Proof That Mouse and Human Metabolism and Biodistribution Is Similar

Isolation Mice Hepatocytes

To apply the information obtained in the knockout mice to humans, mouse and human metabolism were compared using hepatocytes 54 . To this end, the metabolic profile of FP-TZTP was studied in rat and human hepatocytes using liquid chromatography and mass spectrometry and, when possible, compared with independently synthesised standards. In both human and rat hepatocytes, the major metabolite results from oxidation of the nitrogen in the 1-methyltetrahydropy-ridine ring. Other metabolites result...

Electromagnetic Radiation

Electromagnetic radiation is pure energy. The amount of energy associated with each bundle, or quantum, of energy is determined by the wavelength (A) of the radiation. Human senses are capable of detecting some forms of electromagnetic radiation, for example, thermal radiation, or heat, (A 10-5m), and visible light (A 10-7m). The energy of the radiation can be absorbed to differing degrees by different materials light can be stopped (absorbed) by paper, whereas radiation with longer wavelength...

References

International Commission on Radiological Protection. 1990 Recommendations of the International Commission on Radiological Protection. ICRP Publication 60. Oxford Pergamon Press, 1991. 2. International Commission on Radiation Units and Measurements. Determination of Dose Equivalents Resulting from External Radiation Sources. ICRU Report No. 39. Bethesda, MD ICRU, 1985. 3. Dillman LT. Radionuclide decay schemes and nuclear parameters for use in radiation-dose estimation. MIRD Pamphlet No. 4. J...

Lung Carcinoma

There have been numerous studies examining the accuracy of 18F -FDG PET in evaluating solitary pulmonary nodules 32,33 . Analysis of the published data has shown a high sensitivity (average 96 ) and accuracy (average 94 ) for determining malignancy (Figs. 16.2 and 16.3 2,8,34 . The specificity is also high but the variation is slightly greater and is dependent on the local prevalence of the known causes of false posi- Figure 16.2. Coronal sections of a 18F -FDG PET scan performed in a...

Accelerating Drug Discovery

The second SNIDD symposium, which was held in October 2000 16 , discussed whether the use of PET can be implemented fast enough to compensate for the increased time and expense of these studies by decreasing the number of studies that must be completed. The goal of the second SNIDD conference was to discuss how the drug discovery process could be accelerated using well-established radiopharmaceuticals, such as 15O water for blood flow and 2- 18F -fluoro-2-deoxyglucose ( 18F -FDG) for glucose...

Activity kBqml

Pulses are sent down the second circuit to a counter. However, if a signal is being processed on the measurement circuit, a gate is closed on the second circuit for the duration of the processing, preventing pulses from reaching the counter. The number of pulses observed by the counter is then approximately proportional to the live time of the measurement circuit. Other schemes for measuring dead time are described in 27 . Dead time models usually treat system dead time as being separable into...

Analytic 2D Reconstruction Properties of the Xray Transform

In this section, we solve the inverse 2D x-ray transform. A closed-form solution of the integral equation, Eq. (3) is first derived assuming a continuous sampling of the sinogram variables over (s, 0) e Rp,Rp 0, n . An approximation to this exact solution will then be written in terms of the discrete data samples (defined by Eq. (5)), leading to the standard filtered-backprojection algorithm (FBP). We refer for this section to the comprehensive books by Natterer 2,4 , Kak and Slaney 5 , Barrett...

Artefacts

Chemoresistance Apoptosis

Image reconstruction of PET images without attenuation correction may lead to higher apparent activity in superficial structures, that may obscure lesions e.g. cutaneous melanoma metastases 28 . A common artefact arising from this phenomenon is caused by the axillary skin fold, where lymphadenopathy may be mimicked in coronal image sections. However, the linear distribution of activity can be appreciated on transaxial or sagittal slices and should prevent misinterpretation. Another major...

Attenuation Correction Using Coincidence Transmission Data

The most common approach has been to use a long-lived positron emitter, such as 68Ge-68Ga (68Ga is the positron emitter and 68Ge is its parent isotope with a half-life of 271 days), and measure the annihilation photons in coincidence as they pass through the body from an external source. A transmission scan typically takes 2-10 minutes to acquire and may be performed before or after the PET tracer is administered. However, it is not uncommon to perform transmission scans after tracer...

Attenuation Correction Using CT Data

With the advent of dual modality scanners capable of acquiring PET and CT data during the same imaging session, there has been considerable effort put into developing methods to make use of CT data for PET attenuation correction (Fig. 5.18c). The potential advantages of this approach arise because the statistical quality and spatial resolution of CT data is far superior to conventional transmission data used in PET, and because a whole body CT can be acquired in less than 1 minute using current...

Axial Block Profile Factors b aX and Axial Geometric Factors g

The axial block profile factors may be calculated from an acquisition of a central uniform right cylinder source. If scatter is not significant, the calculation is straightforward - the total counts Cu in each of the direct plane (i.e., ring difference 0) sinograms are computed, and the bUx are then given by where Cu is the mean value of the total counts in each sinogram. In 3D imaging, the amount of scatter can be large, and more importantly, the distribution can vary in the axial direction....

Brain Tumours

Brain tumours are a common and often devastating malignancy that impacts on both paediatric and adult populations. In adults, brain tumours are the leading cause of death for males aged 15 to 34 years, and are the fourth commonest cause of cancer death in females of this age group. Paediatric brain tumours are the second commonest cancer, and the second leading cause of death from cancer, in that age group 23, 24 . The evaluation of brain tumours with 18F -FDG PET is the longest established...

Labeling Strategies Biological Considerations

In order to address a given biological, pharmacological or medical question, the design of labeled tracer molecules need special consideration and there are a few points which need to be addressed (i) The labeling position must be considered since the metabolic pathway of the compound might have an impact on the interpretation of the PET data, (ii) Labeling in different positions in the molecule may give additional information. An illustration of this is nC-labeled L-DOPA and...

Calculated Attenuation Correction

Since a transmission scan adds significantly to the time it takes to perform a PET study, alternative methods of attenuation correction have been investigated. One method, which assumes a regular geometric body outline and constant tissue density, is commonly referred to as calculated (as opposed to measured) attenuation correction. This may be valid for brain studies, particularly if the skull is taken into account as well as the soft tissue of the brain. The attenuation factors are calculated...

Cancer Diagnosis and Management

Although FDG is by far the most important radiophar-maceutical at present others such as 11C-labelled methionine and choline and fluorine labelled DNA proliferation markers such as fluoro-L-tyrosine (FLT) will have an increasing role in the years ahead. The applications can be classified according to the generic use for which the PET scan is applied, that is detection, staging tumour response, etc or by tumour types. Both are important to understand although the tumour type approach will be the...

Cardiology and Cardiac Surgery

At present there are three major indications for PET scans using two physiological measurements in clinical practice. The two measurements are (i) to measure the myocardial perfusion using 13N -ammonia (or 82Rb from an on-site generator) and (ii) to measure myocardial viability (using 18F -FDG). There is increasing interest in a third measurement, cardiac innervation by studying myocardial receptors, which may have a greater role in the future. The three applications of these measurements are...

Case Method Analysis of the Drug Discovery Process Using External Imaging

The Society of Noninvasive Imaging in Drug Development (SNIDD) was formed in 1990 by a small Figure 17.1. The percent injected dose per gram ( ID g) in rat brain for 18F -FP-TZTP as a function of the co-injected dose of P-TZTP. Tissues assayed are cortex (Ctx), hippocampus (Hippo), striatum (Striat), thalamus (Thai), pons, medulla (Medu) and cerebrum (Cb). Blood Ctx HippoStriat Thal PonsMedu Cb Blood Ctx HippoStriat Thal PonsMedu Cb Figure 17.1. The percent injected dose per gram ( ID g) in rat...

Characteristics of Scattered Radiation

When a positron annihilates in the body, there is a reasonable chance that one or both of the annihilation photons will scatter in the body or in the detector itself. At the energy of annihilation photons (0.511 MeV), the most likely type of interaction is Compton scattering in which the photon transfers some of its energy to loosely bound electrons and deviates from its initial path 35 . Since the coincidence LOR formed after one or both photons undergo Compton scattering is no longer colinear...

Chemistry of Gallium

Gallium is a group 13 element and exists most commonly in the +3 oxidation state. While lower oxidation states have been observed, all relevant radiopharma-ceuticals occur in this oxidation state. Similar to other group 13 elements (B, Al, and In), Ga3+ is classified as a hard acid, bonding strongly to highly ionic, non-po-larizable Lewis bases. As a result, gallium chemistry is dominated by ligands containing oxygen and nitrogen donor atoms 36 . There are two requirements for using gallium...

Clinical Researchdiagnostic Question

Selected Physiological Pharmacokinetic Pathway or Molecular Target Tracer Molecule & Radiolabelling Position Radiochemical yield, spec.act. & purity In vivo and in vitro testing Max.administered dose of radioactivity - Formulated biological model Scanner spatial & temporal resolution, . . Corrections for attenuation scatter, random normalisation, sensitivity and field-of-view events and scanner dead time Scan protocol Blood and radiolabelled metabolite analysis Reconstruction method...

Colorectal Carcinoma

Staging of Primary Colorectal Cancer The diagnosis of colorectal cancer is principally based on colonoscopy and biopsy, with imaging being performed primarily to assist in initial surgical planning. There have been a number of studies examining the utility of PET for staging primary colorectal carcinoma. In one study of 16 patients with known or suspected primary or recurrent colon and rectal cancer studied with 18F -FDG PET and CT scans, PET detected all 12 sites of disease in bowel, whereas...

Compartmental Modeling

Compartmental modeling is the most commonly used method for describing the uptake and clearance of ra dioactive tracers in tissue 28, 30, 31 . These models specify that all molecules of tracer delivered to the system (i.e., injected) will at any given time exist in one of many compartments. Each compartment defines one possible state of the tracer, specifically its physical location (for example, intravascular space, extracellular space, intracellular space, synapse) and its chemical state...

Compartmental Modeling Assumptions

The successful application of simple compartmental models to a complex biological system requires that many assumptions be true. These assumptions are typically not completely valid, so that successful use of these models depends upon whether errors in these assumptions produce acceptable errors in model measurements (see Error Analysis, below). Compartmental models, by their nature, assume that each compartment is well mixed, i.e., there are no concentration gradients within a single...

Conservation Laws

The principle of the conservation of fundamental properties comes from classical Newtonian physics. The concepts of conservation of mass and conservation of energy arose independently, but we now see that, because of the theory of relativity, they are merely two expressions of the same fundamental quantity. In the last 20-30 years the conservation laws have taken on slightly different interpretations from the classical ones previously they were considered to be inviolate and equally applicable...

Copper bis thiosemicarbazones

One of the most commonly used Cu(II)-bis(thio-semicarbazone) is ( Cu PTSM), (Fig. 11.5). 62 64Cu PTSM is a highly lipophilic complex, and is used as a blood flow tracer. Following administration of 62 64Cu PTSM, tissue uptake is rapid, and the tracer is trapped in most major tissues such as the brain 77-80 , heart 77, 78, 81 , and tumors 82-85 . Tissue retention of 62 64Cu PTSM and other frzs(thiosemicar-bazone) derivatives is believed to result when the lipophilic complex diffuses across the...

Copperlabeled Antibodies Proteins and Peptides

64Cu has labeled monoclonal antibodies (MAbs), proteins, and peptides for PET imaging. Copper is most commonly attached via macrocyclic ligands such as TETA acid), BAD N,N',N,N'-tetraacetic acid), CPTA Figure 11.5. Cu(II) bis(thiosemicarbazone) complexes, Cu PTSM and Cu ATSM. acid)) and DOTA acid). Schematic representations of these ligands are shown in Fig. 11.7. Direct labeling of Cu(I) to antibodies has also been attempted. Stannous tartrate was used to reduce disulfide groups, which then...

Correlation of Voxel Intensities

A slight relaxation of the assumption that registered images differ only by noise is that image intensities are strongly correlated. The correlation coefficient has been widely used in intramodality registration, for example 38 , and is given by where A is the mean voxel value in image A qtas and B is the mean of B r nr s.

Count Rate Performance

Count rate performance refers to the finite time it takes the system to process detected photons. After a photon is detected in the crystal, a series of optical Figure 3.17. The energy spectra for single photons for a BGO PET system. The air and scatter measurements are of a 68Ge line source in air and in a 20 cm-diameter water-filled cylinder respectively, while the distributed source is for a solution of 18F in water in the same cylinder, to demonstrate the effect on energy spectrum of a...

Crest Lines and Other Geometric Features

An alternative to using pre-segmented surfaces is to use distinctive surface features defined by their local geometry. Using the tools of differential geometry it is possible to define two principal curvatures of a surface in 3D space. A crest line is an indication of a ridge in the surface and is defined as the loci of points where the value of the largest curvature is locally maximal in its principal direction 35 . Registration between two images proceeds by applying the ICP algorithm to...

Cu62Zn Generator

62Cu is the daughter isotope of 62Zn and is obtained by eluting the 62Cu 62Zn generator 25, 26 . Due to the short half-life of 62Cu (t- 9.76 m), its production is well suited to a generator. The relatively short half-life of the parent (62Zn, t- 9.13 h) means that these generators must be replaced every few days. An automated 62Cu 62Zn generator that produces the perfusion agent (PTSM) has been used in clinical trials 27 .

Cyclotron PET Radionuclide Production

In general, the majority of radionuclides used in PET imaging are produced by cyclotrons, either on-site or at a site near the scanner. Table 11.1 lists many of the metal PET isotopes produced by a cyclotron. Isotopes that have a suitable half-life (64Cu, 66Ga, 86Y) can potentially be transported over a long distance from the cyclotron facility. The following section contains a brief description of the more commonly used cyclotron-produced metal PET isotopes.

Analytic Reconstruction by Rebinning

The high sensitivity of a PET scanner operated in 3D mode is directly related to the large number of sampled LORs, which is much larger than the number of reconstructed pixels NLOR > > P (by a factor proportional to Nr). We have already mentioned in the previous section that this data redundancy results in the non-uniqueness of the reconstruction filter. From the practical point of view, redundancy increases the data storage requirements and the computational load for reconstruction and...

Data Organization Line of Responses

A PET scanner counts coincident events between pairs of detectors. The straight line connecting the centers of two detectors is called a line of response (LOR). Unscattered photon pairs recorded for a specific LOR arise from annihilation events located within a thin volume centered around the LOR. This volume typically has the shape of an elongated parallelipiped and is referred to as a tube of response. To each pair of detectors da,db is associated an LOR Ld,db and a sensitivity function y...

Filtered Backprojection

Following the same lines as for the 2D FBP inversion, Eq. (58) leads to a two-step inversion formula for a set of non-truncated 2D projections with orientations n e Q, where Q is a subset of the unit sphere that satisfies Orlov's condition. The reconstructed image is a 3D backprojection which, as in 2D, is the sum of the filtered projections pF for all lines containing the point r. The filtered projections are given by pF (s,n) J ds' p(S ,n)hC (s - s',n) In this equation, the 2D convolution...

Definition of the Problem

A coincidence event requires the simultaneous detection of both photons arising from the annihilation of a positron. If either photon is absorbed within the body or scattered out of the field of view, a coincidence will not occur. The probability of detection, therefore, depends on the combined path of both photons. We saw in Chapter 2 that, since the total path length is the same for all sources lying on the line that joins two detectors, the probability of attenuation is the same for all such...

Delayed Coincidence Channel Estimation

The most accurate (and currently the most commonly implemented) method for estimating random coinci dences is the delayed channel method. In this scheme, a duplicate data stream containing the timing signals from one channel is delayed for several times the duration of the coincidence window before being sent to the coincidence processing circuitry. This delay removes the correlation between pairs of events arising from actual annihilations, so that any coincidences detected are random. The...

Design Concept

The design objective for combined PET CT imaging, as a technically straightforward combination of two complementary imaging modalities, was to provide clinical CT and clinical PET imaging capability within a single, integrated scanner (Table 8.1). The short CT scan duration compared with a typical whole-body PET acquisition time essentially eliminates the requirement for simultaneous CT and PET acquisition. The integration of the two modalities within a single gantry is more straightforward...

Design of Copper Celates

The design of copper complexes that are inert poses a significant challenge due to the lability of Cu(II). The choice of ligand can greatly influence the bioki-netics, biodistribution, and metabolism of the radio-pharmaceutical, thus affecting its usefulness. In an attempt to reduce Cu(II) lability, sterically encumbered ligands and macrocyclic ligands based on Cyclan have been utilized 94-97 . Macrocyclic ligands are also used as bifunctional chelators to couple copper to monoclonal antibodies...

Detector Efficiency Variations

In a block detector system, detector elements vary in efficiency because of the position of the element in the block, physical variations in the crystal and light guides and variations in the gains of the photomulti-plier tubes. These variations result in substantial high-frequency non-uniformities in the raw data. In particular there is a systematic variation in detector efficiency with the crystal position within the block (the block profile) which results in significant variations in the...

Development of Mathematical Models

The primary factor affecting the form of a model is the nature of the tracer itself. Usually, a priori information can be used to predict all of the relevant metabolic paths of the tracer in tissue, i.e., a complete model. However, technical and statistical limitations of the available data will prevent the use of such a comprehensive model, which includes all steps in the physiological uptake, metabolism, and clearance of a tracer. Figure 6.1 shows the process of development and application of...

Development of Modern Tomographs

To understand the current state of commercial PET camera design, and why, for example, the development of 3D PET on BGO ring detector systems was only relatively recent, it is instructive to briefly trace the development of full ring PET systems. One of the first widely implemented commercial PET cameras was the Ortec Figure 3.14. A schematic diagram of the block detector system, shown here as an 8 8 array of detectors, and the four PMTs which view the light produced is shown. The light shared...

Discrete Implementation of the FBP

The discrete implementation of Eqs. (12) and (13) using the measured samples of p(s, < j) described in the section on sinogram data and sampling, above (Eq. (5)), involves four approximations (i) The approximation of the kernel h(s) by an apodized kernel where w(v) is a low-pass filter which suppresses the high spatial frequencies, and will be discussed later in the section on the ill-posedness of the inverse X-ray transform. (ii) The approximation of the convolution integral by a discrete...

Dosing Based on Receptor Occupancy

The use of PET for the evaluation of degree and duration of receptor occupancy in relation to dose has become standard for new antipsychotic and antidepressive drugs. Important information derived from such studies include the following (i) drug interaction with the assumed biochemical target and hence information that the drug reaches the target tissue, for example, passes through the blood-brain barrier, (ii) degree of receptor occupancy reached for a given dose, i.e., the dose-occupancy...

Drug Discovery in Neuroscience

PET is frequently used to evaluate neuroreceptor ligands. Salazar and Fischman evaluated BMS 181101, a drug with agonist and antagonist activity at various sites in the serotonin system 10 . The 11C labelled form of the drug was used to show that the residence time in the brain was short and, as a result, specific binding could not be determined by external imaging. These studies showed that the drug may have a narrow therapeutic index and may not be suitable for once or twice daily dosage. In...

Drug Discovery in Oncology

The conventional paradigm of demanding proof of an anti-cancer drug's potency by demonstrating tumour shrinkage using conventional anatomical imaging is not consistent with the newer therapeutics, especially the chemostatic agents where the size of the tumour does not necessarily decrease in successful treatment. The use of proliferation marker agents such as 18F labelled fluorothymidine (FLT) and PET may show an earlier response 9 . Pharmaceutical companies now have the option of using...

Electrophilic Reactions with 18F Low Specific Activity

Fluorine is the most electronegative of all the elements. Fluorine exists as a colorless to pale yellow corrosive gas (F2) that reacts with many organic and inorganic substances. Fluorine is a powerful oxidizing agent and attacks both quartz and glass, making its handling problematic. The use of fluorine gas as a carrier in the production of 18F F2 leads to several orders of magnitude lower-specific-activity reaction products compared to methods using no-carrier added 18F fluoride obtained from...

Enzyme Catalyzed Reactions

Enzyme catalysis has been utilized in labeling synthesis, especially for the preparation of endogenous compounds. Enzyme catalysis has proved to efficiently prepare biomedically interesting compounds in high chemo-, regio-, and stereo-selectivity. The application in labeling synthesis with short-lived radionuclides is particularly rewarding since the small amounts of labeled substance makes it possible to achieve high yields and short reaction times with low enzyme concentrations. Enzyme...

Equilibrium Methods

Another single-scan technique has been developed for quantification of receptors by using infusion to produce true equilibrium 84,134,135 . By administering tracer as a combination of bolus plus continuous infusion (B I), constant radioactivity levels can be reached in blood and in all regions of interest. The total tissue volume of distribution can be determined from the ratio of tissue activity to metabolite-corrected plasma activity. This value will include free, non-specifically bound, and...

Error Analysis

Error analysis is a useful tool in the development of an appropriate model-based method. Performance of a thorough error analysis is a critical step in the assessment of the utility of a given method. Papers dedicated solely to error analysis are common in the literature 155, 156, 171, 186-196 . These analyses usually proceed as follows. Choose a particular source of error. Select values for the model parameters and use the model equations to simulate tissue data including this error effect,...

Estimation from Singles Rates

The total number of randoms on a particular line of response Lij can, in principle, be determined directly from the singles rates t and Tj using equation (1) or (2). Consider an acquisition of duration T. The random coincidences Rj in the data element corresponding to the line of response Lj may be found by integrating equation (1) or (2) over time Rj i Cj (t )dt 2tJ r (t )tj (t )dt (3) If r,(t) and Tj(t) change in the same way over time, we can factor out this variation to obtain Rj 2Tsisj I f...

Examples of Compartmental Models

Figure 6.3 shows examples of compartmental model configurations. In many depictions of models, a rectangular box is drawn for each compartment, with arrows labeled with the rate constants placed between the boxes. In most whole-body compartmental models, the blood is usually counted as a compartment. Measurements from blood are often the primary set of data used to estimate the model rate constants. In the PET applications described here, we are most interested in the model constants associated...

Frequency of Measurement

The geometric factors do not normally change with time and need only be measured once. Depending on their nature, the misalignment factors may either be fixed, or may need to be re-measured as components are replaced. The time window alignment factors should be re-measured whenever detector components are replaced. The detector efficiency and block profile components can change with time, as photo-multiplier tube gains drift, and should be re-measured routinely (usually monthly or quarterly,...

Fully 3D Iterative Reconstruction

Axial and transaxial undersampling techniques were developed to reduce the data to a manageable size while hybrid algorithms were developed to achieve fast reconstruction for clinical PET scanners with limited computer resources. With sufficient CPU power and disk capacity these early approaches are not needed. The application of fully 3D iterative reconstruction methods then allows to overcome the limitations of the hybrid algorithms discussed in the previous section. We have seen that...

Ga68Ge Generator

The 68Ga 68Ge generator produces 68Ga as either 68Ga ethylenediaminetetraacetic-acid ( 68Ga EDTA) or 68Ga Cl3 in 1M HCl 30 . 68Ga has been used to label blood constituents, proteins, peptides, and antibodies (see section below on Gallium). There have been a limited number of patient studies using the 68Ga 68Ge generator. The most common use of 68Ga is in the form of 68Ga citrate, which upon administration produces 68Ga transferrin. This approach has been used to measure pulmonary transcapillary...

Galabeled Brain Imaging Agents

The work on gallium radiopharmaceuticals that can cross the blood-brain barrier (BBB) has been conducted for some time with only limited success. Species such as Ga THM2BED show low brain uptake immediately after injection, but have a very fast washout 71 . Ga EDTA has also been used to show BBB defects at the site of brain tumors and multiple sclerosis plaques 72-75 . The most promising gallium brain imaging ra-diopharmaceutical developed to date is that complexed with the small lipophilic S3N...

Gallium Labeling of Antibodies and Proteins

The monoclonal antibody antimyosin has been labeled with both 66Ga and 68Ga, via the bifunctional chelator DTPA, for the imaging of acute myocardial infarction 59 . The slow antigen-antibody reaction during the diffusion of antimyosin in necrotic myocardium requires several hours to equilibrate, therefore the longer-lived 66Ga would be more appropriate 59 . Twenty-nine hours after administrating 66Ga DTPA-antimyosin, the normal-to-infarcted myocardial ratio was 2.7, and this agent can be viewed...

Galliumcitratetransferrin

67Ga citrate has been used as a tumor imaging agent for over 30 years 38 . It was subsequently discovered that trans-chelation of gallium to the iron-binding protein transferrin was the actual tumor imaging agent 39 . Further work demonstrated that gallium is completely bound to transferrin as soon as 15 minutes after administration of 67Ga citrate 40 . The effectiveness of this radiopharmaceutical is such that it remains in use today in the clinical diagnosis of certain types of neoplasia,...

Gastric and Oesophageal Tumours

Although the detection of primary gastric and oesophageal tumours with 18F -FDG PET has been reported to be excellent, the identification of regional nodal metastases has been restricted by the presence of small volume disease in some lymph nodes (Fig. 16.8) 32 . Unsuspected distant disease may be detected by 18F -FDG PET in up to 20 of cases, and recurrent disease may also be evaluated more accurately than CT scan, which may represent the more appropriate clinical utility of this technique 32...

General Approaches Using Radiolabeled Tracers in Drug Discovery

Most studies used in drug development apply the tracer principle to specific examples involving recep-tor transporter binding drugs. Receptor binding studies generally use one of the following methods 1. To determine the interaction of the drug with a desired binding site (e.g., receptor or enzyme) a. Radiolabelled the potential drug in such a way as to not disturb the biochemical parameter to be measured. b. Use a radioligand with the desired properties and study potential drug candidate...

General Considerations for Fdgpetct Imaging Protocols

For oncology purposes a standard PET CT acquisition protocol, in essence, is a modern-day PET oncology imaging protocol, which consists of three steps (1) patient preparation and positioning, (2) transmission scan, and (3) emission scan. Additional CT scans, such as, e.g., a 3-phase liver CT, or a high-resolution lung scan could be requested by the reviewing physician, but generally these CT scans are not used for attenuation correction. While the clinical acquisition protocols of the PET CT...

Geometric and Solid Angle Effects

Figure 5.6 shows that in a system with segmented detectors, such as a block-detector based system, lines of response close to the edge of the field of view are narrower and more closely spaced than those at the centre. This geometric effect is also apparent axially and can be significant for large area tomographs operating in 3D mode. The narrowing of the LORs results in a tighter acceptance angle and in reduced sensitivity, although in the transaxial plane this effect is partially compensated...

Germ Cell Renal Cell and Other Tumours

Studies of 18F -FDG PET in germ cell tumours and in bone and soft tissue sarcomas have shown high accuracy in detecting metastatic disease and monitoring response to therapy, although reported patient numbers are small 102, 103 . Renal cell carcinoma may also be accurately staged with 18F -FDG PET, and is particularly useful for the detection of metastatic disease, while false negative primary tumours are occasionally observed 19,104,105 . The role of 18F -FDG PET in tumours such as hepatoma...

Graphical Analysis

One increasingly common method applied to tracer kinetic data is that of graphical analysis 90,107-112 . The basic concept of this method is that after appropriate mathematical transformation, the measured data can be converted into a straight-line plot whose slope and or intercept has physiological meaning. This approach has advantages, since it is simple to verify visually the linearity of the data and it is simple to determine the slope and intercept by non-iterative linear regression...

Hardware Approaches to Combined Imaging

An alternative to post hoc image fusion by software is, instead, to fuse the hardware from the two imaging modalities. While presenting a significant number of challenges, such an approach overcomes many of the difficulties of the software fusion methods. In the early nineties, Hasegawa and co-workers at the University of San Francisco developed the first device that could acquire both, anatomical (CT) and functional (SPECT) images, using a single, high-purity germanium detector for both...

Head and Neck Tumours

The presence of lymph node spread of head and neck tumours is associated with substantially worse prognosis, and clinical examination and imaging techniques (CT and MRI) detect fewer than 50 of involved lymph nodes, which may result in unnecessary neck surgery. In patients with head and neck tumours studied prior to initial surgery, the sensitivity and specificity of 18F -FDG PET in detecting nodal metastases has been reported ranging from 71 to 91 , and 88-100 , respectively (Fig. 16.7) 8,...

Image Acquisition

Registration algorithms perform better with images of approximately isotropic spatial resolution and cubic voxels. Conventional multislice MR images are not acquired with overlapping slices and the resulting missing data can cause some data corruption when resampled. As a result, true 3D MR image acquisition is preferred, in which Fourier encoding is applied along all three ordi-nates. MR images should be acquired so as to maximize contrast between anatomical structures of interest. While...

Image Formation in PET

Historically, PET systems have generally developed as circular rings. The earliest tomographs consisted of few detectors that rotated and translated to obtain a complete set of projection data, but soon full ring systems were developed. As PET uses coincidence detection, the detectors have to encompass 360 for complete sampling, unlike SPECT (single photon emission computed tomography) where 180 is sufficient. Today, PET systems use either full ring circular (or partial ring) configurations or...

Imaging Reporter Gene Expression with PET

Imaging therapeutic gene expression involves locating the tissues expressing a therapeutic gene of interest, as well as monitoring the magnitude and time variation of gene expression. Imaging can help to play a critical role in optimizing gene therapy. Two different strategies can be used to image therapeutic gene expression. The first approach involves direct imaging, where a labeled therapeutic protein substrate is used to image the specific expression of that protein. Direct imaging of the...

Implementation of Simulation Based Scatter Correction

There are five main steps which are common to the simulation based scatter correction methods, including analytical and Monte Carlo approaches. These are 1. Reconstruct the attenuation volume This is normally done using conventional 2D reconstruction of the blank and transmission data. However, any method that produces an accurate map of linear attenuation coefficients in units cm-1) in the body can be used, including appropriately registered and scaled CT data if available. 2. Reconstruct an...

Info

High myocardial uptake in a scan looking for small-volume disease in the chest can render the scan uninterpretable. the available glucose and 18F -FDG. One way of doing this is to ensure that the patients have a high caffeine intake prior to, and immediately after, the 18F -FDG injection. This can be achieved simply by encouraging the patient to drink unsweetened black coffee instead of water in the hours leading up to the scan and during the uptake period or, more palatably, a...

Interaction of Particulate Radiation with Matter

When higher energy particles such as alphas, betas, protons, or deuterons interact with atoms in an absorbing material the predominant site of interaction is with the orbital electrons of the absorber atoms. This leads to ionisation of the atom, and liberation of excited electrons by the transfer of energy in the interaction. The liberated electrons themselves may have sufficient energy to cause further ionisation of neighboring atoms and the electrons liberated from these subsequent...

Interaction of Radiation with Matter

When high-energy radiation interacts with matter energy can be transferred to the material. A number of effects may follow, but a common outcome is the ionisation or excitation of the atoms in the absorbing material. In general, the larger the mass of the particle the greater the chance of being absorbed by the material. Large particles such as alpha particles have a relatively short range in matter, whereas beta particles are more penetrating. The extremely small mass of the neutrino, and the...

Interaction with Biochemical Targets

A number of PET tracers have been developed and validated allowing the in vivo monitoring of interaction or binding to specific receptors and enzyme systems. This gives the opportunity of measuring the number of free receptors in a certain anatomical structure on one occasion, and evaluating changes in this receptor population induced during drug treatment. For drugs where a defined biochemical target is assumed, this gives possibilities to verify that the target system is indeed affected and...

Introduction

Positron emission tomography (PET) imaging is set to change the whole impact and role of Nuclear Medicine, not because it does everything better than conventional single photon imaging (planar and single photon emission computed tomography (SPECT)),but because it also has the impact and public relations of the fastest growing diagnostic speciality. PET is a powerful metabolic imaging technique utilising possibly the best radiopharmaceutical we have ever used 18F -fluorodeoxyglucose (FDG)....

Local Correlation for Multimodality Registration

Recently, Netsch et al. 44 have proposed a new measure, local correlation. This measure assumes that for a local region of the image there will be a strong correlation between image intensities at registration. The correlation coefficient is computed in a region local to each voxel in the destination image and the normalized sum of these local correlations is calculated for each trial transformation. The transformation that yields the maximum normalized sum of local correlations should...

Mathematics of Compartmental Models

This section describes the process of converting a com-partmental model into its mathematical form and de- termining its solution. For a more complete discussion of these topics, consult basic texts on differential equations 38 as well as a number of specialized texts on mathematical modeling of biological systems 16,28 . First, we start with a particular model configuration like those in Fig. 6.3. The compartments are numbered 1, 2, , and the radioactivity concentration in each compartment is...

Measurement of Dead Time

To measure the dead time behaviour for a PET scanner as a function of count-rate, a decaying source experiment is performed. A uniform source containing a known quantity of a short-lived positron emitter such as 18F or nC is placed in the field of view of the PET scanner. Repeated measurements of the singles, prompt and random coincidence rates are then made as the activity in the field of view decays. The incident count-rate for a given level of activity in the field of view is obtained by...

Metal Artefacts

High-density implants, such as dental fillings, pacemakers, prostheses, or chemotherapy infusion ports may lead to serious artefacts in CT images 74, 75 . These CT artefacts have been shown to propagate through CT-based attenuation correction into the corrected PET emission images where artificially increased tracer uptake patterns may then be generated 76-78 . It is therefore recommended that PET images from PET CT are routinely correlated with the complementary CT, and that these PET data are...

Model Identifiability

The first step in defining a model is to determine identifiability, meaning that the parameters of a model can be uniquely determined from measurable data. There is an extensive literature on this topic 16, 19, 71-77 , including studies with particular attention to PET applications 78-80 . In some cases, the structure of the model itself does not permit the unique definition of parameter values, even with noise-free data. One example of this is the case of high specific-activity studies with...

Monitoring Biochemical Changes in the Brain

The first symposium emphasised monitoring biochemical changes in the brain using PET and SPECT. This topic played a major role in the second symposium as well. Doudet reviewed the advantages and disadvantages of using 18F -FDG, a dopamine precursor ( 18F -DOPA), a tyrosine derivative (6-fluoro-m-tyro-sine,) and a number of radiolabelled substrates for the dopamine transporter to measure changes in Parkinson's disease 25 . She also reviewed the use of a radioligand for the vesicular monoamine...

Monitoring Response of Tumour to Therapy

An emerging area of clinical utility of PET is in the monitoring of tumour response to therapy, principally with 18F -FDG. Accurate evaluation of response to both chemotherapy and radiation therapy, often prior to CT scan changes, have been reported in glioma, col-orectal, NSCLC, lymphoma, head and neck tumours, and soft tissue sarcomas 2, 8, 16, 17, 42, 61, 107 . The timing and reliability of 18F -FDG PET studies in predicting tumour response is the subject of numerous prospective studies. The...

Monte Carlo Simulation

Monte Carlo methods are frequently used to evaluate scatter correction techniques since this approach allows separation of the simulated scattered and un-scattered contributions to the projections which is not possible using phantom experiments. Furthermore, many Monte Carlo codes are able to simulate the scatter distribution for any specified emission and attenuation distribution and several different PET scanner geometries. As well as providing a powerful method of evaluating the accuracy of...

Multiple Energy Window Methods

The triple energy window (TEW) method is a straightforward extension of DEW which introduces a modification factor that accounts for source size and distribution dependencies in Rsc 45 .Under the assumption that Rsc > > Runsc, the TEW method can be written Robj and Rcalib are the ratios of counts in the two lower energy windows for the object being imaged and a calibration phantom respectively. The parameter b is a relaxation factor that controls the amount of feedback of the modification...

Multiple Energy Window Techniques

Multiple energy window techniques make use of the observations that (1) a greater proportion of Compton scattered events are recorded in the region of the single photon energy spectrum below the photopeak compared with those recorded near the photopeak and (2) there exists a critical energy above which only unscat-tered photons are recorded 39 (Fig. 5.14). Thus, data recorded in energy windows set below or above the photopeak window, or both, can be used to derive an estimate of the scatter...

Multislice 2D Data

So far we have discussed data sampling for a single ring scanner located in the plane z z0. Multi-ring scanners are stacks of NR rings of detectors spaced axially by Az and indexed as r 0, , NR- 1 3 . The coincidences between two detectors belonging to the same ring r are organized in a direct sinogram p(s, < j, z rAz) as described in the previous section. This is the sinogram of the function f(x, y, z rAz) (Fig. 4.3). Multi-ring scanners also collect coincidences between detectors located in...

Noisefree data

Figure 4.6. 2D reconstruction of a mathematical phantom with the ML-EM algorithm (Nr 128,N 256,Nx Ny 256). The Poisson log-likelihood (left scale) and the square reconstruction error with regard to the reference image (right scale) are plotted versus the iteration number. The left plot is for ideal noise-free data. For the right plot, pseudo-random Poisson noise has been added for a total of 400,000 coincidences. The cost function increases monotonically in contrast with the error, which...

Oblique Sinograms

Some analytic algorithms use an alternative parameterization of the parallel projections, where the vari- Figure 4.8. A transverse and a longitudinal view of a multi-ring scanner. An LOR connecting a detector da in ring ra to a detector db in ring rb is shown, with the four variables (s, 0, Z,, 6) used for the oblique sinogram parameterization. The particular LOR represented has 0 0. able u in Eq. (53) is replaced by the axial coordinate u cos 9, the average of the axial coordinates of the two...

Occupational and Public Exposures

Healthcare Workers Within and Outside the PET Facility The radiation dose to a technologist performing a PET study is generally higher than for conventional nuclear medicine imaging 30-32 . Comparison of staff doses between PET facilities is not very informative because of the variability in clinical workload and scan procedures. With attention to shielding and protocols, it should be possible to maintain occupational exposure below approximately 6 mSv y1 in most circumstances 33 . Hand doses...

Optimisation Precision Capture Ranges and Robustness

All registration algorithms except the Procrustes method of point registration rely on a process of optimization to compute the transformation that best aligns the two images. The algorithms require an initial guess, or starting estimate, of the correct transformation. They then compute image similarity for voxel intensity-based methods or distances for feature-based methods, and use this to compute a new (and hopefully better) estimate of the transformation. This process repeats until it...

Optimization Algorithms

The cost function (assuming it has an unique global maximum) defines the looked-for estimate f* of the tracer distribution. To actually calculate f*, an optimization algorithm is needed. Such an algorithm is a prescription to produce a sequence of image estimates fn, n 0, 1, 2, , which should converge asymptotically to the solution Asymptotic convergence is not the only requirement the optimization algorithm should be stable, efficient numerically, and ensure fast convergence independently of...

Other Nucleophilic [18FFluorination Reactions

A classic method for the synthesis of aromatic fluorides, known as the Balz-Schiemann reaction, involves the thermal decomposition of aryl diazonium tetrafluoroborate salts (Fig. 9.17). While this methodology has been applied to the production of aryl 18F fluorides, it suffers several drawbacks 1 . The use of 18F BF4- as the counter anion results in low radiochemical yields as well as low specific activity products. There has been little utilization of this methodology for the synthesis of more...

Other Performance Measures

In addition to the parameters described above (resolution, count rate, scatter, sensitivity), a number of other parameters are specified by bodies such as NEMA to assess PET scanner performance. These include accuracy of corrections for attenuation, scatter, randoms and dead time, and image quality assessments. Uniformity is another parameter that has been found to be useful to test. Energy resolution, though a major determinant of PET performance, has not been included in the latest NEMA PET...

Ovarian Carcinoma

Ovarian carcinoma is the leading cause of death among gynaecological tumours 99 . The treatment of ovarian carcinoma primarily consists of surgical resection followed by chemotherapy and or radiotherapy. Accurate staging is essential, particularly in the restaging of patients with elevated serum markers (CA-125). 18F -FDG PET has been shown to have high accuracy in detecting in ovarian carcinoma lesions greater than 1 cm in size, but the detection of micrometastatic disease (one of the most...

Overview of Modeling

PET imaging produces quantitative radioactivity measurements throughout a target structure or organ. A single static image may be collected at a single specific time post-injection or the full time-course of radioactivity can be measured. Data from multiple studies under different biological conditions may also be obtained. If the appropriate tracer is selected and suitable imaging conditions are used, the activity values measured in a region of interest (ROI) in the image should be most...

Parameter Estimation

The previous sections presented the mathematical techniques necessary to solve the model equations. Thus, with knowledge of the input function Ca(t), the model configuration, and its rate constants, the tissue concentration curve can be predicted mathematically. This section provides an overview of the inverse problem, i.e., given measurements of the tissue activity and the input function and a proposed model configu ration, one can produce estimates of the underlying rate constants. Many...

Partial Volume Correction The Partial Volume Effect

In quantitative PET, the reconstructed image should map the radiotracer concentration with uniform accuracy and precision throughout the field of view. However, due to the partial volume effect, the bias in reconstructed pixel values may vary depending on the size of the structure being sampled and its radioactivity concentration relative to surrounding structures. The partial volume effect may be described as follows. When the object or structure being imaged only partially occupies the...

PET as a Tracer Method in Drug Development

The development of new drugs is a time consuming and expensive process. The costs are markedly increased the closer the drug proceeds towards market approval. This is especially clear when the process has reached the phase of clinical trials. During drug development a number of decisions have to be taken. At each point, adequate information must be available to give an optimal base for decision. The relevance of pre- Figure 10.8. Synthesis of 21-11C -progesterone and 1a-methyl-11C -mesterolone....

PET Camera Performance

PET systems exhibit many variations in design. At the most fundamental level, different scintillators are used. The configuration of the system also varies greatly from restricted axial field of view, discrete (block-detector) systems to large, open, 3D designs. With such a range of variables, assessing performance for the purposes of comparing the capabilities of different scanners is a challenging task. In this section, a number of the determinants of PET performance are discussed. New...

PET Radionuclides in Oncology

The short-lived radionuclides (radioisotopes) required for PET are produced in cyclotrons. In PET oncology clinical applications, the most commonly used positron-emitting tracer is 18F-fluoro-2-deoxy-glucose, or 18F -FDG 6 . The unique versatility of PET lies in the ability to study numerous physiologic and biochemical processes in vivo. The measurement of tissue blood flow, oxygen metabolism, glucose metabolism, amino acid and protein synthesis and nucleic acid metabolism have all been...

PET Scanner Calibration

Once the corrections for the various sources of bias described in this chapter have been applied to PET data, images can be reconstructed which are free of artefacts and which reflect the regional concentration of radiotracer in the body. In most clinical applications of PET this is sufficient as the images are interpreted visually without reference to the absolute voxel values. Indeed, this degree of quantification is sufficient in some types of kinetic research study also. For example,...