Reversed phase free ion selective radiotracer extraction (RP-FISRE): A new tool to assess the dynamic stabilities of metal (-organic) complexes, for complex half-lives spanning six orders of magnitude

Meer, A. van der; Breeman, W. A. P.; Wolterbeek, Bert

doi:10.1016/j.apradiso.2013.06.021

Cited by 4 publications

(6 citation statements)

References 35 publications

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“…Dissociation kinetics of Lu-DOTATATE complex were reported by Van der Meer et al . using a similar system and an order of magnitude difference was calculated when the temperature was increased from 20 to 37 °C23. A higher dissociation rate turns into a higher concentration of dissociated 177m Lu in the mobile phase decreasing the value of the activity ratio and the quality of the elution.…”

Section: Discussionmentioning

confidence: 99%

“…While the use of the metastable 177m Lu as the parent radionuclide for 177 Lu production was proposed by De Vries and Wolterbeek22, the realization of a generator has not been demonstrated yet. In order to prove this concept, we have chosen a reversed phase chromatographic system in which 177m Lu-DOTA-(Tyr 3 )-octreotate (DOTATATE) complex (with a dissociation constant k d = 2·10 −8 s −1 at 20 °C) is retained in a tC-18 silica column23. The tC-18 silica filler has no affinity toward polar metal ions, and thus the bond ruptured 177 Lu ions can be eluted off the column using a mobile phase flow, while the 177m Lu-DOTATATE complex exhibits a very long retention time with the chosen mobile phase, and remains immobilized on the column during the experiments (shown schematically in Fig.…”

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confidence: 99%

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Separation of nuclear isomers for cancer therapeutic radionuclides based on nuclear decay after-effects

Bhardwaj

Meer

Das

et al. 2017

Sci Rep

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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.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Separation of nuclear isomers for cancer therapeutic radionuclides based on nuclear decay after-effects

Bhardwaj

Meer

Das

et al. 2017

Sci Rep

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“…This leads to an estimated dissociation rate constant of 1.3*10 − 7 ± 0.3*10 − 7 s − 1 . For Lu-DOTATATE complex, a dissociation constant rate 2*10 − 8 s − 1 has been reported at pH -4.3 and 20 °C (van der Meer et al, 2013). It has also been shown that the Lu-DOTATATE complex is accompanied by the presence of short-lived unstable, mono- and di-protonated (MHL, MH 2 L) complex species (van der Meer et al, 2013).…”

Section: Discussionmentioning

confidence: 95%

“…For Lu-DOTATATE complex, a dissociation constant rate 2*10 − 8 s − 1 has been reported at pH -4.3 and 20 °C (van der Meer et al, 2013). It has also been shown that the Lu-DOTATATE complex is accompanied by the presence of short-lived unstable, mono- and di-protonated (MHL, MH 2 L) complex species (van der Meer et al, 2013). These species have a dissociation rate constant of 8*10 − 5 s − 1 (MHL) & 2*10 − 4 s − 1 (MH 2 L) at pH -4.3 and 20 °C (van der Meer et al, 2013).…”

Section: Discussionmentioning

confidence: 95%

“…It has also been shown that the Lu-DOTATATE complex is accompanied by the presence of short-lived unstable, mono- and di-protonated (MHL, MH 2 L) complex species (van der Meer et al, 2013). These species have a dissociation rate constant of 8*10 − 5 s − 1 (MHL) & 2*10 − 4 s − 1 (MH 2 L) at pH -4.3 and 20 °C (van der Meer et al, 2013). Therefore, the presently estimated dissociation rate constant does not represent the dissociation of single species, but is rather a combination of the dissociation contribution from three different species i.e.…”

Section: Discussionmentioning

confidence: 99%

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Radionuclide generator-based production of therapeutic 177Lu from its long-lived isomer 177mLu

Bhardwaj

Wolterbeek

Denkova

et al. 2019

EJNMMI radiopharm. chem.

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Background In this work, a lutetium-177 ( 177 Lu) production method based on the separation of nuclear isomers, 177m Lu & 177 Lu, is reported. The 177m Lu- 177 Lu separation is performed by combining the use of DOTA & DOTA-labelled peptide (DOTATATE) and liquid-liquid extraction. Methods The 177m Lu cations were complexed with DOTA & DOTATATE and kept at 77 K for periods of time to allow 177 Lu production. The freed 177 Lu ions produced via internal conversion of 177m Lu 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 177 Lu/ 177m Lu activity ratio of 3500 ± 500 was achieved with [ 177m Lu]Lu-DOTA complex, in comparison to 177 Lu/ 177m Lu activity ratios of 1086 ± 40 realized using [ 177m Lu]Lu-DOTATATE complex. The 177 Lu- 177m Lu separation was found to be affected by the molar ratio of lutetium and DOTA. A 177 Lu/ 177m Lu activity ratio up to 3500 ± 500 was achieved with excess DOTA in comparison to 177 Lu/ 177m Lu activity ratio 1500 ± 600 obtained when lutetium and DOTA were present in molar ratio of 1:1. Further, the 177 Lu ion extraction efficiency, decreases from 95 ± 4% to 58 ± 2% in the presence of excess DOTA. Conclusion The reported method resulted in a 177 Lu/ 177m Lu activity ratio up to 3500 after the separation. This ratio is close to the lower end of 177 Lu/ 177m Lu activity ratios, attained currently during the direct route 177 Lu production for clinical applications (i.e. 4000–10,000). This study forms the basis for further extending the liquid-liquid extraction based 177m Lu- 177 Lu separation in order to lead to a commercial 177m Lu/ 177 Lu radionuclide generator. Electronic supplementary material The online version of this article (10.1186/s41181-019-0064-5) contains supplementary material, which is available to authorized users.

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Modelling of the 177mLu/177Lu radionuclide generator

Bhardwaj

Wolterbeek

Denkova

et al. 2020

Applied Radiation and Isotopes

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Reversed phase free ion selective radiotracer extraction (RP-FISRE): A new tool to assess the dynamic stabilities of metal (-organic) complexes, for complex half-lives spanning six orders of magnitude

Cited by 4 publications

References 35 publications

Separation of nuclear isomers for cancer therapeutic radionuclides based on nuclear decay after-effects

Separation of nuclear isomers for cancer therapeutic radionuclides based on nuclear decay after-effects

Radionuclide generator-based production of therapeutic 177Lu from its long-lived isomer 177mLu

Modelling of the 177mLu/177Lu radionuclide generator

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