Principles of quantitative positron emission tomography

Summary. The central distinguishing feature of positron emission tomography (PET) is its ability to investigate quantitatively regional cellular and molecular transport processes in vivo with good spatial resolution. This review wants to provide a concise overview of the established principles underlying quantitative data evaluations of the acquired PET images. Especially, the compartment modelling framework is discussed on which virtually all quantification methods utilized in PET are based. The aim of the review is twofold: first, to provide the reader with an idea of the theoretical framework and mathematical tools and second, to enable an intuitive grasp of the possibilities and limitations of a quantitative approach to PET data evaluation. This should facilitate an understanding of how PET measurements translate into quantities such as regional blood flow, volume of distribution, and metabolic rates of specific substrates.     

Radiopharmaceutical chemistry for positron emission tomography

Radiopharmaceutical chemistry includes the selection, preparation, and preclinical evaluation of radiolabeled compounds. This paper describes selection criteria for candidates for positron emission tomography (PET) investigations. Practical aspects of nucleophilic and electrophilic (18)F-fluorinations and (11)C-methylations are described. These aspects include production of fluorine-18 and carbon-11, workup of fluorine-18, (18)F radiochemistry, production of [(11)C]methyl iodide and triflate, and (11)C-methylation radiochemistry.     

Targeting peptides and positron emission tomography

Biologically active peptides have during the last decades made their way into conventional nuclear medicine diagnosis using single photon emission computed tomography (SPECT) and gamma-camera. Several clinical trails are also investigating the role of radiolabeled peptides for targeting radionuclide therapy. This has raised the question as to whether positron emission tomography (PET) can be used in order to obtain better quantitative information of the peptide distribution in tumor and healthy organs, i.e., to get a better dosimetry. Positron emitting analogs of the therapeutic radionuclides used have been produced and successfully applied in peptide pharmacokinetic measurements with PET. But the recent boom in (18)FDG-PET ((18)FDG = [(18)F]2-deoxy-2-fluoro-D-glucose), and with this a worldwide increasing number of PET systems, has also inspired several research groups to hunt for alternative labels to be used for peptide diagnostics and PET. The rapid kinetic of short peptides agrees well with the short half-lives of standard PET nuclides like (11)C and (18)F. Especially, (18)F appears to be excellent for labeling bioactive peptides due to its favorable physical and nuclear characteristics. However, with present techniques labeling peptides with (18)F is laborious and time-consuming, and is not yet a clinical alternative. Other halogens like (75, 76)Br and (124)I are, from the chemical point of view, easier to apply. But an even better labeling alternative may be positron emitting metal ions like (55)Co, (68)Ga, and (110m)In since they tend to give better intracellular retention and thus a better signal-to-background ratio than the halogen labels. The main drawback with these radionuclides is that they are not readily available. Some of these radionuclides also emit gamma in their decay that may affect the measuring properties of the PET equipment. This article reviews mainly the present situation of production and use of nonconventional positron emitters for peptide labeling.     

Muscle use during double poling evaluated by positron emission tomography

Due to the complexity of movement in cross-country skiing (XCS), the muscle activation patterns are not well elucidated. Previous studies have applied surface electromyography (SEMG); however, recent gains in three-dimensional (3D) imaging techniques such as positron emission tomography (PET) have rendered an alternative approach to investigate muscle activation. The purpose of the present study was to examine muscle use during double poling (DP) at two work intensities by use of PET. Eight male subjects performed two 20-min DP bouts on separate days. Work intensity was ～ 53 and 74% of peak oxygen uptake (Vo(2peak)), respectively. During exercise 188 ± 8 MBq of [(18)F]fluorodeoxyglucose ([(18)F]FDG) was injected, and subsequent to exercise a full-body PET scan was conducted. Regions of interest (ROI) were defined within 15 relevant muscles, and a glucose uptake index (GUI) was determined for all ROIs. The muscles that span the shoulder and elbow joints, the abdominal muscles, and hip flexors displayed the greatest GUI during DP. Glucose uptake did not increase significantly from low to high intensity in most upper body muscles; however, an increased GUI (P < 0.05) was seen for the knee flexor (27%) and extensor muscles (16%), and for abdominal muscles (21%). The present data confirm previous findings that muscles of the upper limb are the primary working muscles in DP. The present data further suggest that when exercise intensity increases, the muscles that span the lumbar spine, hip, and knee joints contribute increasingly. Finally, PET provides a promising alternative or supplement to existing methods to assess muscle activation in complex human movements.     

Regional lung water and hematocrit determined by positron emission tomography

We have measured with positron emission tomography (PET) the regional distribution of extravascular lung water (EVLW) and hematocrit (HctL) in normal supine dogs. H2(15)O and C15O were used as total lung water (TLW) and intravascular water (IVW) compartment labels, respectively. An additional plasma volume label (68Ga-transferrin) was used to determine regional HctL. EVLW was calculated as the difference between TLW and IVW. In 13 dogs, EVLW was relatively constant along a gravity-dependent vertical gradient, although values in the most anterior regions were statistically less (P less than 0.05) than those in more posterior ones. The average value for EVLW (13 dogs) was 14.4 +/- 2.5 ml H2O/100 ml lung. When EVLW was compared with IVW on a regional basis, the EVLW/IVW ratio decreased significantly in a gravity-dependent direction from 1.95 +/- 0.28 to 0.88 +/- 0.18. In 7 dogs, no significant difference between HctL and systemic hematocrit (average ratio 1.01 +/- 0.08) was found nor was any significant variation of HctL within the lung detected. Thus, in contrast to gravimetric techniques, a hematocrit correction does not appear to be necessary when regional EVLW is studied by PET.     

In vivo characterization of myocardium muscarinic receptors by positron emission tomography

The feasibility of studying myocardium muscarinic receptors, non invasively, in a “live” being can be demonstrated using positron emission tomography (PET) and a ligand labelled by carbon 11, an externally detectable short lived radionuclide. Criteria necessary for in vitro characterization of muscarinic receptors by a specific ligand were verified in vivo by this method. This demonstration was carried out after injecting in a baboon, high specific activity ¹¹C-MQNB (the methiodide salt of quinuclidinyl benzylate) a muscarinic antagonist drug, and displacing the radioactive ligand by increasing amounts of atropine. Displacement was proportionnal to the dose of atropine and a correlation was observed between displacement and pharmacological activity (increase of heart rate). Stereospecificity of the binding was also demonstrated by using two stereoisomers of benzetimide : dexetimide and levetimide.     

Visualization by positron emission tomography of the apparent regional heterogeneity of central type benzodiazepine receptors in the brain of living baboons

The feasibility of visualizing the heterogeneity of benzodiazepine (BDZ) receptors in the brain of living baboons was investigated using Positron Emission Tomography. Ethyl 8-fluoro-5,6-dihydro-5-methyl 6-oxo-4H-imidazo (1,5-a) (1, 4) benzodiazepine-3-carboxylate (RO 15 1788) labelled by carbon 11 (11C-RO 15 1788) was I.V. injected for the "in vivo" labelling of the central type BDZ receptors. Displacement experiments were performed 20 minutes after the administration of the radioligand by two different cold drugs: RO 15 1788 which has an equal affinity for central type BDZ receptors, and propyl B-Carboline-3-carboxylate (B-CCP) which favours the sites located in the cerebellum. Different sensitivities to these two drugs displacement of 11C-RO 15 1788 binding "in vivo" were observed: on the one hand in the regional localization of the displacement, and on the other hand, in the amount of the radioactivity displaced. The apparent interregional heterogeneity of the displacement seen in the cerebellum and in the temporal cortex are discussed in terms of discrepancies observed "in vitro" at physiological temperature, between cerebellar and non-cerebellar BDZ central type binding sites.     

Regional changes in extravascular lung water detected by positron emission tomography

Regional measurements of extravascular lung water (rEVLW) were made with positron emission tomography (PET) and 15O-labeled radionuclides. The label used to measure the total lung water (TLW) content fully equilibrated with TLW prior to scanning in both dogs with normal and low cardiac outputs, and nearly so in areas of lung made edematous by oleic acid injury (the TLW values used were 97% of maximum values). Regional EVLW measurements made by PET (EVLW-PET) and gravimetric techniques in both normal and edematous lung were closely correlated (r = 0.93), and EVLW-PET increased from an average of 0.20 to 0.37 mlH2O/ml lung (P less than 0.05) after regional lung injury. PET measurements of regional blood volume always decreased [from an average of 0.12 to 0.09 ml blood/ml lung (P less than 0.05)] after cardiac output was lowered by hemorrhage in a separate set of animals. Total EVLW (by thermodye indicator dilution) did not change. Likewise, regional EVLW remained constant in areas below the left atrium but decreased in areas above the left atrium. We conclude that PET measurements are accurate, noninvasive, and reproducible and that regional changes may be detected even when measurements of total EVLW by other methods may fail to change significantly.     

Visualizing lung function with positron emission tomography.

Positron emission tomography (PET) provides three-dimensional images of the distributions of radionuclides that have been inhaled or injected into the lungs. By using radionuclides with short half-lives, the radiation exposure of the subject can be kept small. By following the evolution of the distributions of radionuclides in gases or compounds that participate in lung function, information about such diverse lung functions as regional ventilation, perfusion, shunt, gas fraction, capillary permeability, inflammation, and gene expression can be inferred. Thus PET has the potential to provide information about the links between cellular function and whole lung function in vivo. In this paper, recent advancements in PET methodology and techniques and information about lung function that have been obtained with these techniques are reviewed.     

Measuring drug-related receptor occupancy with positron emission tomography

Several techniques can be used to measure indirectly the effect of drugs (e.g., EEG, fMRI) in healthy volunteers and in patients. Although each technique has its merits, a direct link between drug efficacy and site of action in vivo usually cannot be established. In addition, when the specific mode of action of a drug has been determined from preclinical studies, it is often not known whether the administered dose is optimal for humans. Both industry and academia are becoming more and more interested in determining the dose-related occupancy of specific targets caused by administration of drugs under test. Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) are noninvasive imaging techniques that can give insight into the relationship between target occupancy and drug efficacy, provided a suitable radioligand is available. Although SPECT has certain advantages (e.g., a long half-life of the radionuclides), the spatial and temporal resolution as well as the labeling possibilities of this technique are limited. This review focuses on PET methodology for conducting drug occupancy studies in humans.     

Small animal positron emission tomography in food sciences

Summary. Positron emission tomography (PET) is a 3-dimensional imaging technique that has undergone tremendous developments during the last decade. Non-invasive tracing of molecular pathways in vivo is the key capability of PET. It has become an important tool in the diagnosis of human diseases as well as in biomedical and pharmaceutical research. In contrast to other imaging modalities, radiotracer concentrations can be determined quantitatively. By application of appropriate tracer kinetic models, the rate constants of numerous different biological processes can be determined. Rapid progress in PET radiochemistry has significantly increased the number of biologically important molecules labelled with PET nuclides to target a broader range of physiologic, metabolic, and molecular pathways. Progress in PET physics and technology strongly contributed to better scanners and image processing. In this context, dedicated high resolution scanners for dynamic PET studies in small laboratory animals are now available. These developments represent the driving force for the expansion of PET methodology into new areas of life sciences including food sciences. Small animal PET has a high potential to depict physiologic processes like absorption, distribution, metabolism, elimination and interactions of biologically significant substances, including nutrients, ‘nutriceuticals’, functional food ingredients, and foodborne toxicants. Based on present data, potential applications of small animal PET in food sciences are discussed.     

Studying the biodistribution of positron emission tomography reporter probes in mice

Positron emission tomography (PET) reporter probes (PRPs) are used to detect PET reporter gene (PRG) expression in living subjects. This article details protocols for analyzing the biodistribution of a PRP used to detect herpes simplex virus 1 thymidine kinase (HSV1-tk) or mutant HSV1-sr39tk PRG expression. However, the methods described are generalizable to other beta- or gamma/positron-emitting probes. Accumulation of PRPs in animal tissues can be determined by counting PRP activity of isolated tissues, whereas digital whole-body autoradiography (DWBA) provides high-resolution images of PRP biodistribution in 5- to 45-microm tissue slices of killed research animals at a single time point. Biodistribution assay results may be obtained in less than a week after beginning the assay, and DWBA image acquisitions can take up to 3 months depending on the probe's radioisotope.     

Approaches to the design of biochemical probes for positron emission tomography

Since the development of the 2-deoxy-D-glucose procedure by L. Sokoloff considerable advances have been made in the design of radiotracers for estimation of in-vivo biochemical parameters. Many of these advances are due to the development of positron emission tomography. As a result key biochemical processes can now be evaluated with newly developed positron-emitting labeled enzyme probes in man, in-vivo, allowing the study of a wide range of specific cellular processes in health and disease states.Special issue dedicated to Dr. Louis Sokoloff.     

Small-animal imaging using clinical positron emission tomography/computed tomography and super-resolution

Considering the high cost of dedicated small-animal positron emission tomography/computed tomography (PET/CT), an acceptable alternative in many situations might be clinical PET/CT. However, spatial resolution and image quality are of concern. The utility of clinical PET/CT for small-animal research and image quality improvements from super-resolution (spatial subsampling) were investigated. National Electrical Manufacturers Association (NEMA) NU 4 phantom and mouse data were acquired with a clinical PET/CT scanner, as both conventional static and stepped scans. Static scans were reconstructed with and without point spread function (PSF) modeling. Stepped images were postprocessed with iterative deconvolution to produce super-resolution images. Image quality was markedly improved using the super-resolution technique, avoiding certain artifacts produced by PSF modeling. The 2 mm rod of the NU 4 phantom was visualized with high contrast, and the major structures of the mouse were well resolved. Although not a perfect substitute for a state-of-the-art small-animal PET/CT scanner, a clinical PET/CT scanner with super-resolution produces acceptable small-animal image quality for many preclinical research studies.     

Assessing skeletal muscle glucose metabolism with positron emission tomography

Insulin has a marked effect to stimulate the transport and metabolism of glucose in skeletal muscle in healthy individuals, whereas an impaired response, termed insulin resistance, is a major risk factor for diabetes mellitus and other metabolic diseases. Studies of the molecular physiology of insulin action in skeletal muscle indicate that a principal loci of control resides within the proximal steps of glucose transport and phosphorylation. Deoxyglucose, the metabolism of which is limited to these proximal steps, is widely used for in vitro studies of insulin action on glucose transport. The technologies of PET imaging provide a unique opportunity to carry out similar studies in vivo in human skeletal muscle. In this instance, a short-lived positron labeled tracer, [18F] FDG, can be given at sufficiently high specific activity to image not only glucose uptake, but by dynamic PET imaging, by monitoring the time course of [18F] FDG tissue activity, data can be generated to examine the kinetics of glucose transport and phosphorylation. The experimental procedures of this approach, including an overview of the mathematical modeling, are described in this review, along with some of the key findings of the initial applications of PET for the study of glucose metabolism in human skeletal muscle.     

Regional lung hematocrit in humans using positron emission tomography

Regional lung hematocrit ratio (R) was measured in five normal subjects and five patients (2 with pneumonia, 2 with nephrotic syndrome with anemia, and 1 with pancreatitis) using positron emission tomography, a red cell marker 11CO, and a plasma marker [methyl-11C]albumin). The measurements were made in a transaxial thoracic section at midheart level with the subject in supine posture and with a spatial resolution of 1.7 cm. The normal regional hematocrit ratio (means +/- SE) calculated for the lung was 0.90 +/- 0.014, 0.94 +/- 0.023 for the thoracic wall, and 1.00 +/- 0.003 for the heart chambers. The regional lung hematocrit ratio in the patients ranged between 0.81 and 0.86. No correlation was found among the regional lung hematocrit ratio and regional blood volume, lung extravascular density, and the peripheral hematocrit (obtained from venous blood samples). To the extent that 70% of the pulmonary blood in the field of view is in larger vessels with normal hematocrit, the hematocrit in the capillary bed is approximately two-thirds that of the peripheral venous value. Blood volume measurements on the basis of single vascular tracers need to take account of these results.     

Use of positron emission tomography to study tumors in vivo

Positron emission tomography (PET) is a non-invasive imaging technique. The ability of PET to visualize biochemistry and physiology in vivo distinguishes this technique from other imaging modalities and renders it of particular interest for oncological studies. PET studies can of en differentiate between normal and neoplastic tissue, as well as identify early signs of malignant degeneration through biochemical or physiological changes. Over the past several years, PET studies have been useful in the early diagnosis and the selection of treatment, as well as in following the progression or regression of malignant disease processes. Of particular significance, PET findings can be quantified by using mathematical modeling and computerized data analysis, which makes it possible to produce quantitative images of human pathophysiology in vivo.