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

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

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

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

Development of PET Imaging to Visualize Activated Macrophages Accumulated in the Transplanted iPSc-Derived Cardiac Myocytes of Allogeneic Origin for Detecting the Immune Rejection of Allogeneic Cell Transplants in Mice

<div><p>Allogeneic transplantation (Tx) of induced pluripotent stem cells (iPSCs) is a promising tissue regeneration therapy. However, this inevitably induces macrophage-mediated immune response against the graft, limiting its therapeutic efficacy. Monitoring the magnitude of the immune response using imaging tools would be useful for prolonging graft survival and increasing the therapy longevity. Minimally invasive quantitative detection of activated macrophages by medical imaging technologies such as positron emission tomography (PET) imaging targets translocator protein (TSPO), which is highly expressed on mitochondrial membrane, especially in activated macrophage. <i>N</i>,<i>N</i>-diethyl-2-[4-(2-fluoroethoxy) phenyl]-5,7-dimethylpyrazolo[1,5-<i>a</i>]pyrimidine-3-acetamide (DPA-714) is known as a TSPO ligand used in clinical settings. We herein hypothesized that immune rejection of the transplanted iPSC-derived cardiomyocytes (iPSC-CMs) of allogeneic origin may be quantitated using ¹⁸F-DPA-714-PET imaging study. iPSC-CM cell-sheets of C57BL/6 mice origin were transplanted on the surface of the left ventricle (LV) of C57BL/6 mice as a syngeneic cell-transplant model (syngeneic Tx group), or Balb/c mice as an allogeneic model (allogeneic Tx group). ¹⁸F-DPA-714-PET was used to determine the uptake ratio, calculated as the maximum standardized uptake value in the anterior and septal wall of the LV. The uptake ratio was significantly higher in the allogeneic Tx group than in the syngeneic group or the sham group at days 7 and day 10 after the cell transplantation. In addition, the immunochemistry showed significant presence of CD68 and CD3-positive cells at day 7 and 10 in the transplanted graft of the allogeneic Tx group. The expression of TSPO, <i>CD68</i>, <i>IL-1</i> beta, and <i>MCP-1</i> was significantly higher in the allogeneic Tx group than in the syngeneic Tx and the sham groups at day 7. The ¹⁸F-DPA-714-PET imaging study enabled quantitative visualization of the macrophages-mediated immune rejection of the allogeneic iPSC-cardiac. This imaging tool may enable the understanding and monitoring host-immune response of the host, allogeneic cell transplantation therapy.</p></div

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

Infiltration of activated macrophages and T lymphocytes into the transplanted graft.

<p>A, infiltration of CD68 positive activated macrophages into the transplanted grafts in the allogeneic Tx group, the syngeneic Tx group, and sham group at days 1, 7, and 10. bar = 100μm; B, infiltration of CD3 positive T lymphocytes into the transplanted grafts in the allogeneic Tx group, the syngeneic Tx group, and sham group at days 1, 7, and 10. bar = 100μm; C, comparison of the infiltrating CD68 positive cell counts per HPF among the allogeneic Tx group, the syngeneic Tx group, and sham group at days 1, 7, and 10; D, comparison of the infiltrating CD3 positive cell counts per HPF among the allogeneic Tx group, the syngeneic Tx group, and sham group at days 1, 7, and 10 * indicates <i>P</i> <0.05; N.S, not significant.</p

Expression of TSPO and associated proteins after iPSC-cardiac sheet transplantation.

<p>A-E, serial changes in the expression of <i>TSPO</i>, <i>CD68</i>, <i>IL-1beta</i>, <i>MCP-1</i> and <i>IL-2</i> in the allogeneic Tx group, the syngeneic Tx group, and sham group at day 7 after transplantation; F-H, correlation between the uptake ratio and expression of <i>TSPO</i>, <i>CD68</i> and <i>MCP-1; TSPO</i> indicates translocator protein; <i>IL-1</i>, interleukin-1; iPSC, induced pluripotent stem cells; Tx, transplantation; LV, left ventricle; * indicates <i>P</i> <0.05; N.S, not significant.</p