Development of a high performance zinc-62/copper-62 radionuclide generator for positron emission tomography

Clinical utilisation of positron emission tomography could be enhanced by the availability of shortlived radionuclides derived from generator systems. The zinc-62/copper-62 combination is one such system which could be used as a source for a number of copper-62 radiopharmaceuticals. We have developed and optimised a high activity (5.6 GBq, 150 mCi) zinc-62/copper-62 generator to provide ⁶²CU in a form that is suitable for direct labelling of pyruvaldehyde-bis-(N ⁴-methylthiosemicarbazone)-copper(II), Cu(PTSM). The distribution coefficients of Zn(II) and Cu(II) between anion-exchange resin and various hydrochloric acid/organic solvent mixtures were measured. Based on these measurements a generator eluent of 0.3 M HCl/40% ethanol provided ⁶²CU in >90% yield in a 3-ml volume. A very low ⁶²Zn breakthrough of less than 3×10^–7% was achieved. Copper-PTSM was successfully labelled with the no-carrier-added ⁶²Cu eluent directly from the generator with 94% radiochemical yield. Offprint requests to: J. Zweit, The Royal Marsden Hospital     

A new zinc-62/copper-62 generator as a copper-62 source for PET radiopharmaceuticals

A new 62Zn/62Cu generator system was designed to provide a readily available 62Cu source for positron emission tomographic radiopharmaceuticals, based on the differences of complex formation between Zn and Cu. Noncarrier added 62Cu was selectively eluted as a glycine complex from 62Zn-adsorbed cation-exchange resin (CG-120, Amberlite), when a glycine solution (200 mM) was used as the eluant. The elution efficiency and radionuclidic purity of 62Cu were 70% and greater than 99.9%, respectively. Copper in glycine solution showed rapid complex formation with dithiosemicarbazone, which is one of the established Cu-binding agents for bifunctional chelating radiopharmaceutical.     

The Zinc-62/copper-62 generator: A convenient source of copper-62 for radiopharmaceuticals

⁶²Cu is a short-lived (9.8 min) positron emitter results from the decay of ⁶²Zn (9.2 h). ⁶²Zn is easily produced in good yield (2.3 mCi/μAh) by bombardment of a 0.4 mm thick target of natural copper with 22 MeV protons. A simple separation of zinc and copper as chloride complexes using anion exchange chromatography is described.The performance of ⁶²Zn/⁶² Cu generator system based upon a similar anion exchange separation is evaluated. Using a 0.7 cm i.d. × 8.0 cm high column of “Dowex 1-X10” resin of 200–400 mesh, eluted with 0.1 N HCl containing 100 mg/ml NaCl and 1 μg/ml CuCl₂, over 85% of the available ⁶²Cu is recovered in a 3.5 ml volume. The ⁶²Zn is less than 0.001% at the time of elution. A variety of potentially useful radiopharmaceutics using this generator system have been developed and are being evaluated in clinical trials.     

18F-Fluoride positron emission tomography and positron emission tomography/computed tomography

(18)F-Fluoride is a positron-emitting bone-seeking agent, the uptake of which reflects blood flow and remodeling of bone. Assessment of (18)F-fluoride kinetics using quantitative positron emission tomography (PET) methods allows the regional characterization of lesions of metabolic bone diseases and the monitoring of their response to therapy. It also enables the assessment of bone viability and discrimination of uneventful and impaired healing processes of fractures, bone grafts and osteonecrosis. Taking advantage of the favorable pharmacokinetic properties of the tracer combined with the high performance of PET technology, static (18)F-fluoride PET is a highly sensitive imaging modality for detection of benign and malignant osseous abnormalities. Although (18)F-fluoride uptake mechanism corresponds to osteoblastic activity, it is also sensitive for detection of lytic and early marrow-based metastases, by identifying their accompanying reactive osteoblastic changes, even when minimal. The instant fusion of increased (18)F-fluoride uptake with morphological data of computed tomography (CT) using hybrid PET/CT systems improves the specificity of (18)F-fluoride PET in cancer patients by accurately differentiating between benign and malignant sites of uptake. The results of a few recent publications suggest that (18)F-fluoride PET/CT is a valuable modality in the diagnosis of pathological osseous conditions in patients also referred for nononcologic indications. (18)F-fluoride PET and PET/CT are, however, not widely used in clinical practice. The limited availability of (18)F-fluoride and of PET and PET/CT systems is a major factor. At present, there are not enough data on the cost-effectiveness of (18)F-fluoride PET/CT. However, it has been stated by some experts that (18)F-fluoride PET/CT is expected to replace (99m)Tc-MDP bone scintigraphy in the future.     

Diagnostic performance of fluorodeoxyglucose positron emission tomography/magnetic resonance imaging fusion images of gynecological malignant tumors: comparison with positron emission tomography/computed tomography

Purpose

We compared the diagnostic accuracy of fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) and PET/magnetic resonance imaging (MRI) fusion images for gynecological malignancies.

Materials and methods

A total of 31 patients with gynecological malignancies were enrolled. FDG-PET images were fused to CT, T1- and T2-weighted images (T1WI, T2WI). PET-MRI fusion was performed semiautomatically. We performed three types of evaluation to demonstrate the usefulness of PET/MRI fusion images in comparison with that of inline PET/CT as follows: depiction of the uterus and the ovarian lesions on CT or MRI mapping images (first evaluation); additional information for lesion localization with PET and mapping images (second evaluation); and the image quality of fusion on interpretation (third evaluation).

Results

For the first evaluation, the score for T2WI (4.68 ± 0.65) was significantly higher than that for CT (3.54 ± 1.02) or T1WI (3.71 ± 0.97) (P < 0.01). For the second evaluation, the scores for the localization of FDG accumulation showing that T2WI (2.74 ± 0.57) provided significantly more additional information for the identification of anatomical sites of FDG accumulation than did CT (2.06 ± 0.68) or T1WI (2.23 ± 0.61) (P < 0.01). For the third evaluation, the three-point rating scale for the patient group as a whole demonstrated that PET/T2WI (2.72 ± 0.54) localized the lesion significantly more convincingly than PET/CT (2.23 ± 0.50) or PET/T1WI (2.29 ± 0.53) (P < 0.01).

Conclusion

PET/T2WI fusion images are superior for the detection and localization of gynecological malignancies.     

Development of myocardial perfusion tracers for positron emission tomography

Six positron-emitting cations were investigated as possible perfusion tracers: [13N]NH4, 38K, 51Mn, 52mMn, 81Rb, and 82Rb. Aspects of the production of the radionuclides and their separations from the irradiated target materials were addressed. The thick target, saturated yields of several nuclear reactions leading to these radionuclides were studied theoretically and experimentally in the energy range 6-10 MeV. A figure-of-merit describing the production aspects of each tracer was calculated, and tomographic imaging results in normal human subjects were reported.     

Comparison of dedicated breast positron emission tomography and whole-body positron emission tomography/computed tomography images: a common phantom study

Annals of Nuclear Medicine - High-resolution dedicated breast positron emission tomography (dbPET) can visualize breast cancer more clearly than whole-body PET/computed tomography (CT). In Japan,...     

X-ray-based attenuation correction for positron emission tomography/computed tomography scanners

A synergy of positron emission tomography (PET)/computed tomography (CT) scanners is the use of the CT data for x-ray-based attenuation correction of the PET emission data. Current methods of measuring transmission use positron sources, gamma-ray sources, or x-ray sources. Each of the types of transmission scans involves different trade-offs of noise versus bias, with positron transmission scans having the highest noise but lowest bias, whereas x-ray scans have negligible noise but the potential for increased quantitative errors. The use of x-ray-based attenuation correction, however, has other advantages, including a lack of bias introduced from post-injection transmission scanning, which is an important practical consideration for clinical scanners, as well as reduced scan times. The sensitivity of x-ray-based attenuation correction to artifacts and quantitative errors depends on the method of translating the CT image from the effective x-ray energy of approximately 70 keV to attenuation coefficients at the PET energy of 511 keV. These translation methods are usually based on segmentation and/or scaling techniques. Errors in the PET emission image arise from positional mismatches caused by patient motion or respiration differences between the PET and CT scans; incorrect calculation of attenuation coefficients for CT contrast agents or metallic implants; or keeping the patient's arms in the field of view, which leads to truncation and/or beam-hardening (or x-ray scatter) artifacts. Proper interpretation of PET emission images corrected for attenuation by using the CT image relies on an understanding of the potential artifacts. In cases where an artifact or bias is suspected, careful inspection of all three available images (CT and PET emission with and without attenuation correction) is recommended.     

Respiratory motion in positron emission tomography/computed tomography: a review

The development of positron emission tomography/computed tomography (PET/CT) scanners has allowed not only straightforward but also synergistic fusion of anatomical and functional information. Combined PET/CT imaging yields an increased sensitivity and specificity beyond that which either of the 2 modalities possesses separately and therefore provides improved diagnostic accuracy. Because attenuation correction in PET is performed with the use of CT images, with CT used in the localization of disease, accurate spatial registration of PET and CT image sets is required. Correcting for the spatial mismatch caused by respiratory motion represents a particular challenge for the requisite registration accuracy as a result of differences in temporal resolution between the 2 modalities. This review provides a brief summary of the materials, methods, and results involved in multiple investigations of the correction for respiratory motion in PET/CT imaging of the thorax, with the goal of improving image quality and quantitation. Although some schemes use respiratory-phase data selection to exclude motion artifacts, others have adopted sophisticated software techniques. The various image artifacts associated with breathing motion are also described.     

The origins of positron emission tomography.

The development of positron emission tomography (PET) took place through the combination of the following recognitions: (1) a handful of short-lived, positron-emitting radionuclides, carbon-11, nitrogen-13, and oxygen-15, exhibit chemical properties that render them particularly suitable for the tracing of important physiological pathways, and (2) the radiation emitted as a result of the annihilation of positrons in matter exhibited physical properties that made it well-suited for nuclear medicine imaging, particularly for tomographic reconstruction. The scientific building blocks that were necessary for the structure of PET were contributed over a period of several decades by many investigators in physics, mathematics, chemistry, and fundamental biology.     

Radiotracers for positron emission tomography imaging

Over the past 30 years, advances in radiotracer chemistry and positron emission tomography instrumentation have merged to make positron emission tomography a powerful scientific tool in the biomedical sciences. However, despite the increasing reliance of the biomedical sciences on imaging and the new needs for functional information created by the sequencing of the human genome, the development of new radiotracers with the specificity and kinetic characteristics for quantitative analysis in vivo remains a slow process. In this article, we focus on advances in the development of the radiotracers involved in neurotransmission, amino acid transport, protein synthesis, and DNA synthesis. We conclude with a brief section on newer radiotracers that image other molecular targets and conclude with a summary of some of the scientific and infrastructure needs that would expedite the development and introduction of new radiotracers into biomedical research and the practice of medicine.     

Whole-body positron emission tomography: Part I. Methods and performance characteristics.

Methods for whole-body PET imaging have been developed to provide a clinical tool for the detection and evaluation of primary and metastatic cancers. The axial FOV of the PET system is extended by imaging at multiple bed positions to cover the whole body. In typical rectilinear PET scans, only a small fraction of the data is collected to form two-dimensional projection images. In this work, 100% of the projection data was collected to form the two-dimensional projection images. These projection images were generated for continuous angles over 180 degrees by resorting sinogram data. In addition, tomographic images were formed by using filtered backprojection reconstruction without attenuation correction. Coronal and sagittal cuts were then extracted from the three-dimensional data set. The tomographic images were reconstructed to a resolution of 10.8 mm in all dimensions because of statistical limitations of the data. Both methods of image formation resulted in images of high quality with the tomographic reconstruction providing the highest contrast and resolution. An acquisition time of 1-2 min/bed position after a 10-mCi injection of [18F]fluoride ion or [18F]FDG was found to give a sufficient number of counts for producing images of good resolution and contrast, from a total scanning time of 32-64 min.     

Update on 18F-fluorodeoxyglucose/positron emission tomography and positron emission tomography/computed tomography imaging of squamous head and neck cancers

This article summarizes the recent literature in (18)F-fluorodeoxyglucose/positron emission tomography (FDG-PET) imaging of head and neck cancers and extends the previous review in this area by Sch?der and Yeung in the July 2004 issue of Seminars in Nuclear Medicine. Positron emission tomography/computed tomography (PET-CT) imaging is now used widely but has not been adequately evaluated for head and neck cancer. Its accuracy in initial staging is better than CT but may be similar to magnetic resonance imaging. It is not sufficiently accurate in the N0 neck to rule out nodal metastases but may be appropriate if sentinel node mapping is performed in patients with PET studies showing no nodal disease. PET imaging is beginning to be used in radiotherapy treatment planning, where it makes a significant difference by identifying malignant normal size nodes, extent of viable tumor, and distant disease. PET continues to be useful in carcinoma of unknown primary in identification of the primary site. Overall success is around 27% after all other modalities have failed. FDG-PET is being used frequently to assess response to therapy and for surveillance thereafter. The major controversy is when to image after radiotherapy or combined chemo-radiotherapy. One month seems to be too early. The ideal time seems to be 3 to 4 months to avoid both false-positive and false-negative studies. The growing use of PET-CT studies in head and neck cancer will certainly make a significant difference in the treatment and outcome in this disease.     

Thyroid cancer--indications and opportunities for positron emission tomography/computed tomography imaging

Although thyroid cancer is a comparatively rare malignancy, it represents the vast majority of endocrine cancers and its incidence is increasing. Most differentiated thyroid cancers have an excellent prognosis if diagnosed early and treated appropriately. Aggressive histologic subtypes and variants carry a worse prognosis. During the last 2 decades positron emission tomography (PET) and PET/computed tomography (CT), mostly with fluorodeoxyglucose (FDG), has been used increasingly in patients with thyroid cancers. Currently, the most valuable role FDG-PET/CT exists in the work-up of patients with differentiated thyroid cancer status post thyroidectomy who present with increasing thyroglobulin levels and a negative (131)I whole-body scan. FDG-PET/CT is also useful in the initial (post thyroidectomy) staging of high-risk patients with less differentiated (and thus less iodine-avid and clinically more aggressive) subtypes, such as tall cell variant and Hürthle cell carcinoma, but in particular poorly differentiated and anaplastic carcinoma. FDG-PET/CT may help in defining the extent of disease in some patients with medullary thyroid carcinoma and rising postoperative calcitonin levels. However, FDOPA has emerged as an alternate and more promising radiotracer in this setting. In aggressive cancers that are less amenable to treatment with (131)iodine, FDG-PET/CT may help in radiotherapy planning, and in assessing the response to radiotherapy, embolization, or experimental systemic treatments. (124)Iodine PET/CT may serve a role in obtaining lesional dosimetry for better and more rationale planning of treatment with (131)iodine. Thyroid cancer is not a monolithic disease, and different stages and histologic entities require different approaches in imaging and individualized therapy.     

Performance standards in positron emission tomography.

A standard set of performance measurements is proposed for use with positron emission tomographs. This set of measurements has been developed jointly by the Computer and Instrumentation Council of the Society of Nuclear Medicine and the National Electrical Manufacturers Association. The measurements include tests of spatial resolution, scatter fraction, sensitivity, count rate losses and randoms, uniformity, scatter correction, attenuation correction, and count rate linearity correction.     

Kinetic modeling in positron emission tomography.

Most PET kinetic modeling approaches have at their basis a compartmental model that has first-order, constant coefficients. The present article outlines the one-, two-, and three-compartment models used to measure cerebral blood flow, cerebral glucose metabolism, and receptor binding, respectively. The number of compartments of each model is based on specific knowledge of the physiological and/or biochemical compartments into which the tracer distributes. Additional physical and biochemical properties of the tracer distribution are considered in specifying the use of first-order rate constants. For example, in cerebral blood flow and receptor binding studies transport across the blood-brain barrier by diffusion can be modeled as a first-order process. A saturable carrier-mediated process or saturable enzyme catalyzed reaction, when tracer doses of the labeled substrate are used and the natural substrate is in steady-state, also results in first-order rate constants, as in glucose metabolism studies. The rate of ligand binding, on the other hand, depends on the concentrations of both substrate and available receptors. In order to appropriately model the reaction as pseudo first-order during a specified experimental interval, protocols are carefully designed to assure that the number of available binding sites remains approximately constant throughout the given interval. A broad array of scanning protocols is employed for kinetic analyses. These include single-scan approaches, which function like their autoradiographic counterparts in animal studies and are often called "autoradiographic" methods, which allow estimation of a single parameter. Dynamic scanning to obtain the time course of tissue activity allows simultaneous estimation of multiple parameters. Scanning may be conducted during a period of tracer uptake or after attainment of steady-state conditions. All quantitative modeling approaches share the common requirement that an arterial input function be measured or an appropriate surrogate be found. A vast array of methods is available for estimation of model parameters, both micro and macro. In the final analysis, it is the interaction among all elements of the PET study, including careful tracer selection, model specification, experimental protocol design, and sound parameter estimation methods, that determines the quantitative accuracy of the estimates of the physiological or biochemical process under study.     

Clinical applications of positron emission tomography/computed tomography treatment planning

Positron emission tomography/computed tomography (PET/CT) has provided an incremental dimension to the management of cancer patients by allowing the incorporation of important molecular images in radiotherapy treatment planning, ie, direct evaluation of tumor metabolism, cell proliferation, apoptosis, hypoxia, and angiogenesis. The CT component allows 4D imaging techniques, allowing improvements in the accuracy of treatment delivery by compensating for tumor/normal organ motion, improving PET quantification, and correcting PET and CT image misregistration. The combination of PET and CT in a single imaging system to obtain a fused anatomical and functional image data is now emerging as a promising tool in radiotherapy departments for improved delineation of tumor volumes and optimization of treatment plans. PET has the potential to improve radiotherapy planning by minimizing unnecessary irradiation of normal tissues and by reducing the risk of geographic miss. PET influences treatment planning in a high proportion of cases and therefore radiotherapy dose escalation without PET may be futile. This article examines the increasing role of hybrid PET/CT imaging techniques in process of improving treatment planning in oncology with emphasis on non small cell lung cancer.     

Fundamentals of positron emission tomography

Positron emission tomography is a modern radionuclide method of measuring physiological quantities or metabolic parameters in vivo. The method is based on: (1) radioactive labelling with positron emitters; (2) the coincidence technique for the measurement of the annihilation radiation following positron decay; (3) analysis of the data measured using biological models. The basic aspects and problems of the method are discussed. The main fields of future research are the synthesis of new labelled compounds and the development of mathematical models of the biological processes to be investigated.     

Technical aspects of positron emission tomography/computed tomography fusion planning

Emerging technologies in radiation therapy computers and delivery systems allow surgically precise conformal radiation treatment that was not possible with previous generations of equipment. The newest treatment systems can compensate for tumor target motion as well as shape dose distributions to conform precisely to delineated target volumes. These sophisticated technologies now drive the development of imaging modalities able to generate equally high-resolution and lesion-specific roadmaps that are the foundation of these highly accurate radiation plans. Positron emission tomography/computed tomography (PET/CT) is currently becoming a routine imaging tool for radiation oncology because of its combined benefits of positron imaging and high-resolution anatomic display. The improved staging and lesion delineation provided by PET, combined with the 3D anatomic display provided by CT, now allows better treatment stratification and more precise targeting. Additionally, respiratory-gated 4D CT and 4D PET/CT have been used in the simulation process for respiratory-gated radiation therapy. Successful integration of PET/CT into the radiation therapy planning process requires an understanding of how therapy plans are derived and the process by which the patient receives therapy, because these dictate the method of image acquisition. The radiation oncologists, too, must understand the technology of positron imaging to adapt these functional images based on intensities rather than pixels to their targeting process. Modifications to the PET/CT scanner and room are necessary to image the patient in the reproducible position required for treatment planning. Although the impact of these efforts on patient outcome has yet to be determined, the benefit of better treatment choice, due to improved staging, and more precise targeting with less normal tissue exposure resulting in improved quality of life will likely promote PET/CT to the gold-standard for targeted therapies.