Current status and future needs for standards of radionuclides used in positron emission tomography

Applied Radiation and Isotopes 76 (2013) 31–37

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Current status and future needs for standards of radionuclides used in positron emission tomography B.E. Zimmerman n Physical Measurement Laboratory National Institute of Standards and Technology, Gaithersburg, MD 20899-8462, USA

H I G H L I G H T S c c c

Status of international standards for positron emitters is reviewed. Importance of standards and traceability in quantitative PET imaging is discussed. Needs for new standards and comparisons are proposed.

a r t i c l e i n f o

abstract

Available online 23 September 2012

Positron Emission Tomography (PET) is being increasingly used as a quantitative technique for detecting disease and monitoring patient progress during treatment. To ensure the validity of the quantitative information derived from the imaging data, it is imperative that all radioactivity measurements that are part of the imaging procedure be traceable to national or international standards. This paper reviews the current status of standards for positron emitting radionuclides (e.g., 18F, 68Ge/68Ga, and 124I) and suggests needs for future work. Published by Elsevier Ltd.

Keywords: Fluorine-18 Gallium-68 Germanium-68 PET Standards Traceability

1. Introduction The use of Positron Emission Tomography (PET), combined with X-ray computed tomography (PET–CT), continues to increase as an important tool for diagnosing diseases and monitoring patient response to treatment. This imaging modality has been used as a qualitative technique for the detection of disease since the introduction of PET (without CT) in the late 1950s and has seen explosive growth in its use since the first commercial introduction of combined PET–CT in 2001. Ongoing improvement to the reconstruction process is bringing PET-CT closer to realizing its potential as a quantitative method. The primary quantitative application of PET–CT, as well as other imaging modalities, usually involves the comparison of a series of images acquired over time to look for a change in the state of a disease. In the case of PET, the value of interest is generally the amount of a radiotracer that is taken up in the tissue being investigated, indicating the amount of metabolic function. In contrast, it is usually the size or extent of the diseased tissue that is monitored in CT and this is generally indicated by regions of tissue having higher than normal apparent density.

n

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0969-8043/$ - see front matter Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.apradiso.2012.09.011

For PET–CT scans, an apparent change in the uptake of injected radiotracer across scans taken at different times can be used as an indicator of whether or not a disease is progressing or if a particular course of treatment is being effective. Data from PET–CT scans acquired during clinical trials for investigational drugs are being used in a similar way to demonstrate their effectiveness. It should be obvious that in order to be able to make such comparisons of imaging data over time (and often across multiple imaging centers, different scanner models, and different image reconstruction and analysis methods), it is necessary to ensure that the data are acquired and analyzed under standardized, reproducible conditions. There has been much discussion in the literature recently about the need for standardization in PET imaging (c.f., Boellard, 2009, 2011), especially in the use of [18F]fluorodeoxyglucose ( 18F FDG), but most of the focus has been on harmonization of the protocol (with emphasis on preparing the patient). The sources of variability arising during an imaging procedure, and certainly in an aggregated set of imaging procedures conducted under the auspices of a clinical trial, can be loosely separated into two groups: instrumental and biological effects. It is the latter of these that is of greatest interest in the clinical application of PET–CT imaging. In order to reveal these patient-related effects, however, it is important to first have a complete understanding of the measurement process and the way in which the instrument behavior and data acquisition and analysis methodology contribute to the observed variability. For any kind of

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measurement, including those made in a clinical setting, the best way to control variability due to instrumental effects is to ensure that all of the instrumentation is calibrated in a way that is traceable to national or international standards (Zimmerman and Judge, 2007). Currently, the most common PET quantity used clinically to report activity measurement results is the Standardized Uptake Value based on body weight (SUVbw), which can be defined as SUVbw ¼ C A =ðAtot =WÞ

ð1Þ

where CA is the activity concentration of the radionuclide in the volume of interest (typically in units of kBq/mL) as measured from the image, Atot is the total injected radiopharmaceutical dosage (in MBq), and W is the total body mass of the patient (in kg). In practice, the value for CA relies on, among many other factors, the calibration of the scanner. The value for Atot is usually determined from measurements made in an activity calibrator that should be calibrated for the radionuclide being measured using the same geometry that will be used for the injection. In order for the SUV value to have any meaning, the measurement in the activity calibrator and the scanner calibration must be linked together. For most clinics performing PET scans, the scanner and activity calibrator are usually linked by measuring an aliquot of 18F in a specified geometry in the activity calibrator, dispensing a portion of that aliquot into a phantom, then re-measuring the container to determine the amount transferred to the phantom. A calibration protocol (the details of which are usually hidden from the user) is run on the scanner in order to obtain the necessary normalization and scaling factors needed to convert an observed count rate in the scanner to an activity value. In many cases, the18F activity values used in the calibration procedure come from the radiopharmacy. Traceability on the part of the radiopharmacy is important in this case to ensure that successive re-calibrations are linked together, thereby minimizing dispersion in the activity measurement. Such long-term maintenance of traceability is important for data stability in clinical trials because data are being compared over relatively long periods of time amongst multiple sites. Finally, most scanners do not have the capability to directly calibrate in terms of radionuclides other than 18F. In this case, it is impossible to obtain correct SUV values unless the scanner software is able to take into account all the differences in the decay scheme between the radionuclide being measured and the one against which it is calibrated. The scanner manufacturers make an attempt to make such corrections by incorporating half-life factors and positron branching ratio information into the system, but without the proper standards to verify the correctness of the results, they can be considered suspect. Other decay-scheme related factors such as positron energy, which can enhance the partial volume effect and decrease system resolution, and the presence of additional gamma rays, whose Compton scattering can affect the apparent number of counts in an image, are still under investigation (Sanchez-Crespo, this issue). Such research requires proper standards in order to determine the accuracy of any applied correction methods. This paper will explore the current status of standardization for radionuclides of interest to PET and will discuss the needs for additional standards and metrology support.

2. National and international standards for PET radionuclides 2.1. International metrology infrastructure The responsibility for establishing and maintaining national standards for radionuclides rests with National Metrology Institutes (NMIs), which are laboratories designated by their countries

as having the legal mandate to develop national standards for physical quantities. In order to verify the validity of their standards, NMIs are encouraged to participate in the Mutual Recognition Arrangement (MRA) of the International Committee for Weights and Measures (CIPM) (BIPM, 2012a). Under this arrangement, laboratories publish Calibration and Measurement Capability (CMC) claims that are declarations of what measurement services they are able to provide for specific radionuclides and the level of uncertainty associated with that measurement. They are expected to substantiate those claims by participating in comparison exercises amongst each other. In these types of inter-laboratory comparisons, the results of measurements for a specific radionuclide are compared across the NMIs to arrive at ‘‘degrees of equivalence’’, which is a measure of how well an NMI compares to the comparison value (e.g., the mean of all the laboratories’ results, or some other appropriate measure of central tendency), or between each other (based on each laboratory’s reported value). For clinical trials, this type of information is critical when the studies are conducted in different countries. This is because each clinical site would ideally be calibrated against its own local, national standard and comparability of the data requires confidence that each participating laboratories’ local standard is equivalent to the others. This ensures, for example, that the calibrations done in clinics in Germany against a standard from their NMI are relatable to the calibrations done in clinics in the United States against standards from theirs. For most photon-emitting radionuclides with reasonably long half-lives, the usual way that comparisons are conducted involves each laboratory submitting a standardized solution of the radionuclide being compared in a defined measurement geometry (a flame-sealed glass ampoule containing 3.6 g of solution) to the International Reference System (SIR) (Rytz, 1983; Ratel, 2007). The SIR is a well-characterized ionization chamber and associated documentation system that is maintained by the International Bureau of Weights and Measures (BIPM) solely for the purpose of comparing radionuclide standards between NMIs. For these types of comparisons, the reference value is based on the observed ionization current produced in the ionization per unit of activity of that particular radionuclide. The submitted solution is assayed by the participating laboratory for radioactivity content and is assumed to be representative of their standard for that radionuclide. Plans are underway to extend the current SIR to include beta emitters and short-lived gamma-emitting radionuclides (Ratel, 2007). In the case of beta emitters, it is proposed to use liquid scintillation (LS) counting as the main technique by comparing the NMI reported activities of a standardized source that they have prepared to the observed count rate (or some other parameter) in an LS counter maintained at the BIPM. Much more research is required, however, before this approach can be considered fully appropriate for establishing traceability. For short-lived gamma emitters, a system has been established using a traveling NaI(Tl) detector that is linked against the SIR as the comparison device (Ratel, 2007). So far, the device has been used to conduct a comparison of 99mTc with the National Institute of Standards and Technology (NIST) (Michotte and Fitzgerald, 2010) and the Korean Research Institute of Standards and Science (KRISS, the NMI of the Republic of Korea) (BIPM, 2012b). By using this traveling instrument, the results of this comparison were able to be linked to another ongoing SIR comparison of 99mTc that has included only European NMIs because of the need for proximity to the BIPM (outside of Paris). While there are plans to eventually use the traveling instrument for other short-lived radionuclides, specifically 18F, the timing of such a comparison has not yet been established because no new comparisons will be undertaken with the device until the current 99mTc comparison is completed.

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2.2. Current status of radionuclide standards for PET The sections that follow summarize the current status of national standards and of international comparisons for radionuclides of interest to PET. The primary sources of information include the MRA and its Key Comparison Database (BIPM, 2012b) and the listing of declared CMCs (BIPM, 2012c). Information concerning recent standardizations or the availability of standards not declared as CMCs was obtained through searches of the refereed literature. It should be noted that some NMIs may have standardized a particular radionuclide but neither claimed it as a CMC nor published the results in the open literature. It is always best to consult with one’s NMI to determine the latest status of standardization for a particular radionuclide of interest.

2.2.1. 18F To date, 10 NMIs around the world have declared in their CMCs that they hold standards for the measurement of 18F: Australia, Austria, Chinese Taipei, France, Germany, the Netherlands, Spain, Switzerland, the United Kingdom, and the United States (BIPM, 2012c). The combined standard uncertainties on the activities reported by these laboratories are about 1% or less. Three international comparisons have been completed in order to justify the CMCs made by these laboratories (BIPM, 2012b). In one of them, samples of standardized 18F were sent by several European laboratories directly to the SIR, which allowed for a direct comparison between the different standards. These were then linked to another pair of comparisons in which each laboratory standardized their own solutions and measured them in an activity calibrator model that was common to each laboratory using a common ampoule type instead of sending ampoules to the BIPM (Woods and Baker, 2004). For these comparisons, ampoules were not sent to the BIPM. Each one of the activity calibrators used in these comparisons was originally calibrated against a master ionization chamber maintained at the National Physical Laboratory (NPL, the NMI of the UK) before being installed in the respective laboratories and the relative response of each chamber to the master is therefore known. In that particular exercise, each participant was also asked to measure an aliquot of a master solution of 68Ge along with their standardized 18F so that minor deviations in chamber responses could be normalized. By comparing the relative responses of the 18F standard solutions and the 68Ge reference sources and taking into account the known responses of each chamber to the NPL master ionization chamber, a link was made between each of the NMIs that had taken part in any or all of the three comparisons. It should be noted that although such types of comparisons are generally open to only NMIs, there were two non-NMIs that were invited to participate because of the unique nature of this comparison. They were the National Institute of Radiation Hygiene in Denmark and the Comissao~ Nacional de Energia Nuclear in Brazil. Through their participation, they were able to establish traceability to the NMIs for the measurement of 18F with about the same level of uncertainty. In general, the results from all of the laboratories were in agreement to within 1.6% of the comparison reference value, with the exception of NIST, which differed by about 3%. In this case, however, it is hypothesized that the presence of a 48V impurity that was not present in any of the participants’ solutions could have been responsible for the discrepancy. Since the publication of the results of those comparisons, the NMIs of Japan (Yamada et al., 2008) and Argentina (Rodrigues et al., 2011) reported on their standardizations of 18F, but have not declared new CMCs, nor have they participated in any new comparisons.

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2.2.2. 68Ge/68Ga and 68Ga Preparing and distributing solution standards of short-lived radionuclides to end users presents huge challenges to NMIs, particularly those in large countries, because of the need to prepare and calibrate the starting solutions at very high activity levels to account for decay during transit. Delivery logistics and local regulations may create additional hurdles that need to be cleared in order to ensure timely delivery. One potential solution is to use a relatively long-lived positron emitter as a calibration surrogate for the radionuclide of interest. If the appropriate radionuclide could be identified, such a long-lived surrogate calibration source would have the additional advantage of being able to be used repeatedly over relatively long periods of time, thereby providing a means to monitor long-term instrument behavior. For many years, the most widely-used calibration source for positron emitters was 22Na, which has a half-life of about 2.6 a (DDEP, 2012). Its applicability as an activity calibrator source is questionable, however, because nearly every positron decay is accompanied by a 1275-keV gamma ray. This has the effect of producing a larger signal in the activity calibrator per unit activity than a positron emitter that does not have accompanying gamma rays, such as 18F. More recently, 68Ge, in equilibrium with its positron-emitting daughter 68Ga, has been used as a substitute calibration source for 18 F. Like 22Na, it has a reasonably long half-life (T1/2 ¼270.95(16) d (DDEP, 2012)), but the 1077-keV gamma ray that accompanies the positron emission is much lower in intensity (3.22 g/decay vs. 99.4 g/decay) than that of the 1275-keV gamma ray in 22Na. Because of the relatively long half-life of 68Ge compared to its decay daughter 68Ga ((T1/2 ¼1.1285(10) h (DDEP, 2012)), they are almost always found in secular equilibrium. All of the standards of 68Ge prepared by the NMIs are calibrated as equilibrium solutions. Currently, four NMIs have declared the ability to disseminate 68Ge standards (BIPM, 2012c): those of Austria, Germany, the Netherlands, and the United Kingdom, all with combined standard uncertainties on the activity measurement of less than 0.5%. In addition, the NMIs of Romania (Grigorescu et al., 2004) and the United States (Zimmerman et al., 2008) have reported the ability to standardize 68Ge with combined standard uncertainties on the activities of 1.1% and 0.3%, respectively. Besides being a potential calibration surrogate for other positron emitters, 68Ge is in increasing demand as a source of 68Ga for clinical ¨ work using the 68Ge/68Ga generator (Rosch, this issue). The other papers in this Special Issue (c.f., Ray and Pomper, this issue) are indicative of the interest in 68Ga for PET imaging. In terms of standards for 68Ga, all of the NMIs claiming to have standards or calibration capabilities for 68Ge make the same claims for 68Ga (BIPM, 2012c). The NMI of Chinese Taipei claims to hold a standard for 68Ga despite not having one for 68Ge, with the source of traceability being the NPL. Recently, the NMIs for Spain (Roteta et al., 2012) and Romania (Sahagia et al., 2012) reported on their standardizations of 68Ga, with combined standard uncertainties on the activity determinations of about 0.6% and 1%, respectively. For many detection techniques, the measurement of 68Ga does not differ much from those made with 68Ge in equilibrium with 68Ga. This is because 68Ge decays entirely by electron capture, with the emission of only low energy (10 keV) X-rays and Auger electrons. For measurements in ionization chambers (i.e., activity calibrators), which are the basis for many of the CMC entries for both 68Ge and 68 Ga measurement and the sole source of traceability for three of the NMIs (to NPL through an ionization chamber), the 10 keV photons are severely attenuated by the walls of the chamber, as well as by the source itself. Therefore, even for 68Ge measurements, it is only the annihilation photons and the 1077-keV gamma rays from 68Ga that are producing the detected signal. Most other techniques used for measuring these radionuclides, including coincidence and

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liquid-scintillation counting, rely on the condition of secular equilibrium between the two radionuclides and also measure only the 68 Ga radiations, making any necessary corrections for interference from the 68Ge radiations. The activity of the 68Ge is then deduced from the equilibrium condition and the known half-lives. The implication of this is that the calibration factors derived for measurement of 68Ge in a specific geometry in a specific activity calibrator may be applicable for 68Ga as long as the appropriate corrections are made for the 68Ge X-rays. This needs to be verified experimentally, however, by comparing the response of the activity calibrator from standardized solutions of both 68Ge and 68Ga in the actual geometries used. To date, there have been no published international comparisons for either of these radionuclides. With the increasing interest in both 68 Ga based imaging agents and the use of 68Ge as a long-lived surrogate for other positron emitting radionuclides, there is clearly a need for the NMIs around the world to develop their own standards and to demonstrate equivalence to each other. An SIR-based comparison of 68Ge has been proposed to be carried out in late 2012 or early 2013 to help accomplish this.

2.2.3. Very short-lived positron emitters (11C, 13N, 15O, etc.) The very short half-lives of many positron emitters, such as 11C (T1/2 ¼ 20 min), 13N (T1/2 ¼10 min), 15O (T1/2 ¼2 min), and 82Rb (T1/2 ¼ 1.2 min) make it extremely difficult to develop and disseminate standards of these radionuclides. In order for the NMI to standardize the radionuclide, it is necessary for them to be located close to a radiopharmacy with a cyclotron. Such a standardization has been reported by the NPL (Woods et al., 2002), who was able to work with a nearby clinical center to develop a standard for 11C with a combined standard uncertainty of about 0.3% on the activity determination. More recently, the Labortoire National Henri Bequerel (LNHB, the NMI for France) also reported on the development of their standard for this radionuclide, which was accomplished by the use of LS spectrometry with the triple-to-double coincidence (TDCR) method (Thiam et al., 2011) with a combined standard uncertainty of 0.85% on the activity measurement. In 1987, both NIST (then the National Bureau of Standards, NBS) and NPL reported separately on level scheme studies of 82 Sr/82Rb and 82Rb by itself with a possible view towards future development of standards for those radionuclides (Hoppes et al., 1987; Judge et al., 1987). Both of those papers identified large variations in previously published half-lives and gamma emission rates and provided new values for these quantities. While the data reported by the two groups agreed well with each other, they were in wide disagreement with the older values. Renewed interest in the 82Sr/82Rb generator after nearly two decades prompted a new half-life study of 82Sr carried out by NIST (Pibida et al., 2009), the results of which were in excellent agreement with both sets of 1987 data. In none of these cases, however, did the studies result in the development of a declared standard by either laboratory. Another short-lived positron that has been used clinically, albeit in a limited number of cases, is 62Cu (T1/2 ¼9.7 min (Zimmerman et al., 1997)), which is obtained through the 62Zn/62Cu generator (Haynes et al., 2000). A standard with a combined standard uncertainty of about 1.6% on the activity measurement was developed for this radionuclide at NIST by Zimmerman and Cessna (1999). Calibration factors for a commercial activity calibrator were also determined for the clinical measurement geometry, which was a 35 mL plastic syringe. As expected, there have been no interlaboratory comparisons between NMIs for any of the radionuclides in this group because of their short half-lives.

2.2.4. Less common/emerging radionuclides In addition to 68Ga, there has been increased interest in other positron emitters with intermediate half-lives (ranging from several hours to days). Of these, 64Cu (Anderson and Ferdani, 2009) and 124I (Koehler et al., 2010) currently appear to be of most interest clinically. To date, three laboratories have claimed CMCs for 64Cu: the NMIs of Germany, the Czech Republic, and Poland. The standardization of this radionuclide has also recently been reported by the NMIs of Italy (Capogni et al., 2008) and Romania (Sahagia et al., 2012), with combined standard uncertainties on the activity measurements of 0.85% and 2%, respectively. In a recent paper by Be´ et al. (2012), the results of a EURAMET (the regional metrology organization consisting of NMIs in Europe) project aimed at developing and comparing standards and improving the quality of the nuclear data for 64Cu were reported. In this project, the NMIs of France, Germany, the Czech Republic, the United Kingdom, and Romania standardized aliquots of a common master solution and four of the laboratories submitted samples to the SIR as a means to provide equivalence. The measured activities from the five laboratories agreed to within 1.3% of the mean value, with most values falling within 0.5%. The combined standard uncertainties on activity measurements ranged from about 0.5% to 1%. For the measurement of 124I, no NMI has claimed the ability to provide standards and calibrations for this radionuclide, at least in terms of publishing CMCs. Likewise, there are currently no inter-laboratory comparisons registered for activity measurements of this radionuclide. However, the NPL (Woods et al., 1992) has published the results of standardization studies and can presumably provide those standards. 2.3. Secondary standards and ‘‘surrogate’’ sources Developing and maintaining top-level national standards is a critical task for NMIs. However, such standards have little relevance unless they can be easily used and applied by end users. This means that they must be in a geometrical configuration and activity level that are appropriate for the end user’s application. For short-lived medical radionuclides, the national standard is often ‘‘transferred’’ to the end user in the form of a calibration setting for an activity calibrator in a specific geometry (e.g., syringe, dose vial, etc.). Of course, this calibration setting must be determined experimentally by measuring a source containing a top-level, or primary, standard in the correct geometry. Because of the need to make the additional measurements in the activity calibrator and the additional uncertainties introduced by those measurements (as well as other components due to mass transfer, etc.) the resulting transfer standard will have a higher uncertainty than the primary standard. Many NMIs make the development of such a transfer standard a part of the development of their original primary standard, especially for radionuclides used in medicine. Since these calibration settings are generally valid only for a specific measurement geometry and only for that particular calibrator type, it is nearly impossible to ensure that every possible geometry that could be encountered is represented. The NMI would have to prepare sources, based on their standards, for each type of container encountered in the clinic and derive calibration factors for them. This is usually not possible, given the large numbers of measurements needed to derive just a single calibration factor (Zimmerman and Cessna, 2000). A potential solution to this would be for source manufacturers to establish traceability to one or more NMIs and then distribute sources customized for the customer’s needs. For many radionuclides, this is the preferred solution, since the cost is most likely to be lower than one that would be obtained from an NMI, although the

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uncertainty will typically be higher. Several manufacturers produce such sources and these are generally widely available. In order to ensure that sources obtained from these manufacturers are traceable to the appropriate standards, end users should insist on receiving documentation that certifies the traceability, including identification of the NMI to which the measurement is traceable and how the traceability was established. For many practical applications, including clinical measurement, it is often desirable to calibrate an instrument in terms of a particular radionuclide in an uncommon geometry and to monitor that calibration over long periods of time. For short-lived radionuclides, the issue always remains that the calibrated source decays too quickly to be useful for more than a few half-lives of the radionuclide. One of the approaches being taken is for manufacturers to make and sell sources containing a long-lived radionuclide that is meant to substitute for their shorter-lived counterparts. Some of these in current use include 57Co and 133Ba as surrogates for 99mTc and 131I, respectively (Zanzonico, 2008). For positron emitters, these sources usually consist of either 22Na or 68Ge in some type of solid matrix (usually epoxy) in a geometry that either simulates a clinical source (such as a syringe) or other type of useful shape (such as a uniform cylinder). The use of a long-lived surrogate source that mimics both the radionuclide of interest and the clinical measurement geometry is clearly of interest. These sources would be used not only with activity calibrators, but also could potentially be used with gamma counters for use with biodistribution studies, as well as with both clinical and pre-clinical PET scanners. Solid cylindrical sources containing 68Ge are already routinely used by some PET scanner manufacturers as part of their routine calibration and quality assurance protocols. Unfortunately, most of them are not directly calibrated to a national standard simply because such a standard has not been available until recently. As with normal calibration sources, is critical in any type of transfer standard or surrogate source that all of the activity values be traceable back to the original standard for the radionuclides

Fig. 1. Simplified decay schemes for the positron emitters (a)

18

F, (b)

68

35

being used. This of course requires that a primary national or equivalent standard exist for both the surrogate and the radionuclide being mimicked. The mock and mimicked sources must then be directly compared against each other to directly to determine how to relate the sources of the two radionuclides to one another. This type of work was recently done for a commercial 68Ge activity calibrator source meant to mimic 18F (Zimmerman and Cessna, 2010). This direct comparison of standards is vitally important in order to ensure the measurement relationship between the two radionuclides. It is often assumed that the calibration factor for positron emitters in activity calibrators should be the same because the photon energy emitted by the positron annihilation is the same (511 keV). The calibration factor is dependent, however, upon a number of factors, including measurement geometry, the positron branching ratio, and the presence of additional gamma rays. Fig. 1 shows the simplified level schemes for three important positron emitting radionuclides: 18F, 68 Ge/68Ga, and 124I. It is obvious from these data that equal amounts of activity of each of these radionuclides must give very different responses in an activity calibrator. Moreover, the data in the figure suggest that the dependence of the response on measurement geometry will most likely be different for each case because of the differing amounts (and energies) of the low-energy photons that accompany their decay. Finally, more subtle physical effects can also play a role in determining the relative response between radionuclides in an activity calibrator given a specific measurement geometry. For example, in the paper describing their 11C standardization, the group at NPL (Woods et al., 2002) reported significant measurement effects due to different positron ranges between 11C and 18F even when the different positron branches are taken into account. It was only because of the ability to accurately calibrate their instrumentation that this effect (on the order of 1% of the measured activity) was able to be confirmed. If the effect does indeed scale with difference in positron energy, as suggested by

Ge in equilibrium with its

68

Ga daughter, and (c)

124

I. All data are from (DDEP, 2012).

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Woods et al. (2002), then the effect should be particularly noticeable for a radionuclide such as 68Ga, where the endpoint energy is almost a factor of three higher in energy than that of 18F.

3. Needs for radionuclide standards for PET The realization of PET–CT as a truly quantitative technique will firstly depend on the availability of standards of the various radionuclides being studied. Thus, it is imperative that NMIs develop the necessary primary standards for the most widely used radionuclides, such as 11C and 18F, as well as 68Ge as a surrogate. This work should be followed with the development of national standards for other PET radionuclides used in their respective countries. The use of 18F currently accounts for about 93% of all PET studies in the United States and is expected to maintain this dominance for the foreseeable future (Frost and Sullivan, 2008). Outside of the United States, the demand for traceable standards for 18F should certainly rise as PET becomes more widely adopted. Besides 18F and 11C, which accounts for only a minor percentage of all PET scans and remains out of reach for most clinics without an in-house cyclotron, 68Ga and 124I appear to be the next important PET radionuclides, with at least one commercial radiopharmaceutical currently in Phase II clinical trials in the United States for 124I (Frost and Sullivan, 2008) and several 68Ga products currently under development. Following the development of national standards for these radionuclides, work must continue on making traceable secondary, or ‘‘transfer’’ standards for PET radionuclides, particularly activity calibrator settings and long-lived surrogate sources available to the end users. This ensures that the standards will actually be used clinically to calibrate and monitor the performance of the instrumentation used to make the activity measurements in the clinic. As PET radionuclides are used more in biodistribution studies, particularly in pre-clinical drug development, it will become important to have standards not only for activity calibrators and PET scanners, but also for gamma counters (used to count blood and tissue samples), as well as appropriate calibration sources for small animal PET scanners. Clearly more research is needed to explore the use of surrogate radionuclides and how to relate one radionuclide to another. The relationship between the two radionuclides is highly dependent on the measurement equipment that is used and the application for which it will be used. For example, the differences in decay schemes between 18F, 68Ge/68Ga, and 124I (shown in Fig. 1) will result in a very large difference in activity calibrator and gamma counter response for the same activity. It still remains to be seen how this difference will be manifested in the quantification of the PET images, however. Until the appropriate standards are available, any studies that seek to draw concrete conclusions about the magnitude of the effects must be considered suspect. In any case, the methodology used to calibrate the scanner with respect to the activity calibrator for different radionuclides will undoubtedly need to be revisited to take the differences in decay schemes into account. As a next step, interlaboratory comparisons need to be carried out amongst those laboratories that have developed standards for these radionuclides. This will give both the NMIs and their users confidence in the validity of their standards. There is already an effort being made to devise a system for comparison of standards of short-lived radionuclides between NMIs using a traveling transfer instrument, but the current pace of one institution per year for only 99mTc (at this time) will certainly not solve the needs for all the NMIs around the world to compare their standards for other radionuclides such as 18F.

As important as comparisons for primary standards between NMIs are, it is also critical that secondary standards, including surrogate sources, be compared between laboratories. The measurement problems associated with these types of sources are extremely complex and require a large investment in time and resources. Collaborations between NMIs, their users, and commercial suppliers could go a long way towards sharing resources and expertise, resulting in robust standards that are clinically relevant to the user community. A method for validating and comparing the resulting standards, as well as a scheme for ongoing quality assurance would be a necessary part of such a program. A program similar to this involving European NMIs is expected to begin in mid-2012 and will deal with several aspects of radioactivity measurement in nuclear medicine, not just medical imaging (Smyth, 2012).

4. Conclusion With the increasing use of PET as a quantitative medical diagnosis technique, it is critical that standards that are traceable to national and international standards become more widely available to the medical user community. This will require more NMIs around the world developing standards for the most important PET radionuclides (18F and 68Ge) and more comparisons between those laboratories to be conducted in order to validate those standards. Secondary, or ‘‘transfer’’ standards are then needed for these, as well as emerging radionuclides in order to be relevant to the clinic.

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