.1 +/- 9.1% to 25.4 +/- 7.0%. The improvement rate of LVEF was significantly correlated with the improvement rates of the H/M ratio and washout rate after treatment with enalapril. Thus, the long-term effects of enalapril can be observed in the cardiac sympathetic nervous system, and 123I-MIBG imaging appears to be useful for evaluating the therapeutic effects of enalapril on the cardiac sympathetic nervous system in patients with chronic heart failure.     

Synthesis and evaluation of PET probes for the imaging of I2 imidazoline receptors in peripheral tissues

IntroductionTo explore the possible use of positron emission tomography (PET) probes for imaging of I₂-imidazoline receptors (I₂Rs) in peripheral tissues, we labeled two new I₂R ligands, 2-[2-(o-tolyl)vinyl]-4,5-dihydro-1H-imidazole (K_i for I₂Rs, 3.7 nM) and 2-[2-(o-tolyl)ethyl]-4,5-dihydro-1H-imidazole (K_i for I₂Rs, 1.7 nM) with ¹¹C ([¹¹C]metrazoline and [¹¹C]TEIMD), respectively, and evaluated these ligands and the recently developed I₂R ligand 2-[3-fluoro-[4-¹¹C]tolyl]-4,5-dihydro-1H-imidazole ([¹¹C]FTIMD) by in vivo studies.Methods[¹¹C]Metrazoline and [¹¹C]TEIMD were prepared by a palladium-promoted cross-coupling reaction of the tributylstannyl precursor and [¹¹C]methyl iodide. Their biodistribution in mice was investigated by tissue dissection. In addition, PET scans and metabolite analysis were performed.Results[¹¹C]Metrazoline and [¹¹C]TEIMD were successfully synthesized with a suitable radioactivity for injection. In the liver and pancreas expressing I₂Rs, coinjection with the high-affinity I₂R ligand, BU224, induced a reduction in the radioactivity level at 30 min after injection of [¹¹C]metrazoline and [¹¹C]FTIMD. However, the radioactivity level after injection of [¹¹C]TEIMD was unchanged. In the PET study, coinjection with BU224 induced a decrease in the radioactivity level in the liver and pancreas after more than 15 min of injection of [¹¹C]metrazoline and [¹¹C]FTIMD as compared with the results obtained for controls. In metabolite analysis, coinjection with BU224 induced a significant reduction in the percentage of unchanged [¹¹C]metrazoline at 30 min after injection as compared with that in the control, although no significant difference was observed in the percentage of unchanged [¹¹C]FTIMD.Conclusion[¹¹C]Metrazoline may be a more useful PET probe than [¹¹C]FTIMD for imaging of I₂Rs in peripheral tissues.     

PET study using [11C]FTIMD with ultra-high specific activity to evaluate I2-imidazoline receptors binding in rat brains

IntroductionWe recently developed a selective ¹¹C-labeled I₂-imidazoline receptor (I₂R) ligand, 2-(3-fluoro-4-[¹¹C]tolyl)-4,5-dihydro-1H-imidazole ([¹¹C]FTIMD). [¹¹C]FTIMD showed specific binding to I₂Rs in rat brains having a high density of I₂R, as well as to I₂Rs those in monkey brains, as illustrated by positron emission tomography (PET) and autoradiography. However, [¹¹C]FTIMD also showed moderate non-specific binding in rat brains. In order to increase the specificity for I₂R in rat brains, we synthesized [¹¹C]FTIMD with ultra-high specific activity and evaluated its binding.Methods[¹¹C]FTIMD with ultra-high specific activity was prepared by a palladium-promoted cross-coupling reaction of the tributylstannyl precursor and [¹¹C]methyl iodide, which was produced by iodination of [¹¹C]methane using the single-pass method. Dynamic PET scans were conducted in rats, and the kinetic parameters were estimated.Results[¹¹C]FTIMD with ultra-high specific activity was successfully synthesized with an appropriate level of radioactivity and ultra-high specific activity (4470±1660 GBq/μmol at end of synthesis, n=11) for injection. In the PET study, distribution volume (V_T) values in all the brain regions investigated whether I₂R expression was greatly reduced in BU224-pretreatead rats compared with control rats (29–45% decrease). Differences in V_T values between control and BU224-pretreated rats using [¹¹C]FTIMD with ultra-high specific activity were greater than those using [¹¹C]FTIMD with normal specific activity (17–34% decrease) in all brain regions investigated.ConclusionQuantitative PET using [¹¹C]FTIMD with ultra-high specific activity can contribute to the detection of small changes in I₂R expression in the brain.     

Age-related effects of fasting on ketone body production during lipolysis in rats

Objective

The age-related effects of fasting on lipolysis, the production of ketone bodies, and plasma insulin levels were studied in male 3-, 8-, and 32-week-old Sprague–Dawley rats.

Methods

The rats were divided into fasting and control groups. The 3-, 8- and 32-week-old rats tolerated fasting for 2, 5, and 12 days, respectively.

Results

Fasting markedly reduced the weights of perirenal and periepididymal white adipose tissues in rats in the three age groups. The mean rates of reduction in both these adipose tissue weights during fasting periods were higher in the order of 3 > 8 > 32-week-old rats. Fasting transiently increased plasma free fatty acid (FFA), total ketone body, β-hydroxybutyrate, and acetoacetate concentrations in the rats in the three age groups. However, plasma FFA, total ketone body, β-hydroxybutyrate, and acetoacetate concentrations in the 3-week-old rats reached maximal peak within 2 days after the onset of fasting, although these concentrations in the 8- and 32-week-old rats took more than 2 days to reach the maximal peak. By contrast, the augmentation of plasma FFA, total ketone body, β-hydroxybutyrate, and acetoacetate concentrations in the rats in the three age groups had declined at the end of each experimental period. Thus, the capacity for fat mobilization was associated with tolerance to fasting. Plasma insulin concentrations in the rats in the three age groups were dramatically reduced during fasting periods, although basal levels of insulin were higher in the order of 32 > 8 > 3 week-old rats.

Conclusion

These results suggest that differences in fat metabolism patterns among rats in the three age groups during prolonged fasting were partly reflected the metabolic turnover rates, plasma insulin levels, and amounts of fat storage.