177Lu has sprung as a promising radionuclide for targeted therapy. The low soft tissue penetration of its β− emission results in very efficient energy deposition in small-size tumours. Because of this, 177Lu is used in the treatment of neuroendocrine tumours and is also clinically approved for prostate cancer therapy. In this work, we report a separation method that achieves the challenging separation of the physically and chemically identical nuclear isomers, 177mLu and 177Lu. The separation method combines the nuclear after-effects of the nuclear decay, the use of a very stable chemical complex and a chromatographic separation. Based on this separation concept, a new type of radionuclide generator has been devised, in which the parent and the daughter radionuclides are the same elements. The 177mLu/177Lu radionuclide generator provides a new production route for the therapeutic radionuclide 177Lu and can bring significant growth in the research and development of 177Lu based pharmaceuticals.@en

Background In this work, a lutetium-177 (177Lu) production method based on the separation of nuclear isomers, 177mLu & 177Lu, is reported. The 177mLu-177Lu separation is performed by combining the use of DOTA & DOTA-labelled peptide (DOTATATE) and liquid-liquid extraction. Methods The 177mLu cations were complexed with DOTA & DOTATATE and kept at 77 K for periods of time to allow 177Lu production. The freed 177Lu ions produced via internal conversion of 177mLu were then extracted in dihexyl ether using 0.01 M di-(2-ethylhexyl) phosphoric acid (DEHPA) at room temperature. The liquid-liquid extractions were performed periodically for a period up to 35 days. Results A maximum 177Lu/177mLu activity ratio of 3500 ± 500 was achieved with [177mLu]Lu-DOTA complex, in comparison to 177Lu/177mLu activity ratios of 1086 ± 40 realized using [177mLu]Lu-DOTATATE complex. The 177Lu-177mLu separation was found to be affected by the molar ratio of lutetium and DOTA. A 177Lu/177mLu activity ratio up to 3500 ± 500 was achieved with excess DOTA in comparison to 177Lu/177mLu activity ratio 1500 ± 600 obtained when lutetium and DOTA were present in molar ratio of 1:1. Further, the 177Lu ion extraction efficiency, decreases from 95 ± 4% to 58 ± 2% in the presence of excess DOTA. Conclusion The reported method resulted in a 177Lu/ 177mLu activity ratio up to 3500 after the separation. This ratio is close to the lower end of 177Lu/177mLu activity ratios, attained currently during the direct route 177Lu production for clinical applications (i.e. 4000–10,000). This study forms the basis for further extending the liquid-liquid extraction based 177mLu-177Lu separation in order to lead to a commercial 177mLu/177Lu radionuclide generator.@en

In order to determine the potential of 177mLu/177Lu radionuclide generator in 177Lu production it is important to establish the technical needs that can lead to a clinically acceptable 177Lu product quality. In this work, a model that includes all the processes and the parameters affecting the performance of the 177mLu/177Lu radionuclide generator has been developed. The model has been based on the use of a ligand to complex 177mLu ions, followed by the separation of the freed 177Lu ions. The dissociation kinetics of the Lu-ligand complex has been found to be the most crucial aspect governing the specific activity and 177mLu content of the produced 177Lu. The dissociation rate constants lower than 1*10-11 s-1 would be required to lead to onsite 177Lu production with specific activity close to theoretical maximum of 4.1 TBq 177Lu/mg Lu and with 177mLu content of less than 0.01%. Lastly, the calculations suggest that more than one patient dose per week can be supplied for a period of up to 7 months on starting with the 177mLu produced using 3 g Lu2O3 target with 60% 176Lu enrichment. The requirements of the starting 177mLu activity production needs to be adapted depending on the required patient doses, and the technical specifications of the involved 177mLu-177Lu separation process.@en

A solid phase extraction based 177mLu-177Lu separation method has been investigated for its feasibility to be used in the radionuclide generator. The use of 2,2′,2”-(10-(2,6-dioxotetrahydro-2H-pyran-3-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid, (DOTAGA-anhydride) allowed grafting of DOTA (1,4,7,10-tetraazacyclododecane N,N′,N″,N‴-tetraacetic acid) complex on the surface of commercially available amino propyl silica. The grafting of DOTA has been confirmed by several characterization techniques. The thermogravimetric analysis reveals that the 0.33 mmol DOTA groups have been grafted per gram of silica. However, during the Lu ion complexation, a 10 times lower Lu adsorption capacity of 0.03 mmol g−1 could be achieved under the studied reaction conditions. The results indicate that the grafting of DOTA on solid affects the Lu coordination and also influences the kinetics of Lu-DOTA complexation. The weak coordination resulted in high 177mLu leakage, while the unreacted DOTA groups interfer with the 177Lu release. This is evident from the 0.3% 177mLu leakage combined with a177Lu extraction efficiency of 25%. Overall, the results show a177mLu-177Lu separation with a maximum 177Lu/177mLu activity ratio of 25. But this is still far away from clinically acceptable activity ratio of 10,000 for which future work is recommended.@en

Lutetium-177 (177Lu) is a radionuclide with well-established potential in targeted radionuclide therapy (TRNT). 177Lu emits β- particles with a tissue penetration depth of 2 mm, which makes it effective in treating small tumors and causes lower toxicity to nearby healthy cells. The β- emission is also accompanied by gamma ray emission that allows simultaneous imaging of the tumor treatment. The last decade has witnessed a three fold increase in the 177Lu related publications and its demand is expected to grow significantly in the coming years. Currently, the 177Lu availability is completely dependent on the availability of nuclear reactors. They are prone to shutdowns for maintenance, social, economic, political and other unexpected reasons. The exclusive dependency of radionuclide production on nuclear reactors is known to lead to major supply shortages. In general, there is a consensus among the nuclear medicine scientists that new production pathways should be developed that can provide some independence from the nuclear reactor availability...@en

In this work, 177mLu has been produced by irradiation of natural Lu2O3 targets at the BR2 reactor (Mol, Belgium) and the obtained data together with literature values have been used to theoretically investigate the production of 177mLu at different neutron fluxes, irradiation times and enrichment of 176Lu. The irradiation time (tmax) needed to reach the maximum 177mLu production has been found to change from 42, 12, 4 days with the increase in the thermal neutron flux from 2*1014, 8*1014, 2.5*1015 n cm−2 s−1, respectively while keeping the maximum 177mLu activity unaffected. The results of our calculations suggest that 0.11 TBq 177mLu with a specific activity of 0.3 TBq g−1 Lu can be produced in a short irradiation time of 4 days using 1g of 84.44% 176Lu enriched Lu2O3 and a thermal neutron flux of 2.5*1015 n cm−2 s−1.@en

In this work, 177mLu has been produced by irradiation of natural Lu2O3 targets at the BR2 reactor (Mol, Belgium) and the obtained data together with literature values have been used to theoretically investigate the production of 177mLu at different neutron fluxes, irradiation times and enrichment of 176Lu. The irradiation time (tmax) needed to reach the maximum 177mLu production has been found to change from 42, 12, 4 days with the increase in the thermal neutron flux from 2*1014, 8*1014, 2.5*1015 n cm−2 s−1, respectively while keeping the maximum 177mLu activity unaffected. The results of our calculations suggest that 0.11 TBq 177mLu with a specific activity of 0.3 TBq g−1 Lu can be produced in a short irradiation time of 4 days using 1g of 84.44% 176Lu enriched Lu2O3 and a thermal neutron flux of 2.5*1015 n cm−2 s−1.@en

In this work, 177mLu has been produced by irradiation of natural Lu2O3 targets at the BR2 reactor (Mol, Belgium) and the obtained data together with literature values have been used to theoretically investigate the production of 177mLu at different neutron fluxes, irradiation times and enrichment of 176Lu. The irradiation time (tmax) needed to reach the maximum 177mLu production has been found to change from 42, 12, 4 days with the increase in the thermal neutron flux from 2*1014, 8*1014, 2.5*1015 n cm−2 s−1, respectively while keeping the maximum 177mLu activity unaffected. The results of our calculations suggest that 0.11 TBq 177mLu with a specific activity of 0.3 TBq g−1 Lu can be produced in a short irradiation time of 4 days using 1g of 84.44% 176Lu enriched Lu2O3 and a thermal neutron flux of 2.5*1015 n cm−2 s−1.@en