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This review article discusses the most significant aspects related to the conventional positron emitting radionuclides such as nitrogen-13, oxygen-15, and carbon-11. It is based on a comprehensive forty-year literature review and provides a through overview of the various production methods of these radionuclides, their use in the synthesis of radiopharmaceuticals, and their applications in nuclear imaging. [ABSTRACT FROM AUTHOR]

Oxygen-15 (β+, t1/2 = 122 s) radiolabeled diatomic oxygen, in conjunction with positron emission tomography, is the gold standard to quantitatively measure the metabolic rate of oxygen consumption in the living human brain. We present herein a protocol for safe and effective delivery of [15O]O2 over 200 m to a human subject for inhalation. A frugal quality control testing procedure was devised and validated. This protocol can act as a blueprint for other sites seeking to implement similar imaging programs. [ABSTRACT FROM AUTHOR]

Oxygen-15 (β+, t1/2 = 122 s) radiolabeled diatomic oxygen, in conjunction with positron emission tomography, is the gold standard to quantitatively measure the metabolic rate of oxygen consumption in the living human brain. We present herein a protocol for safe and effective delivery of [15O]O2 over 200 m to a human subject for inhalation. A frugal quality control testing procedure was devised and validated. This protocol can act as a blueprint for other sites seeking to implement similar imaging programs.

Purpose: Oxygen extraction fraction (OEF) is a biomarker for the viability of brain tissue in ischemic stroke. However, acquisition of the OEF map using positron emission tomography (PET) with oxygen-15 gas is uncomfortable for patients because of the long fixation time, invasive arterial sampling, and radiation exposure. We aimed to predict the OEF map from magnetic resonance (MR) and PET images using a deep convolutional neural network (CNN) and to demonstrate which PET and MR images are optimal as inputs for the prediction of OEF maps. Methods: Cerebral blood flow at rest (CBF) and during stress (sCBF), cerebral blood volume (CBV) maps acquired from oxygen-15 PET, and routine MR images (T1-, T2-, and T2*-weighted images) for 113 patients with steno-occlusive disease were learned with U-Net. MR and PET images acquired from the other 25 patients were used as test data. We compared the predicted OEF maps and intraclass correlation (ICC) with the real OEF values among combinations of MRI, CBF, CBV, and sCBF. Results: Among the combinations of input images, OEF maps predicted by the model learned with MRI, CBF, CBV, and sCBF maps were the most similar to the real OEF maps (ICC: 0.597 ± 0.082). However, the contrast of predicted OEF maps was lower than that of real OEF maps. Conclusion: These results suggest that the deep CNN learned useful features from CBF, sCBF, CBV, and MR images and predict qualitatively realistic OEF maps. These findings suggest that the deep CNN model can shorten the fixation time for 15O PET by skipping 15O2 scans. Further training with a larger data set is required to predict accurate OEF maps quantitatively. [ABSTRACT FROM AUTHOR]

Objectives: Measurement of cerebral blood flow (CBF), cerebral blood volume (CBV), cerebral oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO2) by PET with oxygen-15 labeled gases is useful for diagnosis and treatment planning in cases of chronic occlusive cerebrovascular disease. In the present study, CBF, CBV, OEF and CMRO2 were measured using the integrated design of PET/MRI scanner system. This is a first attempt to measure cerebral perfusion and oxygen metabolism using PET/MRI with oxygen-15 labeled gases. Methods: PET/MRI measurements with the steady-state method of oxygen-15 labeled gases, carbon monoxide (C15O), oxygen (15O2), and carbon dioxide (C15O2) were performed on nine healthy men. Two kinds of attenuation correction for PET were performed using MRI with Dixon sequence (DIXON) and Dixon sequence with model-based bone segmentation (DIXONbone). A real-time motion correction of PET images was also performed using simultaneously measured MR images to detect head motion. Results: Mean and SD values of CBF, CBV, OEF, and CMRO2 in the cerebral cortices with attenuation correction by DIXON were 31 ± 4 mL/100 mL/min, 2.7 ± 0.2 mL/mL, 0.40 ± 0.07, and 2.5 ± 0.3 mL/100 mL/min without real-time motion correction, and 33 ± 4 mL/100 mL/min, 2.7 ± 0.2 mL/mL, 0.40 ± 0.07, and 2.6 ± 0.3 mL/100 mL/min with real-time motion correction, respectively. Values with of CBF, CBV, OEF, and CMRO2 with attenuation correction by DIXONbone were 35 ± 5 mL/100 mL/min, 2.8 ± 0.2 mL/mL, 0.40 ± 0.07, and 2.8 ± 0.3 mL/100 mL/min without real-time motion correction, and 38 ± 5 mL/100 mL/min, 2.8 ± 0.2 mL/mL, 0.40 ± 0.07, and 3.0 ± 0.4 mL/100 mL/min with real-time motion correction, respectively. Conclusions: Using PET/MRI with oxygen-15 labeled gases, CBF, CBV, OEF, and CMRO2 could be measured. Values of CBF, CBV, and CMRO2 measured with attenuation correction by DIXON were significantly lower than those measured with correction by DIXONbone. One of the reasons for this is that attenuation correction of DIXON does not take into consideration of the photon absorption by bone. OEF values, corresponding to ratios of CMRO2 to CBF, were not affected by attenuation correction methods. Values of CBF and CMRO2 with a real-time motion correction were significantly higher than those without correction. Using PET/MRI with adequate corrections, similar values of CBF, CBV, OEF, and CMRO2 as PET alone scanner system reported previously were obtained. Trail registration: The UMIN clinical trial number: UMIN000033382. [ABSTRACT FROM AUTHOR]

Positron emission tomography (PET) is a molecular imaging technology that provides quantitative information about function and metabolism in biological processes in vivo for disease diagnosis and therapy assessment. The broad application and rapid advances of PET has led to an increased demand for new radiochemical methods to synthesize highly specific molecules bearing positron‐emitting radionuclides. This Review provides an overview of commonly used labeling reactions through examples of clinically relevant PET tracers and highlights the most recent developments and breakthroughs over the past decade, with a focus on 11C, 18F, 13N, and 15O. PET project: The broad range of possible applications for positron emission tomography (PET) has led to an increased demand for new radiochemical methods to synthesize highly specific molecules bearing positron‐emitting radionuclides. This Review gives an overview of commonly used labeling reactions for producing PET tracers, with a focus on 11C, 18F, 13N, and 15O. [ABSTRACT FROM AUTHOR]

The present study aimed to validate the effects of a novel tungsten-impregnated rubber neck shield on the quality of phantom and clinical O-labeled gas positron emission tomography (PET) images. Images were acquired in the presence or absence of a neck shield from a cylindrical phantom containing [O]HO (phantom study) and from three individuals using [O]CO, [O]O and [O]CO gas (clinical study). Data were acquired in three-dimensional (3D) mode using a Discovery PET/CT 710. Values for cerebral blood flow, cerebral blood volume, oxygen extraction fraction, and cerebral metabolic rate of oxygen with and without the neck shield were calculated from O-labeled gas images. Arterial radioactivity and count characteristics were evaluated in the phantom and clinical studies. The coefficient of variance (CV) for the phantom study and the standard deviation (SD) for functional images were also analyzed. The neck shield decreased the random count rates by 25-59% in the phantom and clinical studies. The noise equivalent count rate (NECR) increased by 44-66% in the phantom and clinical studies. Random count rates and NECR in [O]CO images significantly differed with and without the neck shield. The improvement in visual and physical image quality with the neck shield was not observed in the phantom and clinical studies. The novel neck shield reduced random count rate and improved NECR in a 3D PET study using O-labeled gas. The image quality with the neck shield was similar to that without the neck shield. [ABSTRACT FROM AUTHOR]

Objective: Subject head motion during sequential O positron emission tomography (PET) scans can result in artifacts in cerebral blood flow (CBF) and oxygen metabolism maps. However, to our knowledge, there are no systematic studies examining this issue. Herein, we investigated the effect of head motion on quantification of CBF and oxygen metabolism, and proposed an image-based motion correction method dedicated to O PET study, correcting for transmission-emission mismatch and inter-scan mismatch of emission scans. Methods: We analyzed O PET data for patients with major arterial steno-occlusive disease ( n = 130) to determine the occurrence frequency of head motion during O PET examination. Image-based motion correction without and with realignment between transmission and emission scans, termed simple and 2-step method, respectively, was applied to the cases that showed severe inter-scan motion. Results: Severe inter-scan motion (>3 mm translation or >5° rotation) was observed in 27 of 520 adjacent scan pairs (5.2 %). In these cases, unrealistic values of oxygen extraction fraction (OEF) or cerebrovascular reactivity (CVR) were observed without motion correction. Motion correction eliminated these artifacts. The volume-of-interest (VOI) analysis demonstrated that the motion correction changed the OEF on the middle cerebral artery territory by 17.3 % at maximum. The inter-scan motion also affected CBV, CMRO and CBF, which were improved by the motion correction. A difference of VOI values between the simple and 2-step method was also observed. Conclusions: These data suggest that image-based motion correction is useful for accurate measurement of CBF and oxygen metabolism by O PET. [ABSTRACT FROM AUTHOR]

Abstract: Oxygen utilization is central to the human brain''s high metabolic rate. Measurement of this fundamental process, in both disease and health, has been a focus of research attention over the last 35years. This review plots the course of the use of oxygen-15 to study regional cerebral oxygen extraction and metabolism using Positron Emission Tomography (PET) in disease and in health. The scientific discoveries and resulting conceptual changes to both basic and clinical neuroscience, as well as the new methodological approaches brought about by this area of research, are also summarized. We conclude with a brief overview of the current status of oxygen-15 PET in neuroscience, along with our visions for future developments and applications. [Copyright &y& Elsevier]

Background: Clinical positron emission tomography (PET) requires safe and effective PET radiopharmaceuticals. Tracers used for measuring oxygen consumption and blood volume are [15O]O2 and [15O]CO, respectively. In general, these oxygen-15 labelled tracers are produced using a cyclotron that accelerates deuterons onto a target filled with 14N2 containing a trace of oxygen. In recent years, cyclotrons have been developed that only are capable of accelerating protons. The purpose of this study was to validate and assess such a cyclotron for production and administration of oxygen-15 labelled gasses in an hospital setting. Methods: An RDS111 cyclotron (Siemens-CTI, Knoxville, USA) was validated for bolus production of [15O]O2 and [15O]CO gasses. In addition, equipment was developed to administer these tracers to patients. Results: Both [15O]O2 and [15O]CO gasses could be produced in sufficient amounts, whilst meeting European Pharmacopeia requirements. Although produced oxygen-15 gasses contained a minor level of 11C contamination, in clinical studies it was possible to correct for this contamination by delayed blood counting. Conclusion: An 11 MeV proton cyclotron combined with an in-house developed gas delivery system allows for the production and administration of sufficient amounts of [15O]-gasses for routine clinical PET studies in an hospital setting. [ABSTRACT FROM AUTHOR]

Positron emission tomography (PET) is a nuclear medicine imaging modality based on the administration of a positron-emitting radiotracer, the imaging of the distribution and kinetics of the tracer, and the interpretation of the physiological events and their meaning with respect to health and disease. PET imaging was introduced in the 1970s and numerous advances in radiotracers and detection systems have enabled this modality to address a wide variety of clinical tasks, such as the detection of cancer, staging of Alzheimer's disease, and assessment of coronary artery disease (CAD). This review provides a description of the logic and the logistics of the processes required for PET imaging and a discussion of its use in guiding the treatment of CAD. Finally, we outline prospects and limitations of nanoparticles as agents for PET imaging. [ABSTRACT FROM AUTHOR]

Liposome-encapsulated Hb (LEH) is being developed as an artificially assembled, low-toxicity, and spatially isolated Hb-based oxygen carrier (HBOC). Standard methods of evaluating oxygen carriers are based on surrogate indicators of physiology in animal models of shock. Assessment of actual delivery of oxygen by HBOCs and resultant improvement in oxygen metabolism at the tissue level has been a technical challenge. In this work, we report our findings from 15O-positron emission tomographic (15O-PET) evaluation of LEH in a rat model of 40% hypovolemic shock. In vitro studies showed that PEGylated LEH formulation containing ∼7.5% Hb and consisting of neutral lipids (distearoylphosphatidylcholine:cholesterol:α-tocopherol, 51.4:46.4:2.2) efficiently picks up 15O-labeled oxygen gas. The final preparation of LEH contained 5% human serum albumin to provide oncotic pressure. Cerebral PET images of anesthetized rats inhaling 15O-labeled O2 gas showed efficient oxygen-carrying and delivery capacity of LEH formulation. From the PET images, we determined cerebral metabolic rate of oxygen (CMRO2) as a direct indicator of oxygen-carrying capacity of LEH as well as oxygen delivery and metabolism in rat brain. Compared with control fluids [saline and 5% human serum albumin (HSA)], LEH significantly improved CMRO2 to ∼80% of baseline level. Saline and HSA resuscitation could not improve hypovolemia-induced decrease in CMRO2. On the other hand, resuscitation of shed blood was the most efficient in restoring oxygen metabolism. The results suggest that 15O-PET technology can be successfully employed to evaluate potential oxygen carriers and blood substitutes and that LEH resuscitation in hemorrhage enhances oxygen delivery to the cerebral tissue and improves oxygen metabolism in brain. [ABSTRACT FROM AUTHOR]

Abstract: The “classical” positron emitting radionuclides include oxygen-15, nitrogen-13 and carbon-11 which possess unique properties for medical imaging. They are radionuclides of the fundamental elements of biological matter. They each possess short half-lives which allow their use in designed radiotracers for clinical investigations with minimal risk and they are readily able to be produced in sufficient activities by low energy nuclear reactions. At present several accelerator manufacturers offer production packages for these radionuclides emphasizing targetry with consideration of the cyclotron extracted energies for nuclide production and on-line chemistry systems for the continuous production of specific precursors or radiotracers. Following the installation and acceptance of the MSKCC TR 19/9 Cyclotron, our experience with the procured chemistry module for the preparation of oxygen-15 labeled water has forced us to examine the design and the operation of the synthetic unit with a view toward the state of New York’s regulations addressing the environmental pollution from radioactive materials. The chemistry module was refined with subtle modifications to the chemistry procedure/unit and our experience with the unit is presented as an example of our approach to insure regulatory compliance. [Copyright &y& Elsevier]

In the basic research on cerebral perfusion disorders, a new method for measurement of oxygen extraction fraction (OEF) and cerebral metabolic rate for oxygen (CMRO2) has been desired. Although the O-15-labeled gas inhalation method is performed in clinical studies, application of the inhalation method to small animals requires too many intensive procedures. Therefore, this study investigated a new method of assessing OEF in small animals using intravenously injectable oxygen (injectable 15O-O2). Additionally, it was compared with the inhalation method, using a monkey for further validation. Using injectable 15O-O2, 72 MBq/ml of radioactivity was obtained after 15O-O2 gas circulation into an artificial lung. OEF with injectable 15O-O2 was calculated using the same equation as that applied to the bolus inhalation method. The OEF value obtained by injectable 15O-O2 was well in accordance with that evaluated by the arterial-venous difference of oxygen concentration. Furthermore, the OEF and CMRO2 images obtained with two methods using a monkey brain showed a similar distribution. These results indicate that this method is useful for the estimation of OEF and CMRO2 in small animals using an animal positron emission tomography system and may accelerate the basic research of cerebral perfusion diseases. [Copyright &y& Elsevier]

Oxygen-15 can be roduced using a relatively small cyclotron emitting a deuteron beam with the approximate energy of 3 MeV. However, the neutron emission from the cyclotron itself requires a large scale of shield, causing the total size of the system difficult to be placed at clinical department. We have evaluated a novel idea to reduce the neutron roduction from the cyclotron to a negligible level, and examined if it is applicable to a clinical environment. Systematic physics experiments were carried out using a Tandem Van de Graaff accelerator to validate the feasibility of our approach, in which the neutron production was assessed for realistic energy ranges of deuteron. It was shown that neutron production was reduced dramatically by a factor of 10 to the fourth using our approach, whilst enough amount of oxygen-15 was roduced. This study suggested that a small oxygen-15 generator is possible which could be laced next to existing clinical PET cameras. [Copyright &y& Elsevier]

In the basic research about cerebral perfusion disorders, a new method for measurement of oxygen extraction fraction (OEF) and cerebral metabolic rate for oxygen (CMRO2) has been desired. Although O-15-labeled gas inhalation method is performed in clinical studies, application of the inhalation method to small animals requires too many intensive procedures. Therefore, this study investigated a new method of assessing OEF in small animals using intravenously injectable oxygen (injectable 15O-O2). Moreover, OEF after transient ischemia–reperfusion was estimated to validate the usefulness of the method. Injectable 15O-O2, 72 MBq/ml of radioactivity, was obtained after 15O-O2 gas circulation into the artificial lung. OEF after injection of injectable 15O-O2 was calculated using the same equation as that applied to the bolus inhalation method. OEF value obtained by injectable 15O-O2 was well in accordance with that evaluated by arterial-venous difference of oxygen concentration. Furthermore, misery perfusion was depicted in the lesioned hemisphere after transient ischemia–reperfusion. These results indicated that this method is useful for the estimation of OEF and CMRO2 in small animals using an animal positron emission tomography (PET) system and may accelerate the basic research of cerebral perfusion diseases. [Copyright &y& Elsevier]

The production of copious quantities of 15O, (half-life = 122.2 s) for astrophysical applications has been a source of concern at TRIUMF and ISAC for some time. An 15O beam is needed for two experiments (15O(α,γ)19 Ne and 15O(6Li,d)19Ne) at ISAC. The beam flux required for these experiments is extremely high, (between 109 and 1011 15O/s) and thus high efficiencies at all steps in the process will be required. Difficulties arise due to the fact that oxygen is very reactive chemically and thus is difficult to extract from a thick spallation target. The possibility of using one of the small cyclotrons on site (TR13, CP42 or TR30) for the production of this isotope (15O) has been discussed. This production approach will involve the use of low energy protons to interact with a nitrogen gas target via the 15N(p,n)15O reaction, which is accessible with attainable particle energies using these cyclotrons.Preliminary results using the 14N(d,n)15O reaction as a model for the 15N(p,n)15O reaction have been obtained and is presented describing the appropriate on-line chemistry to separate, trap, purify and transfer the 15O. The 15O will be converted to the preferred chemical form of C15O which will be available for introduction into an ECR ion source for the production of the high intensity 15O ion beam at ISAC. [Copyright &y& Elsevier]

15 O (half-life, 122 s) is a useful radionuclide for PET applications. Current production of 15 O typically makes use of the 14 N(d,n) 15 O, 15 N(p,n) 15 O, or 16 O(p,pn) 15 O reactions using an accelerator. A novel approach for the production of 15 O is via the 16 O(γ,n) 15 O reaction using an electron linear accelerator. Photonuclear reactions using an electron linear accelerator may allow for feasible and economical production of 15 O compared with the current methods. Methods: In this work, experiments using a repurposed Clinac were conducted using oxygen-containing alumina as a target material to study the production rate of 15 O. Additional studies were conducted using a water target cell. Simulations using Geant4 were conducted to predict the activity and power dissipation in the target. Results: Bremsstrahlung radiation from the electron beam, and consequently 15 O production via photonuclear reactions, is enhanced when a high- Z material, tungsten, is placed in front of the target. The alumina irradiations provided preliminary data to optimize the beam parameters and target configuration. The optimal thickness of tungsten was 1.4 mm for both the simulated and the measured studies of alumina. Simulations of irradiated water targets showed that tungsten thicker than 1.4 mm resulted in fewer photons available to activate the water; thus, a higher current was required to achieve a fixed dose. Alternatively, for a constant tungsten thickness, more power was deposited in the target with increasing beam energy, requiring a lower current to achieve a fixed dose. Actual irradiations of a water target yielded a quantity of 15 O in the water that was consistent with expectations based on irradiations of alumina. Conclusion: Several parameters should be considered regarding the photonuclear production of 15 O for an average patient dose of 1,850 MBq (50 mCi) in 10 mL. This work illustrates a variety of machine parameters capable of achieving a reasonable patient dose. Our simulations show that the power deposited in the target for these parameters is less than that in commercially operated cyclotron targets for the production of 18 F. Thus, this work demonstrates that the photonuclear production of 15 O may be a new production path for this useful radionuclide., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

Positron emission tomography (PET) is a molecular imaging technology that provides quantitative information about function and metabolism in biological processes in vivo for disease diagnosis and therapy assessment. The broad application and rapid advances of PET has led to an increased demand for new radiochemical methods to synthesize highly specific molecules bearing positron-emitting radionuclides. This Review provides an overview of commonly used labeling reactions through examples of clinically relevant PET tracers and highlights the most recent developments and breakthroughs over the past decade, with a focus on 11 C, 18 F, 13 N, and 15 O., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)