Development of multiple elution cartridge based radioisotope concentrator device for increasing the 99mtc and 188re concentration and the effectiveness of 99mtc99mo utilisation

Development of multiple-elution cartridgebased radioisotope concentrator device for increasing the 99mTc and 188Re concentration and the effectiveness of 99mTc/99Mo utilisation Van So Le, Nabil Morcos & Zac Bogulski Journal of Radioanalytical and Nuclear Chemistry An International Journal Dealing with All Aspects and Applications of Nuclear Chemistry ISSN 0236-5731 J Radioanal Nucl Chem DOI 10.1007/s10967-014-3439-9 23 Your article is protected by copyright and all rights are held exclusively by Akadémiai Kiadó, Budapest, Hungary This e-offprint is for personal use only and shall not be selfarchived in electronic repositories If you wish to self-archive your article, please use the accepted manuscript version for posting on your own website You may further deposit the accepted manuscript version in any repository, provided it is only made publicly available 12 months after official publication or later and provided acknowledgement is given to the original source of publication and a link is inserted to the published article on Springer's website The link must be accompanied by the following text: "The final publication is available at link.springer.com” 23 Author's personal copy J Radioanal Nucl Chem DOI 10.1007/s10967-014-3439-9 Development of multiple-elution cartridge-based radioisotope concentrator device for increasing the 99mTc and 188Re concentration and the effectiveness of 99mTc/99Mo utilisation Van So Le • Nabil Morcos • Zac Bogulski Received: August 2014 Ó Akade´miai Kiado´, Budapest, Hungary 2014 Abstract A self-shielded, sterile and cartridge-based radioisotope concentrator device coupled to 99mTc/188Re generators to increase the 99mTc/188Re-concentration of the generator eluate was developed based on new aminoalkylfunctionalized silica sorbent which conditionally catches and release 99mTc/188Re to concentrate the daughter nuclide of the generator eluates The cartridge can be used for multiple elutions with an overall concentration factor of [100 and daughter nuclide recovery yield of [85 % This device can be used for 10 days extension of 99mTc-generator life-time, saving about 20 % of the generator activity and for ‘‘early’’ generator-elution programs, under which the generator is eluted at an optimized build-up time for increasing the effectiveness of 99mTc/99Mo utilisation Keywords 99Mo/99mTc-generator Á Radioisotopeconcentrator Á 188Re Introduction 99m Tc is used in approximately 85 % of diagnostic imaging procedures in nuclear medicine world-wide 188Re is important radio-therapeutic radionuclide The expansion of 99m Tc and 188Re application depends on the generator availability However, the cost-effective utilisation of 99m Tc and 188Re generators and the quality of the generator eluates are controlled by the 99mTc and 188Re generator V S Le Á N Morcos Á Z Bogulski Cyclopharm Ltd, Lucas Heights, Nsw, Australia V S Le (&) MEDISOTEC, Gymea, Nsw, Australia e-mail: vansole01@gmail.com operation/elution management, which is determined by the 99m Tc and 188Re concentration in the generator eluate The injection dose activity of 99mTc- and 188Re-based radiopharmaceuticals delivered in mL solution (99mTc- or 188 Re- concentration, MBq/mL) is an important factor in determining the quality of 99mTc based SPECT imaging diagnosis or 188Re-based radiotherapy, respectively Generally 99mTc and 188Re eluates are produced from the generators in fixed volume and the 99mTc and 188Re concentration of the eluates decreases with the life time of the generators due to radioactive decay of parent nuclides 99 Mo and 188W, respectively Consequently, the useful life time of the generator is also a function of available 99mTc and 188Re concentration of the eluate Moreover, the 99mTc also decays to 99Tc during his build-up from the decay of 99 Mo This process not only reduces the effectiveness of 99m Tc/99Mo activity utilisation (i.e a large quantity of 99m Tc activity is wasted and the generator is non-economically exploited), but also it makes the specific activity (SA) of 99mTc continuously decreased The low SA may cause the labelling quality of 99mTc eluate is degraded This means that the elution of the generator at a shorter buildup time of the daughter nuclide will result in its better labelling quality and more effectiveness of 99mTc/99Mo activity utilisation In contrast, the 99mTc elution performed at shorter build up time (‘‘early’’ elution) will result a lower 99m Tc yield and thus yields an eluate of lower 99mTcconcentration These facts show that a high labelling quality solution of clinically sufficient 99mTc concentration could be achieved if the generator eluate obtained at an ‘‘early’’ elution is further concentrated by a certified radioisotope concentrator device Obviously, the radioisotope concentrator may not only has positive impact on the extension of useful life time of the generators, but also is capable to increase the effectiveness of 99mTc and 99Mo 123 Author's personal copy J Radioanal Nucl Chem utilisation by performing the early elutions of the generator at any time before maximal build-up of 99mTc This fact has been proved with the performance of the radioisotope concentrator device developed at Cyclopharm Ltd, which is reported in this article Experimental Materials and methods 99m Tc-generator was supplied from ANSTO (Australia) Functional sorbent and strong cation exchange in silver form were provided by MEDISOTEC and IC-Ag resin was purchased from ALTECH Associates Aust Pty Ltd Radioactivity of 99Mo and 99mTc was measured using Capintec radioisotope dose calibrator Gamma-ray spectrometric assays were performed using an Ortec gammaray spectrometer coupled with HpGe detector, which was calibrated using a standard 152Eu radioisotope solution Fig Radioisotope concentrator device with standard accessories a and the radioisotope concentrator device coupled with 99mTc generator for in-line elution/concentration of 99mTc eluate b Radioisotope concentration process Design of Concentrator Device [4, 5] A multi-elution, radioisotope concentrator device [1–3], inline eluted via evacuated-vial and through disposable sterile filters was developed to increase the concentration of 99mTc in the elution of aged commercial 99mTc generators A self-shielded radioisotope concentrator device (Fig 1) was created based on a newly developed sorbent/ concentrator column which selectively retains 99mTcO4ions 99mTc concentration is performed in two steps First, a standard elution of the generator through a tandem of: (1) a competitive ion-selective (CIS) column (Silver-form of strong cation exchange resin or IC-Ag resin) and (2) a sorbent (Isosorb-FS-01) concentration column of the concentrator is performed with or 10 mL saline The Cl- and MoO42- ions are retained on CIS column by forming a stable AgCl and Ag2MoO4 precipitates, while 99mTcO4ions retained on the Isosorb-FS-01 sorbent by an anion exchange reaction 99mTc is then eluted from the concentrator column with \1.0 mL saline into an evacuated vial through a Millipore filter and is ready for injection The design of the device in form of a disposable cartridge was optimised to make elution process effective, simple, sterile and radiation safe Disposable cartridge was designed for 5–10 elutions The early elutions were also performed at the h buildup times to evaluate the effective utilisation of 99mTc generator achieved with an early elution regime, for which the 99mTc-yield ratio (Ry) factor was used as described in the following sections Gentech 99mTc generators of 110 GBq activities eluted with 10 mL saline was chosen to test our radioisotope concentrator device In general, the performance of the concentration process is characterized with the concentration factor n, 123 n ¼ c2 =c1 For a concentration process of solute recovery yield (k), the following mass balance is established: V2  c ¼ k  c  V Relating the above equations, the following is derived: n¼ c2 V1 ¼k c1 V2 where, V1 and V2 are the solution volumes before and after concentration, respectively c1 is the solute concentration in the solution before the concentration and c2 is the solute concentration in the solution after the concentration using a given concentration process In individual case of 99mTc concentration, c1 is the 99mTc radioactivity concentration in the eluate eluted from the 99mTc generator and c2 is the 99m Tc radioactivity concentration in the 99mTc solution concentrated using a given concentration process All the chromatographic column concentration processes are described by the following basic equations V1 ¼ Vm ỵ KS S where S ẳ mc  S and KS ¼ KW = S If V2 is given as a designed value, the concentration factor (n) is evaluated based on the above equations Assuming the dead volume of the concentration column Vm ( V2), the concentration factor (n) is assessed for the designing of the concentrator column as follows: Author's personal copy J Radioanal Nucl Chem Table Effect of radioisotope concentrator on Radioactivity of generator, GBq 99m Tc-generator useful life Life time of generator useful for clinical SPECT imaging (days) Life time of generator useful for the Cyclomedica Technegas Generator (days) Without 99mTc concentration Without With post-elution concentration of 99mTc 99m Tc concentration With post-elution concentration of 99mTc 3.7 11.1 10 18.5 12 37.0 15 111.0 14 20 14 Fig Gamma-ray spectra of 99m Tc-solutions: a, Spectrum of unprocessed 99mTc-generator eluate; b, Spectrum of concentrated 99mTc-eluate  !   V1 Vm S S nẳk ẳk ỵ KS ẳ k  KS  V2 V2 V2 V2 where, KS (mL/m2) and KW (mL/g) are the area and weight distribution coefficients of the solute (99mTcO4-) in a given sorbent-solution system, respectively; S is the surface area of the sorbent loaded in the column (m2); mc is the weight of sorbent loaded in the column (g); S is the specific surface area of the sorbent (m2/g) Results and discussion Use of radioisotope concentrator for increasing the generator life time As a result obtained from our project, the 99mTc eluate was concentrated more than 10-fold with a 99mTc recovery yield of [85 % using this radioisotope concentrator device The increase in 99mTc concentration in the eluate enhances the utilisation of technetium in Technegas generator-based lung perfusion (3.7–9.25 GBq/mL) and other SPECT (740–1,110 MBq/mL) imaging studies 10 or 20 repeated elutions were successfully performed with each cartridge coupled to the 10 or mL saline solutioneluted generators, respectively So, each cartridge can be effectively used for 10 days in the hospital environment for radiopharmaceutical formulation This fact also shows that when a bolus 99mTc-solution is needed to be concentrated, the concentration factor n = 50 can be achieved The useful lifetime of the 99mTc generator (Table 1) was significantly extended from 10 to 20 days for the generators of 11.1–111 GBq activity, respectively This means that about 20 % of the generator activity is saved by extending the life time of the generator as 123 Author's personal copy J Radioanal Nucl Chem Fig Kinetics of radioactive decay/99mTc-activity build-up in the generator eluted with an early elution regime: a, 99Moactivity; b, 99mTc-activity buildup from beginning; c, 99mTcactivity growth after first elution; d, 99mTc-activity growth/eluted at 6-h elutions; e, 99m Tc-SA in the system of 99m Tc-radioactivity build-up from beginning Fig a, Effectiveness of 99m Tc activity utilisation of the generator eluted with an early elution program compared with that normally eluted at the time point of maximal 99mTc-buildup (The dashed line is calculated using Eq and the solid black circles are experimental results); b, Recovery of residual 99mTcactivity of expired generators versus their originally calibrated activities shown in Fig 4b The 99Mo impurity in the 99mTc solution eluted from the Gentech generator was totally eliminated by this radioisotope concentrator device (Fig 2) Use of radioisotope concentrator in optimisation of the generator elution to increase 99mTc-activity yield and effectiveness of 99Mo utilisation [5, 6] The radioisotope concentration process not only has positive impact on the extension of useful life time of the generators, but also is capable to increase the effectiveness of 99mTc and 99Mo utilisation by performing the early elutions of the generator at any time before maximal buildup of 99mTc The 99mTc activity yield of the generator can be increased by performing an optimal regime of multiple ‘‘early’’ elutions (the generator is more frequently eluted) combined with a process of 99mTc-eluate concentration The method for evaluation of the effectiveness of early elution regime in comparison with a single elution 123 performed at maximal build-up time of the generator is described as follows For this evaluation, 99mTc-yield ratio (Ry) is set up and calculated based on quotient of the total of eluted 99mTc-elution yields (or 99mTc-activity produced/ used for scans) in all i elutions (Ei is the index for the ith elution) divcan be increased by performing an optimal ided by the maximal 99mTc-activity (A99mTcðMaxÞ which would be eluted from the generator at maximal build-up time tMax: , i¼n X A99m TcEi ị A99m TcMaxị 1ị Ry ẳ iẳ1 Starting from the basic equations of radioactivity buildÀ Á up/yield A99m TcðMaxÞ and time (maximal build-up time, tMax) for attaining the maximal activity build-up yield of daughter nuclide radioactivity growth-in in the radionuclide generator system, the equation for calculation of the 99m Tc-yield ratio (Ry) is derived as follows: The decay scheme of 99Mo/99mTc system used in the calculation processes is present as follows Author's personal copy J Radioanal Nucl Chem Table Effectiveness of 99mTc elution performed with an early elution regime compared with that normally eluted at the time point of maximal 99m Tc-build-up Elution time AM Day Day Day 15,170.0 7,400.0–5,735.0 4,440.0–3,515.0 2,109.0–1,628.0 Total yield of generator elutions per day (MBq) 15,358.7 25,289.5 15,540.0 7,292.7 99m 3,071.0 15,358.7 2,331.0 11,655.0 1,435.6 7,178.0 673.4 3,370.7 99m Early elution regime of h 99mTc-buid-up time (4 elutions/day) Elution at maximal 99mTcbuild-up time (tMax = 22.86 h) (One elution/day) Tc-concentration (MBq/mL) Tc-concentration (MBq/mL) Total yield of generator elution per day (MBq) Generator activity at calibration day (day 1, 8:00 AM) is 19.425 GBq 99Mo or 17.0 GBq with Ultralute concentrator device; Final concentrated 99mTc solution volume is 1.0 mL 99m Tc; Solvent is mL saline; Generator is coupled elution yields eluted in all i elutions is the sum of 99mTcÀ Á radioactivities at different elution number i A99m TcðEi Þ This amount is described as follows xẳi1 iẳn X h X A99m TcEi ị ẳ k99m Tc  N0;Mo  eÀkMo xtb  b1 x¼0 i¼1 Radioactivity of A99m Tc 99m Tc nuclides in the generator:   kMo ¼ k99m Tc  N0; Mo  b1  k99m Tc À kMo  ðe ÀkMo t Àe Àk99m Tc t  kMo  k99m Tc À kMo ð2Þ Þ  i  ðeÀkMo tb À eÀk99m Tc tb Þ ð6Þ The maximal 99mTc-activity build-up/yield in Mo/99mTc generator system described using Eqs and is as follows   kMo A99m TcMaxị ẳ k99m Tc N0; Mo  b1  k99m Tc À kMo ÀkMo tMax Àk99m Tc tMax  ðe Àe Þ ð7Þ 99 The maximal build-up time (at which the maximal Tc-activity build-up/yield in 99Mo/99mTc generator system is available): 99m tMax ẳ ẵlnk99m TcÀ =k99 Mo ފ=ðk99m Tc À k99 Mo Þ ð3Þ Numbers of Tc atoms at build-up time t: 99m NTc ẳ N99 Tc ỵ N99m Tc ẳ N0;Mo NMo ¼ N0;Mo  ð1 À eÀkMo t Þ ð4Þ 99m 99m Tc in the Tc Specific activity of carrier-included generator system or 99mTc-eluate is calculated by combination of Eqs and as follows: A99m Tc NTc ¼ 6:02213  10 À k t Á k99mTc b1 e Mo À ek99mTc t   k ðGBq=lmolÞ 99mTc  ð1 ekMo t ị kMo Ry ẳ iP ¼n A99m TcðEi Þ i¼1 A99m TcðMaxÞ ¼ x¼iÀ1 P ½eÀkMo xtb  ðeÀkMo tb À e Àk99m Tct b ފ x¼0 ðeÀkMo tMax À e Àk99m Tct Max Þ 8ị SA99m Tc ẳ 99m Tc-yield ratio (Ry) is derived from the above Eqs 6, as follows ð5Þ Tc-yield ratio (Ry) calculation for multiple early elution regimes The Ry value is calculated based on quotient of the total 99mTc-elution yields eluted (or 99mTc-activity produced/used for scans) in all i elution numbers (Ei is the index for the ith elution) divided by the maximal 99mTcÀ Á activity A99m TcðMaxÞ which would be eluted from the generator at maximal build-up time tMax The total 99mTc- i is the number of the early elutions needed for a practical schedule of SPECT scans The build-up time (tb) for each elution is determined as tb = (tMax/i) x is the number of the elution which have been performed before starting a 99mTc-build-up process for each consecutive elution At this starting time point no residual Tc atoms left in the generator from a preceding elution is assumed (i.e 99mTc-elution yield of the preceding elution is assumed 100 %) The results of the evaluation based on the Eqs 2, 5, and are described in Figs and 4a As shown in Fig 4a, the 99m Tc yield of the generator eluted with a early elution regime of build-up/elution time \6 h increases by a factor [2 123 Author's personal copy J Radioanal Nucl Chem With the utilization of 99mTc concentrator device which give a final 99mTc-solution of 1.0 mL volume, the experimental results reported in Table using a *20 GBq generator as an example confirmed that the concentration and the yield of 99mTc solution eluted with a 6-h elutionregime is much better than that achieved with the elution regime performed at the maximal build up time (22.86 h) The effectiveness of this early elution mode was also confirmed experimentally in the prior-of-art of 68Ga/68Ge generator [7] Conclusions We conclude that the radioisotope concentrator device functioned well and is robust in operation This device will, to some extent, mitigate the global 99mTc crisis The extension of the 99mTc-generator life time can save about 20 % of the generator activity 99mTc concentrator device also allows performing an optimal regime of multiple ‘‘early’’ elutions, under which the generator will be eluted at the time before establishment of radioactive decay equilibrium in the 99mTc/99Mo system This elution regime will increase the 99mTc activity use and specific activity of the 99mTc eluate by a factor of [2 All these features of the 99m Tc concentrator device benefit the economic use of the 123 generator for users, the improved quality of labelling/scan for radiopharmacies, the reduced residual radiation dose of 99 Tc for patients, and the lowered cost of scan for patients Thus there is an increase in the effectiveness of 99Mo utilisation References Le VS, McBrayer J, Morcos N (2014) A radioisotope concentrator, PCT International Publication Number WO2014/063198A1, http:// patentscope.wipo.int/search/en/detail.jsf?docId=WO2014063198& recNum=1&office=&queryString=ALLNAMES%3A%28Le%2C ?Van?So%29&prevFilter=&sortOption=Pub?Date?Desc&max Rec=7 Accessed August 2014 Le VS, Morcos N, McBrayer J, Bogulski Z, Buttigieg C, Phillips G (2013) J Label Compd Radiopharm 56(Suppl 1):S190 Le VS, Morcos N (2013) J Nucl Med 54(S2):609 Le VS, Le MK (2013) Australian Patent AU2013903629, 20 September 2013 Le VS, Do ZH, Le MK, Le V, Le NT (2014) Molecules doi:10 3390/molecules19067714 Le VS (2014) 99mTc Generator Development: up-to-date 99mTcrecovery technologies for increasing the effectiveness of 99Mo utilization Sci Technol Nuclear Installations doi:10.1155/2014/ 345252 Le VS (2013) Rec Res Can Res 194:43–75 ... Development of multiple- elution cartridge- based radioisotope concentrator device for increasing the 99mTc and 188Re concentration and the effectiveness of 99mTc/ 99Mo utilisation Van So Le • Nabil Morcos... self-shielded, sterile and cartridge- based radioisotope concentrator device coupled to 99mTc/ 188Re generators to increase the 99mTc/ 188Re- concentration of the generator eluate was developed based on new... standard 152Eu radioisotope solution Fig Radioisotope concentrator device with standard accessories a and the radioisotope concentrator device coupled with 99mTc generator for in-line elution/ concentration