Charles K. Stone

Myocardial free fatty acid and glucose use after carvedilol treatment in patients with congestive heart failure.

Background—Use of &bgr;-adrenoreceptor blockade in the treatment of heart failure has been associated with a reduction in myocardial oxygen consumption and an improvement in myocardial energy efficiency. One potential mechanism for this beneficial effect is a shift in myocardial substrate use from increased free fatty acid (FFA) oxidation to increased glucose oxidation. Methods and Results—We studied the effect of carvedilol therapy on myocardial FFA and glucose use in 9 patients with stable New York Heart Association functional class III ischemic cardiomyopathy (left ventricular ejection fraction ≤35%) using myocardial positron emission tomography studies and resting echocardiograms before and 3 months after carvedilol treatment. Myocardial uptake of the novel long chain fatty acid metabolic tracer 14(R, S)-[18F]fluoro-6-thia-heptadecanoic acid ([18F]-FTHA) was used to determine myocardial FFA use, and [18F]fluoro-2-deoxy-glucose ([18F]-FDG) was used to determine myocardial glucose use. After carvedilol treatment, the mean myocardial uptake rate for [18F]-FTHA decreased (from 20.4±8.6 to 9.7±2.3 mL · 100 g−1 · min−1;P <0.005), mean fatty acid use decreased (from 19.3±7.0 to 8.2±1.8 &mgr;moL · 100 g−1 · min−1;P <0.005), the mean myocardial uptake rate for [18F]-FDG was unchanged (from 1.4±0.4 to 2.4±0.8 mL · 100 g−1 · min−1;P =0.14), and mean glucose use was unchanged (from 11.1±3.1 to 18.7±6.0 &mgr;moL · 100 g−1 · min−1;P =0.12). Serum FFA and glucose concentrations were unchanged, and mean left ventricular ejection fraction improved (from 26±2% to 37±4%;P <0.05). Conclusions—Carvedilol treatment in patients with heart failure results in a 57% decrease in myocardial FFA use without a significant change in glucose use. These metabolic changes could contribute to the observed improvements in energy efficiency seen in patients with heart failure.

Glucose metabolic changes in the prefrontal cortex are associated with HPA axis response to a psychosocial stressor

The prefrontal cortex (PFC) has been well known for its role in higher order cognition, affect regulation and social reasoning. Although the precise underpinnings have not been sufficiently described, increasing evidence also supports a prefrontal involvement in the regulation of the hypothalamus-pituitary-adrenal (HPA) axis. Here we investigate the PFCs role in HPA axis regulation during a psychosocial stress exposure in 14 healthy humans. Regional brain metabolism was assessed using positron emission tomography (PET) and injection of fluoro-18-deoxyglucose (FDG). Depending on the exact location within the PFC, increased glucose metabolic rate was associated with lower or higher salivary cortisol concentration in response to a psychosocial stress condition. Metabolic glucose rate in the rostral medial PFC (mPFC) (Brodman area (BA) 9 and BA 10) was negatively associated with stress-induced salivary cortisol increases. Furthermore, metabolic glucose rate in these regions was inversely coupled with changes in glucose metabolic rate in other areas, known to be involved in HPA axis regulation such as the amygdala/hippocampal region. In contrast, metabolic glucose rate in areas more lateral to the mPFC was positively associated with saliva cortisol. Subjective ratings on task stressfulness, task controllability and self-reported dispositional mood states also showed positive and negative associations with the glucose metabolic rate in prefrontal regions. These findings suggest that in humans, the PFC is activated in response to psychosocial stress and distinct prefrontal metabolic glucose patterns are linked to endocrine stress measures as well as subjective ratings on task stressfulness, controllability as well as dispositional mood states.

A [ 17F]-fluoromethane PET/TMS study of effective connectivity

We used transcranial magnetic stimulation (TMS) in combination with positron emission tomography (PET) to investigate the effective connectivity of four cortical regions within the same study. By employing [17F]-[CH3F] ([17F]-fluoromethane) as a radiotracer of blood-flow, we were able to obtain increased sensitivity compared to [15O]-H2O for both cortical and subcortical structures. The brain areas investigated were left primary motor cortex, right primary visual cortex, and left and right prefrontal areas. We found that each site of stimulation yielded a different pattern of activation/deactivation consistent with its anatomical connectivity. Moreover, we found that TMS of prefrontal and motor cortical areas gave rise to trans-synaptic activation of subcortical circuits.

Synthesis and preliminary evaluation of 18F-labeled 4-thia palmitate as a PET tracer of myocardial fatty acid oxidation

Abstract Interest remains strong for the development of a noninvasive technique for assessment of regional fatty acid oxidation rate in the myocardium. 18 F-labeled 4-thia palmitate (FTP, 16-[ 18 F]fluoro-4-thia-hexadecanoic acid) has been synthesized and preliminarily evaluated as a metabolically trapped probe of myocardial fatty acid oxidation for positron emission tomography (PET). The radiotracer is synthesized by Kryptofix 2.2.2/K 2 CO 3 assisted nucleophilic radiofluorination of an iodo-ester precursor, followed by alkaline hydrolysis and by purification by reverse phase high performance liquid chromatography. Biodistribution studies in rats showed high uptake and long retention of FTP in heart, liver, and kidneys consistent with relatively high fatty acid oxidation rates in these tissues. Inhibition of carnitine palmitoyl-transferase-I caused an 80% reduction in myocardial uptake, suggesting the dependence of trapping on the transport of tracer into the mitochondrion. Experiments with perfused rat hearts showed that the estimates of the fractional metabolic trapping rate (FR) of FTP tracked inhibition of oxidation rate of palmitate with hypoxia, whereas the FR of the 6-thia analog 17-[ 18 F]fluoro-6-thia-heptadecanoic acid was insensitive to hypoxia. In vivo defluorination of FTP in the rat was evidenced by bone uptake of radioactivity. A PET imaging study with FTP in normal swine showed excellent myocardial images, prolonged myocardial retention, and no bone uptake of radioactivity up to 3 h, the last finding suggesting a species dependence for defluorination of the omega-labeled fatty acid. The results support further investigation of FTP as a potential PET tracer for assessing regional fatty acid oxidation rate in the human myocardium.

Technetium 94m-labeled methoxyisobutyl isonitrile: Dosimetry and resting cardiac imaging with positron emission tomography

BackgroundDevelopment of a positronemitting form of technetium has allowed the imaging of technetium radiopharmaceuticals with positron emission tomography (PET). We used94mTc to compare the distribution of the myocardial perfusion agent sestamibi at rest with the conventional PET perfusion tracer13N-labeled ammonia (13N-ammonia).Methods and ResultsDosimetry calculations were performed with the known wholebody distribution of99mTc-labeled sestamibi. Dynamic PET imaging of13N-ammonia and94mTc-labeled sestamibi (94mTc-sestamibi) for 32 minutes was performed in eight patients with previous myocardial infarction. Initial myocardial and extramyocardial distribution of94mTc-sestamibi was compared with that of13N-ammonia by qualitative and quantitative analysis. Quantitative comparison of the two tracers was performed with region-of-interest analysis and circumferential profiles. Qualitatively, the cardiac distribution of the tracers was similar in normal and infarcted myocardium. A decrease in the definition of the epicardial and endocardial borders of the heart was seen with94mTc-sestamibi, presumably because of the lower dose of radionuclide injected. Quantitatively, there was no difference in infarct size, defined prospectively as tracer activity less than 20% of maximum activity for the section, between the two tracers. Circumferential profile analysis with 12-degree radial sections similarly demonstrated no difference in regional cardiac distribution of the tracers.ConclusionsThese results revealed no significant difference in myocardial uptake compared with13N-ammonia suggesting that the myocardial uptake of sestamibi correlates with that of myocardial perfusion.

IMPROVING THE RADIONUCLIDIC PURITY OF 94MTC FOR PET IMAGING

Abstract The production of 94mTc as pertechnetate, a t 1 2 = 53 min positron emitter, was studied with small and medium energy cyclotrons. At a proton energy of 11 MeV, the irradiation of natural molybdenum provides adequate saturated yields (3 mCi/μA) with tolerable radionuclidic purity for radiopharmaceutical investigations in man. The longer lived 95Tc, 95mTc and 96Tc isotopes can be virtually eliminated by irradiating an isotopically-enriched 94MoO3 target. In a study of alternative entrance channels leading to 94mTc, natural niobium and molybdenum targets were irradiated with 3He and 4He beams. The goal was to reach pure 94mTc through the 94Ru/94mTc generator system, bypassing contamination by the 94gTc ground state.

Myocardial Kinetics of a Putative Hypoxic Tissue Marker, 99mTc-Labeled Nitroimidazole (BMS-181321), After Regional Ischemia and Reperfusion

BACKGROUND A new nitroimidazole complex, 99mTc-propylene amine oxime-1,2-nitroimidazole (BMS-181321), has been developed to allow the positive imaging of hypoxic myocardium by standard gamma camera techniques. METHODS AND RESULTS To determine the myocardial kinetics of BMS-181321 during myocardial ischemia and reperfusion, seven open-chest swine were prepared according to a model of extracorporeal coronary perfusion in which left ventricular wall thickening (percent end-diastolic thickness) and substrate use in the left anterior descending (LAD) region ([14C]palmitate and [3H]glucose infusions) were determined. Measurements were obtained at baseline, during 40 minutes of ischemia produced by reducing flow in the LAD distribution by 60%, and during 70 minutes of reperfusion. Three aerobic control hearts were also studied in which LAD blood flow was not reduced. Regional coronary circulation was further assessed in all hearts by use of radiolabeled microspheres injected during ischemia. BMS-181321 (20 to 30 mCi) was injected after 30 minutes of ischemia, and its myocardial uptake was assessed by dynamic planar gamma imaging. Ischemia was associated with declines in fatty acid metabolism (15 +/- 11 mumol.h-1.g dry wt-1, mean +/- SEM), systolic wall thickening (20 +/- 6%), and myocardial oxygen consumption (3 +/- 1 mL.min-1.100 g-1) and an increase in exogenous glucose utilization (75 +/- 13 mumol.h-1.g dry wt-1). Systolic wall thickening recovered by only 8 +/- 3% with reperfusion. Initial distribution of BMS-181321 in the aerobic hearts appeared homogeneous. Washout from the ischemic and reperfused LAD bed was slower than the aerobically perfused LAD bed in the control group (t1/2 = 136 +/- 1 versus 80 +/- 1 minutes, P < .05), allowing visualization of the LAD region during reperfusion. Tissue activity of BMS-181321 was inversely related to LAD blood flow during ischemia (r = -.68 +/- .05), and the ratio of BMS-181321 in the LAD region versus normal myocardium was 1.7 +/- 0.2. Control swine lacked regional deposition of the tracer in the normally perfused LAD distribution. CONCLUSIONS Thus, acute regional ischemia in these studies was visualized as an increase in retention of BMS-181321, suggesting its applicability in the imaging of clinical conditions of myocardial hypoperfusion.

In vivo comparison of tau radioligands 18F-THK-5351 and 18F-THK-5317

This study compared the in vivo imaging characteristics of tau PET ligands 18F-THK-5351 and 18F-THK-5317 in the context of Alzheimer disease (AD). Additionally, reference tissue distribution volume ratio (DVR) estimation methods and SUV ratio (SUVR) timing windows were evaluated to determine the optimal strategy for specific binding quantification. Methods: Twenty-eight subjects (mean age ± SD, 71 ± 7 y) underwent either dynamic 90-min 18F-THK-5317 or 18F-THK-5351 PET scans. Bland–Altman plots were used to compare the simplified reference tissue method, multilinear reference tissue method (MRTM2), and Logan reference tissue DVR estimates and to assess temporal stability of SUVR windows using cerebellar gray matter as a reference region. In vivo kinetics and DVR estimates were directly compared for 10 subjects who underwent both 18F-THK-5317 and 18F-THK-5351 PET scans. Results: THK-5351 exhibited faster cerebellar gray matter clearance, faster cortical white matter clearance, and higher DVR estimates in AD tau-associated regions of interest than THK-5317. The MRTM2 method produced the most reliable DVR estimates for both tracers, particularly when scan duration was shortened to 60 min. SUVR stability was observed 50–70 min after injection for both tracers. Parametric images revealed differences between MRTM2, Logan, and SUVR binding in white matter regions for THK-5317. Conclusion: THK-5317 and THK-5351 show promise for in vivo detection of AD tau. THK-5351 has more favorable pharmacokinetics and imaging characteristics than THK-5317.

First-in-Human Evaluation of 18F-Mefway, a PET Radioligand Specific to Serotonin-1A Receptors

The serotonin-1A (5-HT1A; 5-HT is 5-hydroxytryptamine) receptor is implicated in an array of neurologic and psychiatric disorders. Current PET radioligands targeting 5-HT1A receptors have limitations hindering widespread PET studies of this receptor system. The 5-HT1A–specific antagonist radioligand N-{2-[4-(2-methoxyphenyl)piperazinyl]ethyl}-N-(2-pyridyl)-N-(trans-4-18F-fluoromethylcyclohexane)carboxamide (18F-mefway) exhibited promising in vivo properties in rhesus monkeys. The goal of this work was to examine the in vivo cerebral binding profile and metabolism of 18F-mefway in humans. Methods: Dynamic 18F-mefway PET data were acquired for 6 healthy volunteers (4 women, 2 men; age, 22–38 y). Scans were initiated with the injection of 192–204 MBq of radiotracer, and data were acquired for 2 h. Venous blood samples were collected and assayed to examine the in vivo metabolism profile of 18F-mefway. To examine the test–retest variability of 18F-mefway, a second PET scan was acquired at least 2 wk later for 4 subjects. Regional binding potentials (BPNDs) were calculated with the multilinear reference tissue model, and voxelwise BPND maps were calculated with Logan graphical analysis. Regions surrounding the brain were carefully inspected for uptake of radiolabeled species in bone. Results: 18F-mefway uptake in the brain occurred quickly, with a peak standardized uptake value (SUV) of 1.7. Rapid washout in the cerebellum resulted in SUVs of 0.2 at 120 min, whereas regions with specific 5-HT1A binding exhibited retention of radioligand, yielding SUVs of 0.4–0.9 at 120 min. Rapid metabolism of 18F-mefway was observed, with no detected 18F-fluoride ions in plasma. BPND values of 2.4 were measured in the mesial temporal lobe, with values of 1.6 in the insular cortex and 0.7–1.0 in other cortical regions. Stable BPND estimates were obtained using 90 min of dynamic data. Average test–retest variability was 8%. No evidence of radioactivity uptake in bone was observed. Conclusion: 18F-mefway exhibits favorable in vivo properties for serotonin 5-HT1A receptor measurements in humans. The simple radiosynthesis, high specific binding profile, and absence of PET signal in bone make 18F-mefway an attractive radiotracer for PET experiments examining the 5-HT1A receptor in neuropsychiatric disorders and drug intervention.

A dual-tracer study of extrastriatal 6-[18F]fluoro-m-tyrosine and 6-[18F]-Fluoro-L-dopa uptake in Parkinson's disease

6‐[18F]‐Fluoro‐l‐dopa (FDOPA) has been widely used as a biomarker for catecholamine synthesis, storage, and metabolism—its intense uptake in the striatum, and fainter uptake in other brain regions, is correlated with the symptoms and pathophysiology of Parkinsons disease (PD). 6‐[18F]fluoro‐m‐tyrosine (FMT), which also targets l‐amino acid decarboxylase, has potential advantages over FDOPA as a radiotracer because it does not form catechol‐O‐methyltransferase (COMT) metabolites. The purpose of the present study was to compare the regional distribution of these radiotracers in the brains of PD patients. Fifteen Parkinsons patients were studied with FMT and FDOPA positron emission tomography (PET) as well as high‐resolution structural magnetic resonance imaging (MRI). MRIs were automatically parcellated into neuroanatomical regions of interest (ROIs) in Freesurfer (http://surfer.nmr.mgh.harvard.edu); region‐specific uptake rate constants (Kocc) were generated from coregistered PET using a Patlak graphical approach. The essential findings were as follows: (1) regional Kocc were highly correlated between the radiotracers and in agreement with a previous FDOPA studies that used different ROI selection techniques; (2) FMT Kocc were higher in extrastriatal regions of relatively large uptake such as amygdala, pallidum, brainstem, hippocampus, entorhinal cortex, and thalamus, whereas cortical Kocc were similar between radiotracers; (3) while subcortical uptake of both radiotracers was related to disease duration and severity, cortical uptake was not. These results suggest that FMT may have advantages for examining pathologic changes within allocortical loop structures, which may contribute to cognitive and emotional symptoms of PD. Synapse 68:325–331, 2014.