- Email: [email protected]
Standardisation and half-life of 89Zr
Applied Radiation and Isotopes xxx (xxxx) xxx–xxx
Contents lists available at ScienceDirect
Applied Radiation and Isotopes journal homepage: www.elsevier.com/locate/apradiso
Standardisation and half-life of
89
Zr
⁎
E. García-Torañoa, , V. Peyrésa, M. Rotetaa, M. Mejutoa, A. Sánchez-Cabezudoa, E. Romerob a b
Laboratorio de Metrología de Radiaciones Ionizantes, CIEMAT Avda. Complutense 40, Madrid 28040, Spain Unidad de Aplicaciones Biomédicas y Farmacocinética, CIEMAT Avda. Complutense 40, Madrid 28040, Spain
A R T I C L E I N F O
A B S T R A C T
Keywords: Zr-89 Half-life Standardisation Positron emitters
The nuclide 89Zr is being tested for the labelling of compounds with long blood circulation times. It decays by beta plus emission (22.8%) and by electron capture (77.2%) to 89Y. Its half-life has been determined by following the decay rate with two measurement systems; an Ionisation Chamber and an HPGe detector. The combination of six results gives a value of T1/2 = 78.333 (38) h, slightly lower than the DDEP recommended value of 78.42 (13) h. This radionuclide has also been standardised by liquid scintillation counting, 4πγ counting and coincidence techniques.
1. Introduction
2. Radioactive material
Positron Emission Tomography (PET) plays an important role in the field of molecular imaging. Some radionuclides in this field, i.e. 11C, 13 N, 15O, and 18F, commonly categorised as “standard PET radionuclides”, require an onsite or closely located cyclotron, which decreases the availability and flexibility of radiopharmaceuticals labelled with these radionuclides. As a consequence, the use of “non-standard PET radionuclides” with longer than a few hours half-life for the development of PET imaging probes, has received a growing interest over the last few years (Lin et al., 2016). Among them, 89Zr is an ideal radionuclide for the labelling of compounds with long blood circulation times such as antibodies. It must be noted that one of the most fundamental principles in the construction of effective antibody-based nuclear imaging agents is matching the physical half-life of the radioisotope (Zeglis and Lewis, 2011). The nuclide 89Zr decays by beta plus emission (22.8%) and by electron capture (77.2%) to 89 Y (See Fig. 1.). More than 99% of the decays feed a metastable level of 89Y at 909 keV. The Decay Data Evaluation Project (DDEP) recommended half-life is 78.42 (13) h (Bé at al, 2016), one of the longest among current commercially available beta plus emitters which allows imaging studies up to a 1 week after the injection of a 89Zr-based probe. In fact, 89Zr has recently been recognised as one of the most promising radionuclides for developing new immuno-PET agents (Wright and Lapi, 2013). This paper describes the standardisation and half-life determination of this nuclide. The flowchart of both procedures is presented in Fig. 2.
All 89Zr materials used for these measurements were produced in several batches at BV Cyclotron VU by a (p,n) reaction on natural yttrium-89 (89Y) and isolated with a hydroxamate column. It was commercially available in 1 M oxalic acid solution. After reception at CIEMAT the solutions were adjusted to a total volume of 200 μl using 1 M oxalic acid, subsequently 90 μl of 2 M Na2CO3 were added and incubated for 3 min at room temperature. Finally, 1 mL of an acyclic chelating agent solution, 50 mM DTPA, was added in order to contribute to the stability of the solution and incubated at room temperature for 10–20 min. According to the manufacturer's data sheet, the radionuclide purity, determined by gamma-ray spectrometry, was better than 99.9%. This was confirmed by measurements made at CIEMAT. The individual source preparation is described separately in each section.
⁎
3. Half-life measurements A new half-life determination has been obtained as a combination of measurements taken with an ionisation chamber and an HPGe spectrometer. The use of seven different batches of material minimises possible effects caused by contaminated or impure solutions. 3.1. Measurements with an Ionisation Chamber Half-life determination was carried out by analysing the decay rate of several sources. Sealed 5 mL penicillin-type vials containing about 4 mL of the 89Zr solution described in Section 2 were placed inside the
Corresponding author. E-mail address: [email protected] (E. García-Toraño).
http://dx.doi.org/10.1016/j.apradiso.2017.10.033 Received 10 March 2017; Received in revised form 16 October 2017; Accepted 16 October 2017 0969-8043/ © 2017 Elsevier Ltd. All rights reserved.
Please cite this article as: García-Toraño, E., Applied Radiation and Isotopes (2017), http://dx.doi.org/10.1016/j.apradiso.2017.10.033
Applied Radiation and Isotopes xxx (xxxx) xxx–xxx
E. García-Toraño et al.
assessed following the recommendations given in JCGM100 (2008) and Pommé et al. (2008). An uncertainty component of the half-life value was obtained from the fitting results as the square root of the corresponding value in the covariance matrix multiplied by the reduced chisquare of the fit. This component takes into account both the components due to the statistics of the data and to the fitting procedure. Major components of the uncertainty were the background variation and electrometer response. The first was especially important, as measurements lasted several weeks and the samples were not removed from their position inside the chamber until the end of the measurements. Typical ionisation currents at the start of the measurements were in the order of 10−10 A and the background current about 10–13 A. The weighted mean half-life of all values obtained with this technique was T1/2 =78.333(35) h, where the uncertainty given in parentheses corresponds to the standard deviation of the individual result. Fig. 3 presents the results of the fitting of decay data from one measurement. Residuals are presented in terms of their statistical significance. 3.2. Measurements with a germanium detector
Fig. 1. Simplified decay scheme of
89
Measurements were carried out with an extended-range coaxial HPGe detector from CANBERRA electrically cooled using the pulse tube technology. The detector is surrounded by a cylindrical lead shield, 5 cm. thick. Its relative efficiency is about 35% and the lower practical limit of measurement is about 12 keV. A small sealed vial containing about 1 mL of 89Zr solution was placed at 0.5 cm from the detector window and kept in the same position during the measurements. The electronic setup was formed by an ORTEC DspecPro digital multichannel unit plugged to the detector preamplifier. This unit controls the acquisition setup and was configured to periodically register the spectrum area in an energy region (ROI) from 110 keV to 1045 keV. These limits were selected so that any drift in the electronics would produce a minimum effect in the ROI area. Two sets of measurements were carried out whose characteristics are presented in Table 1. Typical count rates were 1900 s−1 and 54 s−1 at the start and end of the measurements, respectively. The decay curves, after background correction, were fitted using the same procedure mentioned above. The results of the two measurements are given in Table 1 and the uncertainty budget is presented in Table 2. The mean value was T1/2 = 78.332 (61) h, in excellent agreement with the value determined by the IC. As for the previous measurements, the
Zr. Nuclear data taken from Bé et al. (2016).
well of an IG-11 re-entrant ionisation chamber. The ionisation current was measured with a Keithley 6514 spectrometer for periods up to 6 half-lives (about 20 days). The system is controlled by a computer so that the ionisation current can be integrated and registered for subsequent analysis. Complete details of the experimental setup have been given elsewhere (García-Toraño et al., 2010). A set of four measurements were made between May 2014 and November 2016. Ionisation values were registered and analysed for the time intervals indicated in Table 1. Samples were kept in the chamber for the complete measurement time. Half-life values were determined by nonlinear fitting of the decay distributions, after subtracting the background contribution. The Levenberg-Marquardt algorithm was used for non-linear fitting of data. The fitting procedure can take into account possible impurity contributions, but given the high purity of the solution, this was not necessary. Table 1 presents the results of the four individual results whose main uncertainty components are detailed in Table 2. They were
Fig. 2. Diagram of the half-life measurements and the standardisation setups followed at CIEMAT in the study of 89Zr.
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Table 1 Evaluated value, results obtained at CIEMAT by two measurement techniques and final value obtained in the present work for the half-life of 89Zr. Uncertainties are given in parentheses in units of the last significant figure. Measurement Technique
T1/2 (min)
Evaluation (Bé et al., 2016) This work Ionisation chamber Ionisation chamber Ionisation chamber Ionisation chamber Weighted mean value Ionisation chamber (σ) HPGe detector HPGe detector Mean value HPGe detector (σ) This work: Final value
78.42 (13) 78.380 (60) 78.315 (30) 78.341 (30) 78.332 (35) 78.333 (35) 78.341 (61) 78.324 (57) 78.332 (61) 78.333 (38)
Number of data points in decay curve
Number of half-lives followed
71 (× 50 readings) 380 (× 50 readings) 480 (× 50 readings) 395 (× 50 readings)
2 6.1 6.1 6.1
268 (3600 s each) 581 (1800 s each)
5.0 4.6
uncertainty in parentheses corresponds to the standard deviation of the individual result. Given that the signal to background ratio was, at the end of the measurements, about unity, the uncertainty budget is dominated by the effect of the background contribution to the fitting of the decay curve. It was estimated by using a set of characteristic background data and by observing the effect of the number of experimental points included in the fit. 3.3. The half-life of
89
Zr
All results are presented in Fig. 4. No significant differences exist between the mean of both groups and the final value was obtained as the weighted mean of all results (JCGM100, 2008):
T =
∑i = 1
7
Ti si2
7
1 si2
∑i = 1
(1)
Fig. 3. Decay rate data of a 89Zr source measured with an ionisation chamber for a period of time corresponding to more than six half-lives (top) and residuals from a fitted decay curve (bottom), expressed in terms of their statistical significance.
Given that the experimental standard deviation of the set of data is lower than the uncertainty calculated according to Table 2, the variance was taken as the variance within a single technique. The final result obtained for the half-life of 89Zr is T1/2 =78.333 (38) h. The result is lower than the DDEP recommended value of 78.42 (13) (Bé at al, 2016) and has a lower uncertainty than the recommended value or any other previous measurement.
check the consistency of measurements within different batches.
4.1. Liquid scintillation counting Although LSC measurements were carried out using three different systems and two scintillating cocktails, only results obtained with the CIEMAT TDCR prototype were used in the final steps. Two sets of four samples, each with masses between 15 mg and 32 mg, were prepared by gravimetric methods directly from the mother solution. Measured activities varied between 6000 Bq and 2300 Bq, depending on the masses and the day of measurement.
4. Standardisation The standardisation of 89Zr was carried out using the following three techniques: Liquid Scintillation Counting (LSC) with Triple to Double Coincidence ratio (TDCR), 4πγ counting and 4πβ(PPC)−γ (Ge) coincidence counting. Additional measurements were carried out by other methods (CIEMAT/NIST, Gamma-ray spectrometry), and the ionisation chamber used in the decay rate measurements was used to Table 2 Uncertainty budget in the measurement of the considered.
89
Zr half-life with ionisation chambers and HP-Ge detectors. Values are “typical” and may differ depending on the specific sample
Uncertainty Component
Ion Chamber HP-Ge detector Relative uncertainty (k = 1) (%)
Statistics component and fitting uncertainty Electrometer response (including range switching)
0.013 0.030
0.030 –
Background variation Radionuclide impurity
0.045 0.01
0.067 0.01
Time measurements Dead time System stability (detector and electronics)
0.01 – 0.01
0.005 0.03 0.008
Combined uncertainty
0.048
0.073
Evaluation method Counting statistics and least squares fitting Excluding the regions affected by electrometer switching and comparing the results From results using several backgrounds from the historic recording Considering a potential contribution of a contaminant with an activity ratio of 1.10–5 Estimation based on PC timing accuracy (1 ms) (Ion chamber) Evaluating the results for several dead times Characterizing the detector stability from measurement of a long-lived radionuclide
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Table 3 Uncertainty components in the standardisation of 89Zr at CIEMAT. Values are expressed in % of the activity per mass. Values are “typical” and may differ depending on the specific result considered.
Fig. 4. Results of the six measurements of the half-life of 89Zr made in this work, with indication of the measurement technique used. The final value, obtained by combination of all results, is also shown.
4.1.1. Efficiency calculations Efficiency calculations were carried out with a program (NUR) which processes data generated with the PENNUC package (GarcíaToraño et al., 2017) that allows the Monte Carlo generation of the decay process by following the decay pathways for any nuclide using nuclear data from the DDEP's NUCLEIDE database (Dulieu et al., 2017). Atomic re-arrangements are followed using a set of routines taken from the PENELOPE simulation package (Salvat, 2015). For 89Zr, a special shape factor was used in the calculation of the positron spectrum (Hamilton et al., 1960), although its effect on the total detection efficiency was small. As a first step, a large number of cascades are generated using the program PENNUC which are then processed by the program NUR to compute the detection efficiency of the problem nuclide. The calculation is performed as follows: for each cascade, the counting efficiency is calculated as the sum of all contributions from the cascade components. For electrons, the calculation is straightforward; for photons, a Monte Carlo simulation of the photon-system interaction is started using the composition and dimensions of the scintillator, the vial and the thickness of the vial wall. If, as a result of Compton or photoelectric interactions, a number of electrons are created, they are added as new components to the original cascade. For positron emitters, two 511 keV photons are also simulated and their contributions accounted for in the calculation process.
METHOD Uncertainty Component
TDCR
4πγ
Coincidences
Counting statistics Extrapolation (inc. counting) Weighing Dead time Efficiency determination Zero-energy extrapolation Background Pile up Counting time Impurities Nuclear data kB value Half-life Resolving time Source stability Combined uncertainty
0.1 – 0.1 0.08 – – 0.05 – 0.01 – 0.25 0.25 0.05 0.1 0.05 0.40
0.09 – 0.1 0.05 0.60 0.13 0.05 – 0.01 – 0.27 – 0.18 – – 0.70
– 0.4 0.1 0.03 – – 1.2 – 0.01 – 1.3 – 0.20 0.03 0.1 1.82
include the contribution from the gamma ray depopulating the metastable level at 909 keV. Results of the measurements with both scintillators gave similar results, 465.0 (19) Bq mg−1 and 464.5 (19) Bq mg−1 for Hisafe 3 and Hionic-Fluor, respectively. The activity per unit mass was obtained as the mean of eight values, and resulted to be 464.7 (19) Bq mg−1 at the reference time. Uncertainty components are presented in Table 3. Two components dominate the uncertainty budget: the effect of the uncertainty on the EC/β+ branching ratio and the determination of the kB value. 4.2. 4πγ counting The application of the 4πγ counting method to the standardisation of positron emitters was presented elsewhere (García-Toraño et al., 2007). Here, the calculation model has been modified and the counting efficiency was computed using the PENELOPE/PENNUC combination (García-Toraño et al., 2017) on a cascade by cascade basis. A set of five sources with masses between 8 mg and 18 mg were prepared by dropping aliquots of the mother solution onto thin polyethylene films sealed after drying and covering with similar foils. The diameter of the active part was about 3 mm. The experimental setup was based on a NaI (Tl) well detector followed by preamplifier, a delay line amplifier, model 460 from ORTEC and analog to digital converter model 7411 from SILENA. Given the high energy of the gamma-rays from the metastable state, a large NaI (Tl) well detector from SCIONIX (17.8 × 17.8 cm.) was preferred to the usual 7.5 × 7.5 cm arrangement. The threshold detection level for photons was established at 5 keV. In these conditions, the detection efficiency of the 909 keV gamma ray was 0.835 and the total detection efficiency was about 1.15. A second set of measurements with a higher threshold (25 keV) confirmed the results. At the reference time, the activity per unit mass was 463.3 (32) Bq mg−1, obtained as the mean of five values, one per sample. Uncertainty components are detailed in Table 3. Major contributions correspond to the detector model, nuclear data (EC/β+ branching ratio) and decay corrections.
4.1.2. Measurements TDCR measurements were carried out with a TDCR prototype built at CIEMAT and were complemented with measurements with a commercial HIDEX counter. The basis of the TDCR method is well covered in the literature (Broda et al., 2007). The CIEMAT counter is built around three photomultiplier tubes from ET Enterprises, model 9807B, powered by a programmable power supply, model N1470 from CAEN. A quad discriminator unit, model 821 and a six-channel variable amplifier, model 612AM, both from LeCroy, are followed by a MAC3 unit from LNHB (Bouchard and Cassette, 2000) that processes all pulses and makes the appropriate dead-time corrections using an external reference clock. A stainless steel shield surrounds the measurement chamber and phototubes to reduce the background contribution. The signal to background ratio was typically 300. Eight samples with masses between 17 mg and 34 mg were prepared gravimetrically in four vials containing 15 mL of Hisafe 3 scintillating cocktail and four more with Hionic-Fluor. Vials were placed in the TDCR system and counted until the logical sum of double coincidences reached, at least, 105 counts. Five measurements were taken consecutively for each vial. Typical counting efficiencies for both scintillators were close to 0.76 for the logical sum of double coincidences and
4.3. Coincidence counting Α set of three sources with masses around 10 mg were prepared by gravimetric deposition onto metalised VYNS foils. The measurement setup included a pressurised proportional counter with P10 counting gas at 1000 kPa in the beta channel and a coaxial Ge detector in the
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5. Conclusion
gamma channel. The complete setup has been described previously (Roteta et al., 2012). The standardisation procedure is based on an extrapolation by changing the efficiency in the β+ channel through threshold variation. In order to obtain the source activities, coincidences were measured between the β+ pulses and the annihilation γ rays of 511 keV rays emitted in 22.8% of the decays. For this purpose, a γ window was selected around the full energy peak of 511 keV. This peak includes a proportion of Compton-scattered 909 keV photons which interferes in the measurements. The spectrum of the gamma window has been analysed with the GRILS program (IAEA, 1991) to calculate the net contribution of the annihilation peak and to eliminate the Compton contribution. The energies of the X-rays and Auger electrons following electron capture decay are around 1–17 keV. They are detected in the proportional counter, but as the low discrimination level was set at 17 keV, they were not taken into account. The calculated total β+ efficiency in coincidence with 511 keV gamma rays is around 0.98, but as a consequence of the threshold setting, the extrapolation was performed from a maximum β+ efficiency of 0.72 to a minimum of 0.65. Since the electron capture branch emissions are not registered, the standardisation depends on the β+ branch. All calculations were made from the binary data files created by the digitising unit. A dead time of 10 μs was imposed by the analysis software. Corrections for dead time, accidental coincidences, background and decay were performed using classical formulae (Gandy, 1963; Smith, 1978). Activity per unit mass at the reference time was 465 (9) Bq mg−1. This value corresponds to the mean of three measurement results. The corresponding uncertainty budget is presented in Table 3. Nuclear data are the major component, as results are only based on the β+ branch and the relative uncertainty on the EC/β+ branching ratio is directly transmitted to the final uncertainty. The second contribution, indicated as background in Table 3, corresponds to the calculation of the area of the annihilation peak in the gamma spectrum.
The half-life of 89Zr has been measured by a combination of two techniques, which resulted in a new value of 78.333 (38) h that is lower than the currently recommended value of 78.42 (13) h and has a lower uncertainty than previous measurements. A 89Zr solution was also standardised by liquid scintillation counting (TDCR), 4πγ counting and coincidence measurements with good agreement. References Bé, M.-M., et al., 2016. Table of Radionuclides 8 Bureau International des Poids et Mesures, Sèvres, France. Beattie, B.J., Pentlow, K.S., O'Donoghue, J., Humm, J.L., 2014. A recommendation for revised dose calibrator measurement procedures for 89Zr and 124I. PLoS One 9 (9), e106868. http://dx.doi.org/10.1371/journal.pone.0106868. Bouchard, J., Cassette, P., 2000. MAC3: an electronic module for the processing of pulses delivered by a three photomultiplier liquid scintillation counting system. Appl. Radiat. Isot. 52, 669–672. Broda, R., Cassette, P., Kossert, K., 2007. Radionuclide metrology using liquid scintillation counting. Metrologia 44 (4), S36–S52. Dulieu, C., Kellett, M.A., Mougeot, X., 2017. Dissemination and visualisation of reference decay data from Decay Data Evaluation Project (DDEP). EPJ Web Conf. 146, 07004. Gandy, A., 1963. Mesure Absolue de l′Activité des Radionuclides par la Méthode des Coincidences β-γ. Etude d′une Méthode de Correction Automatique des Erreurs Instrumentales. Int. J. Appl. Radiat. Isot. 14, 385–396. García-Toraño, E., Peyrés, V., Roteta, M., 2007. On the standardization of positron emitters by 4πγ counting. Nucl. Instrum. Methods Phys. Res. A 570, 84–88. García-Toraño, E., Peyrés, M., Roteta, M., 2010. The half-life of 18F. Appl. Radiat. Isot. 68 (7–8), 1561. García-Toraño, E., et al., 2017. Simulation of decay processes and radiation transport times in radioactivity measurements. Nucl. Instrum. Methods Phys. Res. B 396, 46–49. Hamilton, J.H., Langer, L.M., Smith, W.G., 1960. Evidence for small deviations in the allowed positron spectrum of Zr89. Phys. Rev. 119, 772–776. IAEA, International Atomic Energy Agency, 1991. Nuclear Analysis Software, Part 2: Gamma Spectrum Analysis, Activity Calculations and Neutron Activation Analysis (GANAAS). Computer Manual Series no. 3. JCGM100, 2008. Evaluation of Measurement Data–Guide to the Expression of Uncertainty in Measurement (ISO/IEC Guide 98-3). Lin, M., Mukhopadhyay, U., Waligorski, G.J., Balatoni, J.A., González-Lepera, C., 2016. Semi-automated production of 89Zr-oxalate/89Zr-chloride and the potential of 89Zrchloride in radiopharmaceutical compounding. Appl. Radiat. Isot. 107, 317–322. Pommé, S., Camps, J., Ammel, R.V., Paepen, J., 2008. Protocol for uncertainty assesment of half-lives. J. Radioanal. Nucl. Chem. 276 (2), 335–339. Roteta, M., et al., 2012. Standardization of 68Ga by coincidence measurements, liquid scintillation counting and 4πγ counting. Appl. Radiat. Isot. 70, 2006–2011. Salvat, F., 2015. Penelope-2014: A Code System for Monte Carlo Simulation of Electron and Photon Transport. OECD/NEA Data Bank, Issy-les-Moulineaux, France (NEA/ NSC/DOC(2015) 3). Smith, D., 1978. Improved correction formulae for coincidence counting. Nucl. Instrum. Methods 152, 505–519. Wright, B.D., Lapi, S.E., 2013. Designing the magic bullet? The advancement of immunoPET into clinical use. J. Nucl. Med. 54, 1171–1174. Zeglis, B.M., Lewis, J.S., 2011. A practical guide to the construction of radiometallated bioconjugates for positron emission tomography. Dalton Trans. 40, 6168–6195.
4.4. Final value The activity per unit mass values obtained from the three techniques are in very good agreement. Given that the results of the coincidence measurements are subject to large uncertainties, the final result was obtained by the weighted mean of results from the TDCR and 4πγ methods. Activity per unit mass was 464.3 (16) Bq mg−1 at the reference time. It must be mentioned that measurements taken with a CRC-15 Beta Capintec activimeter using the calibration factors presented by Beattie et al. (2014) differ approximately 3% from those obtained in this work.
5
Contents lists available at ScienceDirect
Applied Radiation and Isotopes journal homepage: www.elsevier.com/locate/apradiso
Standardisation and half-life of
89
Zr
⁎
E. García-Torañoa, , V. Peyrésa, M. Rotetaa, M. Mejutoa, A. Sánchez-Cabezudoa, E. Romerob a b
Laboratorio de Metrología de Radiaciones Ionizantes, CIEMAT Avda. Complutense 40, Madrid 28040, Spain Unidad de Aplicaciones Biomédicas y Farmacocinética, CIEMAT Avda. Complutense 40, Madrid 28040, Spain
A R T I C L E I N F O
A B S T R A C T
Keywords: Zr-89 Half-life Standardisation Positron emitters
The nuclide 89Zr is being tested for the labelling of compounds with long blood circulation times. It decays by beta plus emission (22.8%) and by electron capture (77.2%) to 89Y. Its half-life has been determined by following the decay rate with two measurement systems; an Ionisation Chamber and an HPGe detector. The combination of six results gives a value of T1/2 = 78.333 (38) h, slightly lower than the DDEP recommended value of 78.42 (13) h. This radionuclide has also been standardised by liquid scintillation counting, 4πγ counting and coincidence techniques.
1. Introduction
2. Radioactive material
Positron Emission Tomography (PET) plays an important role in the field of molecular imaging. Some radionuclides in this field, i.e. 11C, 13 N, 15O, and 18F, commonly categorised as “standard PET radionuclides”, require an onsite or closely located cyclotron, which decreases the availability and flexibility of radiopharmaceuticals labelled with these radionuclides. As a consequence, the use of “non-standard PET radionuclides” with longer than a few hours half-life for the development of PET imaging probes, has received a growing interest over the last few years (Lin et al., 2016). Among them, 89Zr is an ideal radionuclide for the labelling of compounds with long blood circulation times such as antibodies. It must be noted that one of the most fundamental principles in the construction of effective antibody-based nuclear imaging agents is matching the physical half-life of the radioisotope (Zeglis and Lewis, 2011). The nuclide 89Zr decays by beta plus emission (22.8%) and by electron capture (77.2%) to 89 Y (See Fig. 1.). More than 99% of the decays feed a metastable level of 89Y at 909 keV. The Decay Data Evaluation Project (DDEP) recommended half-life is 78.42 (13) h (Bé at al, 2016), one of the longest among current commercially available beta plus emitters which allows imaging studies up to a 1 week after the injection of a 89Zr-based probe. In fact, 89Zr has recently been recognised as one of the most promising radionuclides for developing new immuno-PET agents (Wright and Lapi, 2013). This paper describes the standardisation and half-life determination of this nuclide. The flowchart of both procedures is presented in Fig. 2.
All 89Zr materials used for these measurements were produced in several batches at BV Cyclotron VU by a (p,n) reaction on natural yttrium-89 (89Y) and isolated with a hydroxamate column. It was commercially available in 1 M oxalic acid solution. After reception at CIEMAT the solutions were adjusted to a total volume of 200 μl using 1 M oxalic acid, subsequently 90 μl of 2 M Na2CO3 were added and incubated for 3 min at room temperature. Finally, 1 mL of an acyclic chelating agent solution, 50 mM DTPA, was added in order to contribute to the stability of the solution and incubated at room temperature for 10–20 min. According to the manufacturer's data sheet, the radionuclide purity, determined by gamma-ray spectrometry, was better than 99.9%. This was confirmed by measurements made at CIEMAT. The individual source preparation is described separately in each section.
⁎
3. Half-life measurements A new half-life determination has been obtained as a combination of measurements taken with an ionisation chamber and an HPGe spectrometer. The use of seven different batches of material minimises possible effects caused by contaminated or impure solutions. 3.1. Measurements with an Ionisation Chamber Half-life determination was carried out by analysing the decay rate of several sources. Sealed 5 mL penicillin-type vials containing about 4 mL of the 89Zr solution described in Section 2 were placed inside the
Corresponding author. E-mail address: [email protected] (E. García-Toraño).
http://dx.doi.org/10.1016/j.apradiso.2017.10.033 Received 10 March 2017; Received in revised form 16 October 2017; Accepted 16 October 2017 0969-8043/ © 2017 Elsevier Ltd. All rights reserved.
Please cite this article as: García-Toraño, E., Applied Radiation and Isotopes (2017), http://dx.doi.org/10.1016/j.apradiso.2017.10.033
Applied Radiation and Isotopes xxx (xxxx) xxx–xxx
E. García-Toraño et al.
assessed following the recommendations given in JCGM100 (2008) and Pommé et al. (2008). An uncertainty component of the half-life value was obtained from the fitting results as the square root of the corresponding value in the covariance matrix multiplied by the reduced chisquare of the fit. This component takes into account both the components due to the statistics of the data and to the fitting procedure. Major components of the uncertainty were the background variation and electrometer response. The first was especially important, as measurements lasted several weeks and the samples were not removed from their position inside the chamber until the end of the measurements. Typical ionisation currents at the start of the measurements were in the order of 10−10 A and the background current about 10–13 A. The weighted mean half-life of all values obtained with this technique was T1/2 =78.333(35) h, where the uncertainty given in parentheses corresponds to the standard deviation of the individual result. Fig. 3 presents the results of the fitting of decay data from one measurement. Residuals are presented in terms of their statistical significance. 3.2. Measurements with a germanium detector
Fig. 1. Simplified decay scheme of
89
Measurements were carried out with an extended-range coaxial HPGe detector from CANBERRA electrically cooled using the pulse tube technology. The detector is surrounded by a cylindrical lead shield, 5 cm. thick. Its relative efficiency is about 35% and the lower practical limit of measurement is about 12 keV. A small sealed vial containing about 1 mL of 89Zr solution was placed at 0.5 cm from the detector window and kept in the same position during the measurements. The electronic setup was formed by an ORTEC DspecPro digital multichannel unit plugged to the detector preamplifier. This unit controls the acquisition setup and was configured to periodically register the spectrum area in an energy region (ROI) from 110 keV to 1045 keV. These limits were selected so that any drift in the electronics would produce a minimum effect in the ROI area. Two sets of measurements were carried out whose characteristics are presented in Table 1. Typical count rates were 1900 s−1 and 54 s−1 at the start and end of the measurements, respectively. The decay curves, after background correction, were fitted using the same procedure mentioned above. The results of the two measurements are given in Table 1 and the uncertainty budget is presented in Table 2. The mean value was T1/2 = 78.332 (61) h, in excellent agreement with the value determined by the IC. As for the previous measurements, the
Zr. Nuclear data taken from Bé et al. (2016).
well of an IG-11 re-entrant ionisation chamber. The ionisation current was measured with a Keithley 6514 spectrometer for periods up to 6 half-lives (about 20 days). The system is controlled by a computer so that the ionisation current can be integrated and registered for subsequent analysis. Complete details of the experimental setup have been given elsewhere (García-Toraño et al., 2010). A set of four measurements were made between May 2014 and November 2016. Ionisation values were registered and analysed for the time intervals indicated in Table 1. Samples were kept in the chamber for the complete measurement time. Half-life values were determined by nonlinear fitting of the decay distributions, after subtracting the background contribution. The Levenberg-Marquardt algorithm was used for non-linear fitting of data. The fitting procedure can take into account possible impurity contributions, but given the high purity of the solution, this was not necessary. Table 1 presents the results of the four individual results whose main uncertainty components are detailed in Table 2. They were
Fig. 2. Diagram of the half-life measurements and the standardisation setups followed at CIEMAT in the study of 89Zr.
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Table 1 Evaluated value, results obtained at CIEMAT by two measurement techniques and final value obtained in the present work for the half-life of 89Zr. Uncertainties are given in parentheses in units of the last significant figure. Measurement Technique
T1/2 (min)
Evaluation (Bé et al., 2016) This work Ionisation chamber Ionisation chamber Ionisation chamber Ionisation chamber Weighted mean value Ionisation chamber (σ) HPGe detector HPGe detector Mean value HPGe detector (σ) This work: Final value
78.42 (13) 78.380 (60) 78.315 (30) 78.341 (30) 78.332 (35) 78.333 (35) 78.341 (61) 78.324 (57) 78.332 (61) 78.333 (38)
Number of data points in decay curve
Number of half-lives followed
71 (× 50 readings) 380 (× 50 readings) 480 (× 50 readings) 395 (× 50 readings)
2 6.1 6.1 6.1
268 (3600 s each) 581 (1800 s each)
5.0 4.6
uncertainty in parentheses corresponds to the standard deviation of the individual result. Given that the signal to background ratio was, at the end of the measurements, about unity, the uncertainty budget is dominated by the effect of the background contribution to the fitting of the decay curve. It was estimated by using a set of characteristic background data and by observing the effect of the number of experimental points included in the fit. 3.3. The half-life of
89
Zr
All results are presented in Fig. 4. No significant differences exist between the mean of both groups and the final value was obtained as the weighted mean of all results (JCGM100, 2008):
T =
∑i = 1
7
Ti si2
7
1 si2
∑i = 1
(1)
Fig. 3. Decay rate data of a 89Zr source measured with an ionisation chamber for a period of time corresponding to more than six half-lives (top) and residuals from a fitted decay curve (bottom), expressed in terms of their statistical significance.
Given that the experimental standard deviation of the set of data is lower than the uncertainty calculated according to Table 2, the variance was taken as the variance within a single technique. The final result obtained for the half-life of 89Zr is T1/2 =78.333 (38) h. The result is lower than the DDEP recommended value of 78.42 (13) (Bé at al, 2016) and has a lower uncertainty than the recommended value or any other previous measurement.
check the consistency of measurements within different batches.
4.1. Liquid scintillation counting Although LSC measurements were carried out using three different systems and two scintillating cocktails, only results obtained with the CIEMAT TDCR prototype were used in the final steps. Two sets of four samples, each with masses between 15 mg and 32 mg, were prepared by gravimetric methods directly from the mother solution. Measured activities varied between 6000 Bq and 2300 Bq, depending on the masses and the day of measurement.
4. Standardisation The standardisation of 89Zr was carried out using the following three techniques: Liquid Scintillation Counting (LSC) with Triple to Double Coincidence ratio (TDCR), 4πγ counting and 4πβ(PPC)−γ (Ge) coincidence counting. Additional measurements were carried out by other methods (CIEMAT/NIST, Gamma-ray spectrometry), and the ionisation chamber used in the decay rate measurements was used to Table 2 Uncertainty budget in the measurement of the considered.
89
Zr half-life with ionisation chambers and HP-Ge detectors. Values are “typical” and may differ depending on the specific sample
Uncertainty Component
Ion Chamber HP-Ge detector Relative uncertainty (k = 1) (%)
Statistics component and fitting uncertainty Electrometer response (including range switching)
0.013 0.030
0.030 –
Background variation Radionuclide impurity
0.045 0.01
0.067 0.01
Time measurements Dead time System stability (detector and electronics)
0.01 – 0.01
0.005 0.03 0.008
Combined uncertainty
0.048
0.073
Evaluation method Counting statistics and least squares fitting Excluding the regions affected by electrometer switching and comparing the results From results using several backgrounds from the historic recording Considering a potential contribution of a contaminant with an activity ratio of 1.10–5 Estimation based on PC timing accuracy (1 ms) (Ion chamber) Evaluating the results for several dead times Characterizing the detector stability from measurement of a long-lived radionuclide
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Table 3 Uncertainty components in the standardisation of 89Zr at CIEMAT. Values are expressed in % of the activity per mass. Values are “typical” and may differ depending on the specific result considered.
Fig. 4. Results of the six measurements of the half-life of 89Zr made in this work, with indication of the measurement technique used. The final value, obtained by combination of all results, is also shown.
4.1.1. Efficiency calculations Efficiency calculations were carried out with a program (NUR) which processes data generated with the PENNUC package (GarcíaToraño et al., 2017) that allows the Monte Carlo generation of the decay process by following the decay pathways for any nuclide using nuclear data from the DDEP's NUCLEIDE database (Dulieu et al., 2017). Atomic re-arrangements are followed using a set of routines taken from the PENELOPE simulation package (Salvat, 2015). For 89Zr, a special shape factor was used in the calculation of the positron spectrum (Hamilton et al., 1960), although its effect on the total detection efficiency was small. As a first step, a large number of cascades are generated using the program PENNUC which are then processed by the program NUR to compute the detection efficiency of the problem nuclide. The calculation is performed as follows: for each cascade, the counting efficiency is calculated as the sum of all contributions from the cascade components. For electrons, the calculation is straightforward; for photons, a Monte Carlo simulation of the photon-system interaction is started using the composition and dimensions of the scintillator, the vial and the thickness of the vial wall. If, as a result of Compton or photoelectric interactions, a number of electrons are created, they are added as new components to the original cascade. For positron emitters, two 511 keV photons are also simulated and their contributions accounted for in the calculation process.
METHOD Uncertainty Component
TDCR
4πγ
Coincidences
Counting statistics Extrapolation (inc. counting) Weighing Dead time Efficiency determination Zero-energy extrapolation Background Pile up Counting time Impurities Nuclear data kB value Half-life Resolving time Source stability Combined uncertainty
0.1 – 0.1 0.08 – – 0.05 – 0.01 – 0.25 0.25 0.05 0.1 0.05 0.40
0.09 – 0.1 0.05 0.60 0.13 0.05 – 0.01 – 0.27 – 0.18 – – 0.70
– 0.4 0.1 0.03 – – 1.2 – 0.01 – 1.3 – 0.20 0.03 0.1 1.82
include the contribution from the gamma ray depopulating the metastable level at 909 keV. Results of the measurements with both scintillators gave similar results, 465.0 (19) Bq mg−1 and 464.5 (19) Bq mg−1 for Hisafe 3 and Hionic-Fluor, respectively. The activity per unit mass was obtained as the mean of eight values, and resulted to be 464.7 (19) Bq mg−1 at the reference time. Uncertainty components are presented in Table 3. Two components dominate the uncertainty budget: the effect of the uncertainty on the EC/β+ branching ratio and the determination of the kB value. 4.2. 4πγ counting The application of the 4πγ counting method to the standardisation of positron emitters was presented elsewhere (García-Toraño et al., 2007). Here, the calculation model has been modified and the counting efficiency was computed using the PENELOPE/PENNUC combination (García-Toraño et al., 2017) on a cascade by cascade basis. A set of five sources with masses between 8 mg and 18 mg were prepared by dropping aliquots of the mother solution onto thin polyethylene films sealed after drying and covering with similar foils. The diameter of the active part was about 3 mm. The experimental setup was based on a NaI (Tl) well detector followed by preamplifier, a delay line amplifier, model 460 from ORTEC and analog to digital converter model 7411 from SILENA. Given the high energy of the gamma-rays from the metastable state, a large NaI (Tl) well detector from SCIONIX (17.8 × 17.8 cm.) was preferred to the usual 7.5 × 7.5 cm arrangement. The threshold detection level for photons was established at 5 keV. In these conditions, the detection efficiency of the 909 keV gamma ray was 0.835 and the total detection efficiency was about 1.15. A second set of measurements with a higher threshold (25 keV) confirmed the results. At the reference time, the activity per unit mass was 463.3 (32) Bq mg−1, obtained as the mean of five values, one per sample. Uncertainty components are detailed in Table 3. Major contributions correspond to the detector model, nuclear data (EC/β+ branching ratio) and decay corrections.
4.1.2. Measurements TDCR measurements were carried out with a TDCR prototype built at CIEMAT and were complemented with measurements with a commercial HIDEX counter. The basis of the TDCR method is well covered in the literature (Broda et al., 2007). The CIEMAT counter is built around three photomultiplier tubes from ET Enterprises, model 9807B, powered by a programmable power supply, model N1470 from CAEN. A quad discriminator unit, model 821 and a six-channel variable amplifier, model 612AM, both from LeCroy, are followed by a MAC3 unit from LNHB (Bouchard and Cassette, 2000) that processes all pulses and makes the appropriate dead-time corrections using an external reference clock. A stainless steel shield surrounds the measurement chamber and phototubes to reduce the background contribution. The signal to background ratio was typically 300. Eight samples with masses between 17 mg and 34 mg were prepared gravimetrically in four vials containing 15 mL of Hisafe 3 scintillating cocktail and four more with Hionic-Fluor. Vials were placed in the TDCR system and counted until the logical sum of double coincidences reached, at least, 105 counts. Five measurements were taken consecutively for each vial. Typical counting efficiencies for both scintillators were close to 0.76 for the logical sum of double coincidences and
4.3. Coincidence counting Α set of three sources with masses around 10 mg were prepared by gravimetric deposition onto metalised VYNS foils. The measurement setup included a pressurised proportional counter with P10 counting gas at 1000 kPa in the beta channel and a coaxial Ge detector in the
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5. Conclusion
gamma channel. The complete setup has been described previously (Roteta et al., 2012). The standardisation procedure is based on an extrapolation by changing the efficiency in the β+ channel through threshold variation. In order to obtain the source activities, coincidences were measured between the β+ pulses and the annihilation γ rays of 511 keV rays emitted in 22.8% of the decays. For this purpose, a γ window was selected around the full energy peak of 511 keV. This peak includes a proportion of Compton-scattered 909 keV photons which interferes in the measurements. The spectrum of the gamma window has been analysed with the GRILS program (IAEA, 1991) to calculate the net contribution of the annihilation peak and to eliminate the Compton contribution. The energies of the X-rays and Auger electrons following electron capture decay are around 1–17 keV. They are detected in the proportional counter, but as the low discrimination level was set at 17 keV, they were not taken into account. The calculated total β+ efficiency in coincidence with 511 keV gamma rays is around 0.98, but as a consequence of the threshold setting, the extrapolation was performed from a maximum β+ efficiency of 0.72 to a minimum of 0.65. Since the electron capture branch emissions are not registered, the standardisation depends on the β+ branch. All calculations were made from the binary data files created by the digitising unit. A dead time of 10 μs was imposed by the analysis software. Corrections for dead time, accidental coincidences, background and decay were performed using classical formulae (Gandy, 1963; Smith, 1978). Activity per unit mass at the reference time was 465 (9) Bq mg−1. This value corresponds to the mean of three measurement results. The corresponding uncertainty budget is presented in Table 3. Nuclear data are the major component, as results are only based on the β+ branch and the relative uncertainty on the EC/β+ branching ratio is directly transmitted to the final uncertainty. The second contribution, indicated as background in Table 3, corresponds to the calculation of the area of the annihilation peak in the gamma spectrum.
The half-life of 89Zr has been measured by a combination of two techniques, which resulted in a new value of 78.333 (38) h that is lower than the currently recommended value of 78.42 (13) h and has a lower uncertainty than previous measurements. A 89Zr solution was also standardised by liquid scintillation counting (TDCR), 4πγ counting and coincidence measurements with good agreement. References Bé, M.-M., et al., 2016. Table of Radionuclides 8 Bureau International des Poids et Mesures, Sèvres, France. Beattie, B.J., Pentlow, K.S., O'Donoghue, J., Humm, J.L., 2014. A recommendation for revised dose calibrator measurement procedures for 89Zr and 124I. PLoS One 9 (9), e106868. http://dx.doi.org/10.1371/journal.pone.0106868. Bouchard, J., Cassette, P., 2000. MAC3: an electronic module for the processing of pulses delivered by a three photomultiplier liquid scintillation counting system. Appl. Radiat. Isot. 52, 669–672. Broda, R., Cassette, P., Kossert, K., 2007. Radionuclide metrology using liquid scintillation counting. Metrologia 44 (4), S36–S52. Dulieu, C., Kellett, M.A., Mougeot, X., 2017. Dissemination and visualisation of reference decay data from Decay Data Evaluation Project (DDEP). EPJ Web Conf. 146, 07004. Gandy, A., 1963. Mesure Absolue de l′Activité des Radionuclides par la Méthode des Coincidences β-γ. Etude d′une Méthode de Correction Automatique des Erreurs Instrumentales. Int. J. Appl. Radiat. Isot. 14, 385–396. García-Toraño, E., Peyrés, V., Roteta, M., 2007. On the standardization of positron emitters by 4πγ counting. Nucl. Instrum. Methods Phys. Res. A 570, 84–88. García-Toraño, E., Peyrés, M., Roteta, M., 2010. The half-life of 18F. Appl. Radiat. Isot. 68 (7–8), 1561. García-Toraño, E., et al., 2017. Simulation of decay processes and radiation transport times in radioactivity measurements. Nucl. Instrum. Methods Phys. Res. B 396, 46–49. Hamilton, J.H., Langer, L.M., Smith, W.G., 1960. Evidence for small deviations in the allowed positron spectrum of Zr89. Phys. Rev. 119, 772–776. IAEA, International Atomic Energy Agency, 1991. Nuclear Analysis Software, Part 2: Gamma Spectrum Analysis, Activity Calculations and Neutron Activation Analysis (GANAAS). Computer Manual Series no. 3. JCGM100, 2008. Evaluation of Measurement Data–Guide to the Expression of Uncertainty in Measurement (ISO/IEC Guide 98-3). Lin, M., Mukhopadhyay, U., Waligorski, G.J., Balatoni, J.A., González-Lepera, C., 2016. Semi-automated production of 89Zr-oxalate/89Zr-chloride and the potential of 89Zrchloride in radiopharmaceutical compounding. Appl. Radiat. Isot. 107, 317–322. Pommé, S., Camps, J., Ammel, R.V., Paepen, J., 2008. Protocol for uncertainty assesment of half-lives. J. Radioanal. Nucl. Chem. 276 (2), 335–339. Roteta, M., et al., 2012. Standardization of 68Ga by coincidence measurements, liquid scintillation counting and 4πγ counting. Appl. Radiat. Isot. 70, 2006–2011. Salvat, F., 2015. Penelope-2014: A Code System for Monte Carlo Simulation of Electron and Photon Transport. OECD/NEA Data Bank, Issy-les-Moulineaux, France (NEA/ NSC/DOC(2015) 3). Smith, D., 1978. Improved correction formulae for coincidence counting. Nucl. Instrum. Methods 152, 505–519. Wright, B.D., Lapi, S.E., 2013. Designing the magic bullet? The advancement of immunoPET into clinical use. J. Nucl. Med. 54, 1171–1174. Zeglis, B.M., Lewis, J.S., 2011. A practical guide to the construction of radiometallated bioconjugates for positron emission tomography. Dalton Trans. 40, 6168–6195.
4.4. Final value The activity per unit mass values obtained from the three techniques are in very good agreement. Given that the results of the coincidence measurements are subject to large uncertainties, the final result was obtained by the weighted mean of results from the TDCR and 4πγ methods. Activity per unit mass was 464.3 (16) Bq mg−1 at the reference time. It must be mentioned that measurements taken with a CRC-15 Beta Capintec activimeter using the calibration factors presented by Beattie et al. (2014) differ approximately 3% from those obtained in this work.
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