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Production and chemical processing of Lu-177 for nuclear medicine at the Munich research reactor FRM-II
Abstract
Das Ziel der Dissertation war die Untersuchung der Realisierbarkeit der Produktion von <sup>177</sup>Lu am Forschungsreaktor FRM-II. Die Ausbeute von <sup>177</sup>Lu über der direkten (<sup>176</sup>Lu(n,gamma)<sup>177</sup>Lu) und der indirekten (<sup>176</sup>Yb(n,gamma)<sup>177</sup>Yb beta<sup>-</sup> Zerfall <sup>177</sup>Lu) Produktionsweg wurde bestimmt. Es wurde ein verlässlicher Berechnungsalgorithmus für die <sup>177</sup>Lu Ausbeute entwickelt. Auf dem direkten Produktionsweg wurde das Isomer <sup>177m</sup>Lu als einzige langlebige radiochemische Kontamination identifiziert. Zur chemischen Aufarbeitung von <sup>177</sup>Lu unter Ausschluß von Querkontaminationen wurde ein Verfahren in einem geschlossenen System erarbeitet.
... It also emits γ photons of 113 keV (6.4%) and 208 keV (11%), which are good for imaging the localization under study with a gamma camera. All over the world, a need in lutetium-177 increases from year to year (Dash et al., 2015;Dvorjakova, 2007;Barkhausen, 2011;Tarasov et al., 2013;Kuznetsov et al., 2019). ...
... The experimentally determined yields of 177 Lu produced in the direct route exceeded the theoretical ones, obtained with k = 1, by up to 180%. Following (Dash et al., 2015;Dvorjakova, 2007;Barkhausen, 2011;Zhernosekov et al., 2008;Mishra et al., 2017), the coefficient « k», chosen by comparison between estimated values and experimental one, being dependent of neutron spectrum, taken equal to 1.5-2.5 is individual constant of a reactor. ...
... Disadvantages: availability of parasite isotope Lu-177m, having long half-life (160.44 days). However, as is known (Dash et al., 2015;Dvorjakova, 2007;Bhardwaj et al., 2020), its fraction in the yield is quite small (1-5%). ...
Production of lutetium-177 using direct nuclear reaction 176Lu(n,γ)177Lu by WWR-K reactor neutrons on enriched LuCl3 (up to 82% of 176Lu) is described. Calculations were performed by MCNP6 transport code. Two different irradiation positions of the WWR-K research reactor were considered. Estimates of the maximum specific activity of the luthetium-177 are obtained for the reactor irradiation positions located: (a) in the reactor core centre, (b) in the core periphery. In these positions, thermal neutron flux is two times different.
Experimental data was shown that k-factor is 1.5 for considered irradiation positions. The study shows that for the position located in the core center, the estimated maximum specific activity of lutetium-177 is 819 GBq/mg, is to be achieved after 15 days of irradiation. For the position located in the core periphery, specific activity of lutetium-177 is 561 GBq/mg, is to be achieved after 20 days of irradiation. Ratio of Lu-177m to Lu-177 specific activity is not more than 0.025 for both irradiation positions.
... Despite this setback, the Lu route has potential to grow as the most popular method for the production of the 177 Lu medical isotope. It is reported that enrichment of natural Lu to > 60% in 176 Lu is adequate for medical applications [2]. ...
... Applying the selection rules for a single-photon electric dipole transition, it is found that 28 hyperfine excitation pathways exist for a two-step resonance excitation in the case of each of the Lu isotopes (Table 4). Simulated hyperfine spectra of the Lu isotopes for the 5d 6s 2 [4] for the selective photoionization of 176 Lu. The ground state of 2 D 3/2 has four hyperfine levels: 11/2, 13/2, 15/2, and 17/2; therefore, when a narrowband laser is employed, only 25% population of the fine structure state 2 D 3/2 can be accessed through the 17/2-19/2-17/2 hyperfine excitation pathway. ...
... Dvorakova [2] reported that the enrichment to the level of >60% is adequate for using 176 Lu as a medical isotope. To achieve this level of degree of enrichment, the upper limits to the spectral bandwidths of first and second excitation lasers are 100 MHz and 180 MHz, respectively. ...
Numerical computations of ionization efficiency and isotope selectivity of $^{176}{\rm Lu}$ 176 L u have been carried out for the following three-step ladder type photoionization scheme, $5d6{s^2}^2\, D_{3/2}(0.0\;{\rm cm}^{- 1})\mathop{-\!\!-\!\!-\!\!\longrightarrow}\limits^{540.4068\,{\rm nm}} 5d6s6p$ 5 d 6 s 2 2 D 3 / 2 ( 0.0 c m − 1 ) − − − ⟶ 540.4068 n m 5 d 6 s 6 p ${}^4\!F_{5/2}^o(18504.58\;{\rm cm}^{- 1})\,\mathop{-\!\!-\!\!-\!\!\longrightarrow}\limits^{535.0626\,{\rm nm}}\,$ 4 F 5 / 2 o ( 18504.58 c m − 1 ) − − − ⟶ 535.0626 n m $5d6s7s\,{}^4\!D_{3/2}({37193.98\;{\rm cm}}^{- 1})\,\mathop{-\!\!-\!\!-\!\!\longrightarrow}\limits^{618.0061\,{\rm nm}}\, 53375\;{{\rm cm}^{- 1}}\,{\rm Autoionization}\,{\rm State}\, \to$ 5 d 6 s 7 s 4 D 3 / 2 ( 37193.98 c m − 1 ) − − − ⟶ 618.0061 n m 53375 c m − 1 A u t o i o n i z a t i o n S t a t e → ${{\rm Lu}^ +}$ L u + , by invoking the density matrix formalism for the laser–atom interactions. Equations of motion have been derived for the odd isotopes by inclusion of hyperfine levels. The line shapes and their effect on the ionization efficiency and isotope selectivity have been discussed in detail. The effects of power of excitation and ionization lasers, spectral bandwidths, pulse delays, Doppler broadening of the atomic ensemble on the ionization efficiency, and degree of enrichment have been presented. Optimum conditions for the power of excitation, detunings, and other system parameters for the selective yet efficient photoionization of $^{176}{\rm Lu}$ 176 L u have been identified.
... However, because of intense burn-up of the nuclei of the starting material in the course of irradiation, the specific activity of the reaction product does not coincide with its yield (maximal activity). Detailed analysis of nuclear transmutations in 177 Lu production, made in [7][8][9], has shown that, for medium-flux reactors with the flux density of thermal neutrons of 5 × 10 14 cm -2 s -1 , the specific activity of 45 000 Ci g -1 can be reached, and for high-flux reactors, in particular, SM (Research Institute of Atomic Reactors, Dimitrovgrad, Russia) and HFIR (ORNL, Oak Ridge, the United States) with the flux density of 2 × 10 15 cm -2 s -1 , the specific activity as high as ~76 000 Ci g -1 is reached upon 10-day irradiation. This value amounts to approximately 70% of the theoretical specific activity of 177 Lu (~110 000 Ci g -1 ) and is probably limiting in the production of 177 Lu from 176 Lu using the existing reactors. ...
... High neutron capture cross section causes high neutron absorption in the target, decreasing the yield and specific activity of the desired radionuclide. To reduce the absorption, it is recommended that the Lu weight in the target be restricted to several milligrams [9,10]. Quantitative evaluation of the self-absorption was not made in these studies. ...
... At a standard time of the SM re-actor campaign (20-21 effective days), the 177 Lu yield will be 470-480 Ci g -1 . For medium-flux reactors, the yield is substantially lower and does not exceed 110-115 Ci g -1 at the neutron flux density of 5 × 10 14 cm -2 s -1 and irradiation time of 20 days, with 40% of the saturation activity reached in the first 5 days of irradiation and 64%, in 10 days [7,9]. However, a decrease in the yield does not affect the specific activity of 177 Lu. ...
Papers dealing with the ¹⁷⁷Lu production technology are analyzed with the aim of evaluating the readiness of the existing processes to setting up regular large-scale production, which is the necessary condition for the progress of the market of ¹⁷⁷Lu-based radiopharmaceuticals. This is now on the initial step of its development. The ¹⁷⁷Lu production processes are based on irradiation of isotopically enriched ¹⁷⁶Lu or ¹⁷⁶Yb with reactor neutrons, followed by radiochemical processing of the irradiated targets. Specific production features are analyzed with emphasis on process aspects of the reactor and radiochemical stages. The evaluation shows that the presently reached level of the ¹⁷⁷Lu production technology allows only the current demand of nuclear medicine for this radionuclide, corresponding to the initial step of its clinical use, to be met. Further growth of the market of ¹⁷⁷Lu radiopharmaceuticals requires the upgrading of existing or construction of new facilities, which is possible only with significant improvement of both reactor and radiochemical processes.
... Second, the reaction cross section, which is a function of neutron velocity [σ (v n )], exhibits a strong resonance at 0.1413 eV and therefore it deviates from the 1/v n law. For such situations, the Westcott convention has to be adopted for calculating the activity produced [29]: ...
... is the Westcott spectral index, s o (α) is the s o (E r ) -α , where s o and E r are constants. The k-factor depends upon several parameters such as, thermal energy cross-section at a reference temperature, resonance integral, epithermal index, epithermal flux shape factor, Westcott g-factor, temperature, Cadmium cut-off energy, effective resonance energy and flux attenuation factor for thermal and epithermal neutrons [29]. Generally, the value of 'k' is reported to be between 1.5 and 2.5 [30]. ...
Lutetium-177 [T½ = 6.76 d; Eβ (max) = 0.497 MeV; maximum tissue range ~2.5 mm; 208 keV γ-ray] is one of the most important theranostic radioisotope used for the management of various oncological and non-oncological disorders. The present review chronicles the advancement in the last decade in 177Lu-radiopharmacy with a focus on 177Lu produced via direct 176Lu (n, γ) 177Lu nuclear reaction in medium flux research reactors. The specific nuances of 177Lu production by various routes are described and their pros and cons are discussed. Lutetium, is the last element in the lanthanide series. Its chemistry plays a vital role in the preparation of a wide variety of radiopharmaceuticals which demonstrate appreciable in vivo stability. Traditional bifunctional chelators (BFCs) that are used for 177Lu-labeling are discussed and the upcoming ones are highlighted. Research efforts that resulted in the growth of various 177Lu-based radiopharmaceuticals in preclinical and clinical settings are provided. This review also summarizes the results of clinical studies with potent 177Lu-based radiopharmaceuticals that have been prepared using medium specific activity 177Lu produced by direct neutron activation route in research reactors. Overall, the review amply demonstrates the practicality of the medium specific activity 177Lu towards formulation of various clinically useful radiopharmaceuticals, especially for the benefit of millions of cancer patients in developing countries with limited reactor facilities.
... The 177 Lu thus obtained is of relatively high specific activity. Natural abundance of 176 Lu is only 2.6% thereby requiring enriched Lu 2 O 3 target for this route of production, the limitation being only carrieradded 177 Lu) present in the target reduce the specific activity of 177 Lu obtained in (n,ϒ) activation [6,17]. ...
... Carrier free production requires enriched target material that in principle should be recycled as the neutron capture cross section of 176 Yb is low. Radiochemical separation of Yb/Lu in the irradiated target also forms a crucial parameter for high specific yield of 177 Lu [17]. ...
With the innovations in nuclear medicine techniques, Lutetium 177 (177Lu) has epitomized as a revolutionary theranostic agent- with both scintigraphic and therapeutic properties. The present review focusses on the introduction of 177Lu as a promising modality for tumor diagnosis and therapy in widespread metastases . Being a shorter β-range emitter providing better irradiation of smaller tumor volumes, 177Lu- based PRRT is being increasingly used in patients with somatostatin receptor positive neuroendocrine tumors. Clinical trials with 177Lu–DOTATATE and 177Lu–DOTATOC have gained considerable interest in recent years with successful tumor regression in patients with malignant metastatic neuroendocrine tumors. Especially, therapy with 177Lu-DOTATATE PRRT has reported to significantly improve the quality of life of Gastroenteropancreatic NET patients because of higher affinity of DOTATATE for the somatostatin type 2 receptors. In addition, this review also sheds light on the diagnostic and palliative aspects of 177Lu which also serves to be an attractive candidate for the preparation of radiopharmaceuticals for radiation synovectomy of small to medium sized joints. Enlisting all the said features, 177Lu is strongly emerging as a promising theranostic agent that could possibly endow Nuclear Medicine an edge over other conventional therapies in near future.
... Aktivitas jenis 161 Tb yang diperoleh dari hasil iradiasi bahan sasaran Gd2O3 alam masih belum memadai untuk aplikasinya dalam penandaan biomolekul sebagai radiofarmaka untuk terapi kanker. Aktivitas jenis 161 Tb yang dibutuhkan diperkirakan mirip dengan aktivitas jenis 177 Lu yang telah diaplikasikan selama ini di kedokteran nuklir dalam penandaan biomolekul, yaitu > 15 -20 Ci/mg (20,21) . Untuk mendapatkan radioisotop 161 Tb dengan aktivitas jenis yang lebih tinggi dapat diupayakan dengan menggunakan bahan sasaran isotop 160 Gd diperkaya (6,11) . ...
ABSTRAK KARAKTERISASI FISIKO-KIMIA RADIOISOTOP TERBIUM-161-KLORIDA (161TbCl3) HASIL IRADIASI BAHAN SASARAN GADOLINIUM OKSIDA ALAM. Saat ini jumlah penderita kanker meningkat setiap tahun di Indonesia dan menjadi penyebab kematian ke tiga setelah penyakit jantung dan darah tinggi. Terbium-161 (161Tb) merupakan pemancar-β- lemah (Eβ- = 0,155 MeV, T1/2 = 6,9 hari) yang sangat mirip dengan 177Lu baik dari segi waktu paro, energi beta dan sifat kimianya. Akan tetapi, 161Tb juga memancarkan elektron konversi dan elektron Auger yang dapat memberikan efek terapi yang lebih besar dibanding 177Lu. Radioisotop 161Tb dapat dibuat dalam bentuk bebas pengemban (carrier-free) untuk digunakan dalam penandaan biomolekul sebagai radiofarmaka spesifik target untuk terapi sel kanker. 161Tb diperoleh melalui reaksi inti 160Gd (n,γ) 161Tb dengan penembakan neutron termal pada bahan sasaran gadolinium oksida alam sebanyak 100 mg di RSG-G.A.Siwabessy pada fluks neutron termal ~1014 n.cm-2.s-1 dan diikuti dengan pemisahan radiokimia 161Tb dari isotop Gd menggunakan metode kromatografi ekstraksi. Karakterisasi fisiko-kimia larutan radioisotop 161TbCl3 telah dilakukan meliputi penentuan kemurnian radionuklida menggunakan spektrometry-γ dengan detektor HP-Ge yang dilengkapi multichannel analyzer (MCA). Kemurnian radiokimia ditentukan menggunakan metode kromatografi kertas dan elektroforesis kertas. Hasil menunjukkan bahwa radioisotop 161TbCl3 memiliki pH 2, kemurnian radiokimia 99,64 ± 0,34%, kemurnian radionuklida sebesar 99,69 ± 0,20%, aktivitas jenis dan konsentrasi radioaktif pasca iradiasi masing-masing sebesar 2,26 – 5,31 Ci/mg dan 3,84 – 9,03 mCi/mL. Larutan 161TbCl3 stabil selama 3 minggu pada temperatur kamar dengan kemurnian radiokimia sebesar 98,41 ± 0,42%. Larutan radioisotop 161TbCl3 hasil iradiasi bahan sasaran gadolinium oksida alam memiliki karakteristik fisiko-kimia yang memenuhi persyaratan untuk digunakan sebagai prekursor dalam pembuatan radiofarmaka.
... Lutetium-177 (Lu-177), in combination with sophisticated molecular carriers, is used extensively in hospitals for targeted radionuclide therapy in an outpatient setting (1)(2)(3)(4) . Radiation doses to staff and members of the public need to be estimated, limited and optimised (5) for this radiopharmaceutical to be used responsibly in the context of occupational and public health. ...
External dose rates were measured 1 m away from 230 Lu-177 patients to characterise the variability in normalised dose rates as a function of administered activity, body mass index (BMI) and sex. The largest dose rate observed was 0.07 mSv/h associated with an administered activity of 7.2 GBq. Substantial variability was found in the distribution of the normalised dose rate associated that had an average of 0.0037 mSv/h per GBq and a 95% confidence interval of 0.0024-0.0058 mSv/h per GBq. Based on this study, estimating the patient dose rate based on the Lu-177 gamma exposure factor overestimates the dose rate by a factor of 2. A statistically significant inverse relationship was found between the patient dose rate and patient BMI and an empirically derived equation relating these two quantities was reported. On average, male patient dose rates were 3.5% lower than female dose rates, which may be attributed to the larger average BMI of the male patient group.
... Apart from actinides, it has already been shown that AVLIS can be effectively used for the separation of isotopes for medical applications [3][4][5][6][7]. For example, the 177 Lu medical isotope can be produced by neutron irradiation in a nuclear reactor of either enriched 176 Yb (Yb-route) or enriched 176 Lu (Lu-route) [8]. Lu-route is a preferred choice due to the high thermal neutron absorption cross section of 176 Lu (σ = 2090 b) over 176 Yb (σ = 2.85 b) [9]. ...
A 540-535-618 three-step photoionization scheme has been theoretically investigated for the laser isotope separation of $^{177}{\rm Lu}$ 177 L u through density matrix formalism. Equations of motion for the three-step photoionization of odd isotopes have been derived. The effects of Doppler broadening, bandwidth and peak power density of excitation lasers, number density of atoms on the degree of enrichment of $^{177}{\rm Lu}$ 177 L u and production rate have been studied. Optimum conditions for the laser isotope separation of $^{177}{\rm Lu}$ 177 L u for the cases of initial abundances corresponding to the irradiation of natural Lu in low, medium, and high flux reactors have been derived. Under optimum conditions, the production rates of $^{177}{\rm Lu}$ 177 L u in ranges of 0.87, 14.5, and 92.5 mg/h can be achieved with degrees of enrichment of 66%, 97%, and 100%, respectively, for the cases of initial abundances corresponding to the irradiation of natural Lu in low, medium, and high flux reactors. It has also been shown that the content of $^{177{\rm m}}{\rm Lu}$ 177 m L u in the enriched isotope mixture will be in the range of ${{10}^{- 2}}\%$ 10 − 2 % to ${{10}^{- 4}}\%$ 10 − 4 % . This provides a comprehensive solution to the application of $^{177}{\rm Lu}$ 177 L u for cancer therapy.
... However, natural Lu cannot be used for the production of 177 Lu due to the low natural abundance of its precursor isotope 176 Lu (2.59%). It is required to be enriched to ≥ 50% level 5 . ...
We propose a novel and simple method for the laser isotope separation of 176Lu a precursor for the production of177Lu medical isotope. The physics of the laser-atom interaction has been studied through the dynamics of the atomic level populations using the density matrix formalism. It has been shown that a combination of cw excitation lasers and pulsed ionization laser can be used for the laser isotope separation of 176Lu. The optimum conditions for the efficient and selective separation of 176Lu have been derived by studying the time evolution of level population under laser excitation. It has also been shown that, it is possible to produce ~100% enriched 176Lu isotope at a rate of 5 mg / hour, which is higher than all previously reported methods so far. The isotope separation process proposed can be easily adopted using off-the-shelf lasers, for similar atomic systems.
... However, natural Lu cannot be used for the production of 177 Lu due to the low natural abundance of its precursor isotope 176 Lu (2.59%). It is required to be enriched to ≥ 50% level 5 . ...
We propose a novel and simple method for the laser isotope separation of 176Lu a precursor for the production of177Lu medical isotope. The physics of the laser-atom interaction has been studied through the dynamics of the atomic level populations using the density matrix formalism. It has been shown that a combination of cw excitation lasers and pulsed ionization laser can be used for the laser isotope separation of 176Lu. The optimum conditions for the efficient and selective separation of 176Lu have been derived by studying the time evolution of level population under laser excitation. It has also been shown that, it is possible to produce ~100% enriched 176Lu isotope at a rate of 5 mg / hour, which is higher than all previously reported methods so far. The isotope separation process proposed can be easily adopted using off-the-shelf lasers, for similar atomic systems.
... The irradiated targets were placed at the same position as the standard calibration source (161 mm) from the detector end-cap. The nuclear data of the target materials are presented in Table 2 [31,32]. ...
To assess the capability of Kyoto University Research Reactor to supply the domestic needs of medical isotopes, its neutron flux has been fully characterized. The production rates of theranostics radionuclides 177Lu (from 176Lu (n, γ) 177Lu), 176Lu (n, γ) 177mLu/177Lu and 176Yb (n, γ) \(^{177} {\text{Yb}}\mathop{\longrightarrow}\limits{{\beta^{ - } (1.88\;{\text{hr}})}}^{177} {\text{Lu}}\) reactions), and 47Sc (from 46Ca (n, γ) \({^{47} {\text{Ca}}} \mathop{\longrightarrow}\limits^{{\beta^{ - } (4.54\;{\text{d}})}} {^{47} {\text{Sc}}}\) and Ti (n, p) 47Sc) were evaluated. The activity (per gram of target) of 47Sc produced from Ti was found to be 10 times higher than that produced from Ca. Production of 177Lu from the decay of its isomer 177mLu was found to be produce less radioactive wastes than Yb route and can be used as a generator for long-time use.
... Barkhausen et al. performed gamma spectrometry measurements three weeks after irradiation, to confirm these data and the obtained results showed the presence of only 169 Yb (T 1/2 : 32.026 d) and 65 Zn (T 1/2 : 244.26 d) as contaminants. However, at the end of irradiation, their relative activities were very low 1.3 × 10 −4 and 1.8 × 10 −4 %, respectively [150]. ...
The production of novel radionuclides is the first step towards the development of new effective radiopharmaceuticals, and the quality thereof directly affects the preclinical and clinical phases. In this review, novel radiometal production for medical applications is briefly elucidated. The production status of the imaging nuclide 44Sc and the therapeutic β--emitter nuclide 161Tb are compared to their more established counterparts, 68Ga and 177Lu according to their targetry, irradiation process, radiochemistry, and quality control aspects. The detailed discussion of these significant issues will help towards the future introduction of these promising radionuclides into drug manufacture for clinical application under Good Manufacturing Practice (GMP).
... Two alternative production routes are generally applied to obtain 177 Lu; namely, the direct route based on neutron irradiation of lutetium targets and the indirect route based on neutron irradiation of ytterbium targets followed by radiochemical separation of 177 Lu from ytterbium isotopes [23]. The formation of a small amount of long-lived 177 Lu (T 1/2 = 160.5 days) is one of the drawbacks of the direct route. ...
Skeletal uptake of β⁻ emitters of DOTMP complexes is used for the bone pain palliation. In this study, two moderate energy β⁻ emitters, ¹⁷⁷Lu (T1/2 = 6.7 days, Eβmax = 497 keV) and ¹⁷⁵Yb (T1/2 = 4.2 days, Eβmax = 480 keV), are considered as potential agents for the development of the bone-seeking radiopharmaceuticals. Since the specific activity of the radiolabelled carrier molecules should be high, the non-carrier-added (NCA) radionuclides have an effective role in nuclear medicine. Many researchers have presented the synthesis of NCA ¹⁷⁷Lu. Among these separation techniques, extraction chromatography has been considered more capable than other methods. In this study, a new approach, in addition to production of NCA ¹⁷⁷Lu by EXC procedure is using pure ¹⁷⁵Yb that was usually considered as a waste material in this method but because of high radionuclidic purity of ¹⁷⁵Yb produced by this method we used it for radiolabeling as well as NCA ¹⁷⁷Lu. To obtain optimum conditions, some effective factors on separation of Lu/Yb by EXC were investigated. The NCA ¹⁷⁷Lu and pure ¹⁷⁵Yb were produced with radionuclidic purity of 99.99 and 99.97% respectively by irradiation of enriched ¹⁷⁶Yb target in thermal neutron flux of 5 × 10¹³ n/cm² s for 14 days. ¹⁷⁷Lu-DOTMP and ¹⁷⁵Yb-DOTMP were obtained with high radiochemical purities (> 95%) under optimized reaction conditions. Two radiolabeled complexes exhibited excellent stability at room temperature. Biodistribution studies in rats showed favorable selective skeletal uptake with rapid clearance from blood along with insignificant accumulation of activity in other non-target organs for two radiolabelled complexes.
177Lu can be produced by neutron irradiation of 176Lu (direct route) or 176Yb (indirect route). In direct route, the thermal neutron capture cross-section of 176Lu does not vary as 1/v and shows strong temperature (temperature of medium as well as that of the thermalized neutrons) dependence, resulting in added complexities in radioactivity estimation. We use an analytical model to estimate the activity of 177Lu produced from direct as well as indirect routes. For direct route, we have used both Westcott convention-based method and one-group effective cross sections generated using multigroup cross-section library. Our estimations are also validated against known experimental results and compared to measured activity produced in Indian research reactors.
We propose a novel and simple method for the laser isotope separation of 176Lu a precursor for the production of 177Lu medical isotope. The physics of the laser-atom interaction has been studied through the dynamics of the atomic level populations using the density matrix formalism. It has been shown that a combination of cw excitation lasers and pulsed ionization laser can be used for the laser isotope separation of 176Lu. The optimum conditions for the efficient and selective separation of 176Lu have been derived by studying the time evolution of level population under laser excitation. It has also been shown that, it might be possible to produce ~ 100% enriched 176Lu isotope at a rate of 5 mg/h, which is higher than all previously reported methods so far. The isotope separation process proposed can be easily adopted using off-the-shelf lasers, for similar atomic systems.
Background:
Due to the suitable nuclear decay characteristics, 177Lu is an attractive radionuclide for various therapeutic applications. The non-carrier added form of 177Lu has drawn many attention because of its high specific activity needed in radiolabeling studies. There have been several separation methods for NCA 177Lu production.
Objectives:
Among the various separation methods, the electro-amalgamation separation method has got a large potential for large scale production. Li presence is a significant problem in this separation method, which seriously affects the radiolabeling efficiency.
Method:
In this study, Li was separated from the final product of electro-amalgamation separation by adding an ion-exchange chromatography column to the separation process.
Results:
NCA 177Lu was obtained by 84.09% ELM separation yield, 99.9% radionuclide purity and, 65 Ci/g specific activity. Then, 177Lu (177LuCl3 chemical form) was separated from Li using the ion exchange chromatography method by a separation yield of 94%. The obtained results of the radiolabeling efficacy studies showed that the radiochemical purity and radio-complex stability were significantly increased by separating of NCA 177Lu from Li.
Conclusion:
This new separation setup consisting of two steps allows using 177Lu of such a favorable quality for labeling studies.
The latest used radiopharmaceuticals at clinical trials still are not covered by pharmacopeas and this IAEA publication covers a review on examples of quality control for these agents such as Ga-68 peptides, Bi213 and other alpha emitters, Zr89 antibodies, cyclitron based Tc99m, Cu-64 radiopharmaceuticals etc.
Skeletal uptake of radiolabeled‐1, 4, 7, 10‐tetraazacyclododecane‐1, 4, 7, 10‐tetramethylene phosphoric acid (e.g., ¹⁷⁷Lu‐DOTMP) complex, is used for bone pain palliation. The moderate energy of β‐emitting 177Lu (T1/2=6.7 d,Eβmax=497 keV) has been considered as a potential radionuclide for development of the bone‐seeking radiopharmaceutical. Since the specific activity of the radiolabeled carrier molecules should be high, the “no‐carrier‐added radionuclides” have significant roles in nuclear medicine. Many researchers illustrated no‐carrier‐added ¹⁷⁷Lu production; among these separation techniques such as ion exchange chromatography, reversed phase ion‐pair, and electrochemical method, extraction chromatography has been considered more capable than other methods. In order to optimize the conditions, some effective factors on separation of Lu/Yb were investigated by EXC. The NCA ¹⁷⁷Lu, produced by this method, was mixed with 300μ1 of DOTMP solution (20 mg in 1 mL of 0.5 M NaHCO3, pH=8) and incubated under stirring at room temperature for 45 min. Radiochemical purity of the ¹⁷⁷Lu‐DOTMP complex was determined using radio‐thin‐layer chromatography (RTLC) method. The complex was injected to wild‐type rats and biodistribution was then studied for seven days. The NCA ¹⁷⁷Lu was produced with specific activity of 48 Ci/mg and with a radinuclidic purity of 99.99% through irradiation of enriched ¹⁷⁶Yb target (1 mg) in a thermal neutron flux of 4×1013 n.cm−2.s−1 for 14 days. ¹⁷⁷Lu‐DOTMP was obtained with high radiochemical purities (>98%) under optimized reaction conditions. The radiolabeled complex exhibited excellent stability at room temperature. Biodistribution of the radiolabeled complex studies in rats showed favorable selective skeletal uptake with rapid clearance from blood along with insignificant accumulation within the other nontargeted organs.
PACS number(s): 87.57.un, 87.57.uq
In this study, the radiocomplexation of risedronic acid, a potent bisphosphonate with a no carrier added (NCA) 177Lu, was investigated and followed by quality control studies, biodistribution evaluation, and dosimetry study for human based on biodistribution data in Wistar rats. The moderate energy β− emitter, 177Lu (T½ = 6.7 days, Eβmax = 497 keV), has been considered as a potential agent for development of bone-seeking radiopharmaceuticals. Because the specific activity of the radiolabeled carrier molecules should be high, the NCA radionuclides have an effective role in nuclear medicine. Many researchers illustrated an NCA 177Lu production; among these separation techniques, extraction chromatography has been considered more capable than other methods. The NCA 177Lu was produced with specific activity of 48 Ci/mg and radionuclidic purity of 99.99% by the irradiation of enriched 176Yb target in thermal neutron flux of 4 × 1013 n·cm−2·s−1 for 14 days. The NCA 177Lu was mixed to a desired amount of sodium risedronate (15 mg/mL, 200 μL) and incubated with stirring at 95°C for 30 minutes. The radiochemical purity of 177Lu-risedronate was determined by radio thin-layer chromatography, and high radiochemical purities (>97%) were obtained under optimized reaction conditions. The complex was injected to Wistar rats, and complex biodistribution was performed 4 hours to 7 days postinjections showing high bone uptake (9.8% ± 0.24% ID/g at 48 hours postinjection). Also, modeling the radiation dose delivery by RADAR software for the absorbed dose evaluation of each human organ showed a major accumulation of the radiocomplex in bone tissue.
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