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Quantitative four-dimensional (4D) image reconstruction methods with respiratory and cardiac motion compensation are an active area of research in ECT imaging, including SPECT and PET. They are the extensions of three-dimensional (3D) statistical image reconstruction methods with iterative algorithms that incorporate accurate models of the imaging process and provide significant improvement in the quality and quantitative accuracy of the reconstructed images as compared to that obtained from conventional analytical image reconstruction methods. The new 4D image reconstruction methods incorporate additional models of the respiratory and cardiac motion of the patient to reduce image blurring due to respiratory motion and image noise of the cardiac-gated frames of the 4D cardiac-gated images. We describe respiratory motion estimation and gating method based on patient PET list-mode data. The estimated respiratory motion is applied to the respiratory gated data to reduce respiratory motion blur. The gated cardiac images derived from the list-model data are used to estimate cardiac motion. They are then used in the cardiac-gated images summing the motion-transformed cardiac-gated images for significant reduction in the gated images noise. Dual respiratory and cardiac motion compensation is achieved by combining the respiratory and cardiac motion compensation steps. The results are further significant improvements of the 4D gated cardiac PET images. The much improved gated cardiac PET image quality increases the visibility of anatomical details of the heart, which can be explored to provide more accurate estimation of the cardiac motion vector field and cardiac contractility.

This report describes details of the requirements and practical procedures for quantitative assessments of biological functional parametric images of the brain using I-labeled tracers and clinical SPECT systems. With due understanding of the physics and the biological background, this is considered achievable even under clinical environments, provided that data are appropriately acquired, processed, and analyzed. This article discusses how potential hurdles have been overcome for quantitatively assessing quantitative functional parametric images in clinical settings, with successful examples that provided additional clinically useful information.

Positron emission tomography (PET) plays important roles in cancer diagnosis, neuroimaging, and molecular imaging research. However potential points remain for which big improvements could be made, including spatial resolution, sensitivity, and manufacturing costs. Depth-of-interaction (DOI) measurement in the radiation sensor will be a key technology to get any significant improvement in sensitivity while maintaining high spatial resolution. We have developed four-layered DOI detectors based on our original light-sharing method. DOI measurement also has a potential to expand PET application fields because it allows for more flexible detector arrangement. As an example, we are developing the world’s first, open-type PET geometry, “OpenPET,” which is expected to lead to PET imaging during treatment. The DOI detector itself continues to evolve with the help of recently developed semiconductor photodetectors, often referred to as silicon photomultipliers (SiPMs). We are developing a SiPM-based DOI detector “X’tal cube” to achieve sub-mm spatial resolution, which is reaching the theoretical limitation of PET imaging. Innovation of SiPMs encourages our development of PET/MRI, which is attracting great notice in terms of smaller radiation exposure and better contract in soft tissues compared with current PET/CT.

Semiconductor detectors have the potential to improve the quantitative accuracy of nuclear medicine imaging with their better energy and intrinsic spatial resolutions than those of conventional scintillator-based detectors. The fine energy resolution leads to a better image contrast due to better scatter rejection. The fine intrinsic spatial resolution due to a pixelated structure leads to a better image contrast and lower partial volume effect. Their pixelated structures also improve the count-rate capability. The authors developed CdTe semiconductor detector-based positron emission tomography (CdTe-PET) and single-photon emission computed tomography (CdTe-SPECT) in order to test the potential of using semiconductor detectors in nuclear medicine. The physical performances of both systems were measured in several phantom experiments. The capability of using CdTe-PET to measure the metabolic distribution of tumors was evaluated through scans of cancer patients and rat tumor models. The feasibility of using CdTe-SPECT for simultaneous dual-radionuclide imaging was evaluated through scans of phantoms and healthy volunteers. The results suggest that the prototype CdTe-PET can identify intratumoral metabolic heterogeneous distribution and that CdTe-SPECT can accurately acquire dual-radionuclide images simultaneously. Although there are still problems to be solved, semiconductor detectors will play significant roles in the future of nuclear medicine.

PET has the ability to evaluate functional information as well as visualization of radiotracer uptake. Compartmental model is a basic idea to analyze dynamic PET data. C-HED has been the most frequently used PET tracer for the evaluation of cardiac sympathetic nervous system (SNS) function. The washout of norepinephrine from myocardium is associated with increasing SNS activity in heart failure (HF). However, the existence of washout of C-HED from the myocardium is controversial. Although “retention index” (RI) is commonly calculated to quantify the uptake of HED, RI is not purely able to distinguish washout parameter and uptake parameter. Therefore, in this study, we aimed to evaluate whether HED was washed out from the myocardium using compartment model analysis.

We compared HED parameters in ten normal volunteers (32.4 ± 9.6 years) and nine HF patients (age: 57.3 ± 17.3 years, LVEF: 36.1 ± 16.7 %). Each subject underwent rest C-HED PET. We estimated RI, inflow rate K1, and washout rate k2 using single-compartment model analysis using C-HED PET.

HF patients showed lower RI and inflow rate K1 compared to normal volunteers (RI: 0.06 ± 0.02 vs. 0.15 ± 0.03 min,  < 0.001, K1: 0.14 ± 0.05 vs 0.20 ± 0.03 ml/min/g,  < 0.001). Washout rate k2 also significantly increased in HF patients (k2: 0.036 ± 0.026 vs. 0.016 ± 0.011 min,  = 0.041).

HF patients showed reduced RI, reduced K1, and higher washout rate k2 compared to normal. This result may imply that HED PET is able to evaluate washout parameter using compartment model.

PET radiopharmaceuticals are currently produced using a centralized approach, which makes sustainable the distribution to few imaging centers of an only small set of tracers (virtually only [F]FDG). However, a wider set of structures have demonstrated a potential applicability for imaging in a specific manner several disease condition. In order to allow this wider and more personalized use of PET imaging, the production paradigms need to be changed. In this contribution we will explain how Dose-On-Demand systems can be conceptualized and what are the challenges that are still to be overcome in order for such approach to be of widespread utility.

Positron emission tomography (PET) provides quantitative 3D visualization of physiological parameters (e.g., metabolic rate, receptor density, gene expression, blood flow) in real time in the living body. By enabling measurement of differences in such characteristics between normal and diseased tissues, PET serves as vital tool for basic research as well as for clinical diagnosis and patient management. Prior to a PET scan, the patient is injected with a short-lived tracer labeled with a positron-emitting isotope. Safe preparation of the tracer is an expensive process, requiring specially trained personnel and high-cost equipment operated within hot cells. The current centralized manufacturing strategy, in which large batches are prepared and divided among many patients, enables the most commonly used tracer (i.e., [F]FDG) to be obtained at an affordable price. However, as the diversity of tracers increases, other strategies for cost reduction will become necessary. This challenge is being addressed by the development of miniaturized radiochemistry instrumentation based on microfluidics. These compact systems have the potential to significantly reduce equipment cost and shielding while increasing diversity of tracers produced in a given facility. The most common approach uses “flow-through” microreactors, which leverage the ability to precisely control reaction conditions to improve synthesis times and yields. Several groups have also developed “batch” microreactors which offer significant additional advantages such as reduced reagent consumption, simpler purifications, and exceptionally high specific activity, by reducing operating volumes by orders of magnitude. In this chapter, we review these “batch” approaches and the advantages of using small volumes, with special emphasis on digital microfluidics, in which reactions have been performed with volumes as low as ~1 μL.

: The application of microreactors to positron emission tomography (PET) probe radiosynthesis has attracted a great deal of interest because of its potential to increase specific activity and yields of probes and to reduce reaction time, expensive regent consumption, and the footprint of the device/instrument. To develop a microreactor platform that enables the synthesis of various F-labeled PET probes, a prototype microreactor with a novel “split-flow and interflow mixing” (split mixing) was fabricated and applied to F-labeling reactions.

: The split mixing microreactor, made of AlO resistant to several solvents, had higher mixing performance than that of the conventional batch method. Two F-labeling reactions (F labeling of bovine serum albumin (BSA) by N-succinimidyl-4-[F] fluorobenzoate (SFB) and 1-(2′-nitro-1′-imidazolyl)-2-O-tetrahydropyranyl-3-O-toluenesulfonylpropanediol (NITTP) by F) were conducted using the microreactor.

: The F-labeling yield of BSA obtained by using the microreactor was almost the same as that by using the conventional batch method; however, the reaction time of the microreactor was slightly shorter than that of the batch method. Conversely, the F-labeling yield of NITTP obtained by using the microreactor was about half that by using the batch method. The low NITTP-labeling yield was due to adsorption of naked F to the surface of micro-mixing channel in the microreactor. The prescreening of candidate materials with lower F adsorption for the microreactor was carried out with solvent resistance and solvent absorption as indexes. As a result of this prescreening, cyclo olefin polymer (COP) was selected as a candidate. A prototype COP microreactor has been fabricated and is being evaluated in terms of F labeling.

: Although the higher mixing performance of the split mixing microreactor did not significantly contribute to increasing F-labeling yield, it did contribute to shortening reaction time. Moreover, the material used for the microreactor should be carefully selected from the viewpoint of developing a microreactor platform that enables the synthesis of various F-labeled PET probes.

The expression of thymidine phosphorylase (TP) is closely associated with angiogenesis, tumor invasiveness, and activation of antitumor agents. We developed a radiolabeled uracil derivative, I-123-labeled 5-iodo-6-[(2-iminoimidazolidinyl)methyl]uracil ([I]IIMU), as a novel SPECT probe for TP. A clinical study to verify the safety of [I]IIMU injection was approved by the Institutional Review Board of Hokkaido University Hospital for Clinical Research, and first-in-human (FIH) clinical studies of healthy adults were started.

Here, we will introduce our research, including the synthesis of [I]IIMU and its efficacy and safety evaluation, toward its FIH clinical study.

The usage of biomarkers reflecting atherosclerosis progression is important for preventing serious incidence of cardiovascular events. To elucidate clinically relevant molecular determinants in atherosclerosis, we have taken a comprehensive approach to combine mass spectrometry-based differential proteomics using both clinical and animal model specimens. Clinical plasma samples were collected from patients with acute myocardial infarction (AMI), stable angina (SA), and healthy/low-risk individuals (H-LR). We also obtained plasma and arterial tissue samples from apolipoprotein E-deficient and wild-type mice at various pathognomonic points of age. Cleavable isotope-coded affinity tags were used for differential mass spectrometry. Differential proteomics of clinical plasma samples revealed that more than 10 proteins appeared to be upregulated (relative abundance AMI/H-LR or SA/H-LR >1.5) and 5 proteins downregulated (AMI/H-LR or SA/H-LR <1/1.5). These trends associated with the disease progression are not always coincident with those of mouse ortholog proteins, suggesting a pathophysiological difference between humans and the mouse model. Among the downregulated proteins, the complement factor D (CFD) showed monotonic decrease that was in good agreement with the enzyme-linked immunosorbent assay. These results suggest that the comprehensive and systematic proteomic approach may be promising in terms of the selection and evaluation of biomarker candidates.