Preserved Cerebral Oxygen Metabolism in Astrocytic Dysfunction: A Combination Study of ¹⁵O-Gas PET with ¹⁴C-Acetate Autoradiography

Fluorocitrate (FC) is a specific metabolic inhibitor of the tricarboxylic acid (TCA) cycle in astrocytes. The purpose of this study was to evaluate whether inhibition of the astrocyte TCA cycle by FC would affect the oxygen metabolism in the rat brain. At 4 h after the intracranial FC injection, the rats (n = 9) were investigated by 15O-labeled gas PET to measure the cerebral blood flow (CBF), the cerebral metabolic rate of oxygen (CMRO2), oxygen extraction fraction (OEF), and cerebral blood volume (CBV). After the 15O-gas PET, the rats were given an intravenous injection of 14C-acetate for autoradiography. 15O-gas PET showed no significant differences in any of the measured parameters between the ipsilateral and contralateral striatum (high dose group: CBF (54.4 ± 8.8 and 55.3 ± 11.6 mL/100 mL/min), CMRO2 (7.0 ± 0.9 and 7.1 ± 1.2 mL/100 mL/min), OEF (72.0 ± 8.9 and 70.8 ± 8.2%), and CBV (4.1 ± 0.8 and 4.2 ± 0.9 mL/100 mL), respectively). In contrast, the 14C-acetate autoradiography revealed a significant inhibition of the astrocyte metabolism in the ipsilateral striatum. The regional cerebral oxygen consumption as well as the hemodynamic parameters were maintained even in the face of inhibition of the astrocyte TCA cycle metabolism in the rat brain

Whole-Body Distribution of Donepezil as an Acetylcholinesterase Inhibitor after Oral Administration in Normal Human Subjects: A 11C-donepezil PET Study

Objective(s): It is difficult to investigate the whole-body distribution of an orally administered drug by means of positron emission tomography (PET), owing to the short physical half-life of radionuclides, especially when 11C-labeled compounds are tested. Therefore, we aimed to examine the whole-body distribution of donepezil (DNP) as an acetylcholinesterase inhibitor by means of 11C-DNP PET imaging, combined with the oral administration of pharmacological doses of DNP.Methods: We studied 14 healthy volunteers, divided into group A (n=4) and group B (n=10). At first, we studied four females (mean age: 57.3±4.5 y), three of whom underwent 11C-DNP PET scan at 2.5 h after the oral administration of 1 mg and 30 μg of DNP, respectively, while one patient was scanned following the oral administration of 30 μg of DNP (group A). Then, we studied five females and five males (48.3±6.1 y), who underwent 11C-DNP PET scan, without the oral administration of DNP (group B). Plasma DNP concentration upon scanning was measured by tandem mass spectrometry. Arterialized venous blood samples were collected periodically to measure plasma radioactivity and metabolites. In group A, 11C-DNP PET scan of the brain and whole body continued for 60 and 20 min, respectively. Subjects in group B underwent sequential whole-body scan for 60 min. The regional uptake of 11C-DNP was analyzed by measuring the standard uptake value (SUV) through setting regions of interest on major organs with reference CT.Results: In group A, plasma DNP concentration was significantly correlated with the orally administered dose of DNP. The mean plasma concentration was 2.00 nM (n=3) after 1 mg oral administration and 0.06 nM (n=4) after 30 μg oral administration. No significant difference in plasma radioactivity or fraction of metabolites was found between groups A and B. High 11C-DNP accumulation was found in the liver, stomach, pancreas, brain, salivary glands, bone marrow, and myocardium in groups A and B, in this order. No significant difference in SUV value was found among 11C-DNP PET studies after the oral administration of 1 mg of DNP, 30 μg of DNP, or no DNP.Conclusion: The present study demonstrated that the whole-body distribution of DNP after the oral administration of pharmacological doses could be evaluated by 11C-DNP PET studies, combined with the oral administration of DNP

Oxygen-15 labeled CO2, O2, and CO PET in small animals: evaluation using a 3D-mode microPET scanner and impact of reconstruction algorithms

Abstract Background Positron emission tomography (PET) studies using 15O-labeled CO2, O2, and CO have been used in humans to evaluate cerebral blood flow (CBF), the cerebral oxygen extraction fraction (OEF), and the cerebral metabolic rate of oxygen (CMRO2) and cerebral blood volume (CBV), respectively. In preclinical studies, however, PET studies using 15O-labeled gases are not widely performed because of the technical difficulties associated with handling labeled gases with a short half-life. The aims of the present study were to evaluate the scatter fraction using 3D-mode micro-PET for 15O-labeled gas studies and the influence of reconstruction algorithms on quantitative values. Nine male SD rats were studied using the steady state inhalation method for 15O-labeled gases with arterial blood sampling. The resulting PET images were reconstructed using filtered back projection (FBP), ordered-subset expectation maximization (OSEM) 2D, or OSEM 3D followed by maximum a posteriori (OSEM3D-MAP). The quantitative values for each brain region and each reconstruction method were calculated by applying different reconstruction methods. Results The quantitative values for the whole brain as calculated using FBP were 46.6 ± 12.5 mL/100 mL/min (CBF), 63.7 ± 7.2% (OEF), 5.72 ± 0.34 mL/100 mL/min (CMRO2), and 5.66 ± 0.34 mL/100 mL (CBV), respectively. The CBF and CMRO2 values were significantly higher when the OSEM2D and OSEM3D-MAP reconstruction methods were used, compared with FBP, whereas the OEF values were significantly lower when reconstructed using OSEM3D-MAP. Conclusions We evaluated the difference in quantitative values among the reconstruction algorithms using 3D-mode micro-PET. The iterative reconstruction method resulted in significantly higher quantitative values for CBF and CMRO2, compared with the values calculated using the FBP reconstruction method

Additional file 1: Figure S1. of Quantitative evaluation of oxygen metabolism in the intratumoral hypoxia: 18F-fluoromisonidazole and 15O-labelled gases inhalation PET

Multiple VOI settings on coronal fusion image of 18F-FMISO PET (window level 0–3 in SUV) and TBF PET (window level 0–80 ml/100 mL/min). VOIs (1-mm sphere) were manually placed over the entire tumor where there is an uptake of 18F-FMISO or TBF on the fusion PET images. Figure S2. Relationships between the 18F-FMISO SUV and quantitative values of TBF, TMRO2, OEF, and TBV of each tumor. Decreased trend of TBF and TBV, increased trend of OEF, and stable TMRO2 against the increase of 18F-FMISO SUV were observed. (DOC 673 kb

The relationships among Vt by Logan plot analysis, SUV at 30 min, radioactivity count by well counter, and AChE activity by fluorometric assay.

<p>The relationships among Vt by Logan plot analysis, SUV at 30 min, radioactivity count by well counter, and AChE activity by fluorometric assay.</p

Additional file 1: Figure S1. of Oxygen-15 labeled CO2, O2, and CO PET in small animals: evaluation using a 3D-mode microPET scanner and impact of reconstruction algorithms

Schema of the tube connection for the 15O-gas supply. Figure S2. Workflow for image reconstruction and data analysis. Figure S3. Relationship between the radioactivity of 15O-gas flow and the radioactivity concentration in the lung. Figure S4. Percent change in the radioactivity concentration against FBP (**P < 0.01). (DOCX 312 kb

Whole body images after the administration of ¹¹C-DNP: (a) dynamic maximum intensity projection images of PET, (b) coronal images of PET, CT, and PET/CT (20–40 min, arrow: left adrenal gland).

<p>Whole body images after the administration of ¹¹C-DNP: (a) dynamic maximum intensity projection images of PET, (b) coronal images of PET, CT, and PET/CT (20–40 min, arrow: left adrenal gland).</p

Time activity curves of major organs on ¹¹C-DNP PET.

<p>Time activity curves of major organs on ¹¹C-DNP PET.</p

Distribution of Intravenously Administered Acetylcholinesterase Inhibitor and Acetylcholinesterase Activity in the Adrenal Gland: ¹¹C-Donepezil PET Study in the Normal Rat

<div><p>Purpose</p><p>Acetylcholinesterase (AChE) inhibitors have been used for patients with Alzheimer's disease. However, its pharmacokinetics in non-target organs other than the brain has not been clarified yet. The purpose of this study was to evaluate the relationship between the whole-body distribution of intravenously administered ¹¹C-Donepezil (DNP) and the AChE activity in the normal rat, with special focus on the adrenal glands.</p><p>Methods</p><p>The distribution of ¹¹C-DNP was investigated by PET/CT in 6 normal male Wistar rats (8 weeks old, body weight  = 220±8.9 g). A 30-min dynamic scan was started simultaneously with an intravenous bolus injection of ¹¹C-DNP (45.0±10.7 MBq). The whole-body distribution of the ¹¹C-DNP PET was evaluated based on the Vt (total distribution volume) by Logan-plot analysis. A fluorometric assay was performed to quantify the AChE activity in homogenized tissue solutions of the major organs.</p><p>Results</p><p>The PET analysis using Vt showed that the adrenal glands had the 2nd highest level of ¹¹C-DNP in the body (following the liver) (13.33±1.08 and 19.43±1.29 ml/cm³, respectively), indicating that the distribution of ¹¹C-DNP was the highest in the adrenal glands, except for that in the excretory organs. The AChE activity was the third highest in the adrenal glands (following the small intestine and the stomach) (24.9±1.6, 83.1±3.0, and 38.5±8.1 mU/mg, respectively), indicating high activity of AChE in the adrenal glands.</p><p>Conclusions</p><p>We demonstrated the whole-body distribution of ¹¹C-DNP by PET and the AChE activity in the major organs by fluorometric assay in the normal rat. High accumulation of ¹¹C-DNP was observed in the adrenal glands, which suggested the risk of enhanced cholinergic synaptic transmission by the use of AChE inhibitors.</p></div

Relationships between (a) well count and SUV (R = 0.93, p<0.001), (b) AChE activity and ACh level (R = 0.86, p<0.001), and (c) Vt and AChE activity (R = 0.17, p = 0.60).

<p>Relationships between (a) well count and SUV (R = 0.93, p<0.001), (b) AChE activity and ACh level (R = 0.86, p<0.001), and (c) Vt and AChE activity (R = 0.17, p = 0.60).</p