Optimization of a Labeling and Kit Preparation Method for Ga-68 Labeled DOTATATE, Using Cation Exchange Resin Purified Ga-68 Eluates Obtained from a Tin Dioxide 68Ge/68Ga Generator

Prince, Deidré; Rossouw, Daniel D.; Rubow, Sietske

doi:10.1007/s11307-018-1195-x

Cited by 10 publications

(4 citation statements)

References 25 publications

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“…In the past few years, 68 Ge/ 68 Ga generators have increasingly played an important role in nuclear medicine clinics. , It is known that 68 Ga generator-based PET imaging agents have several unique advantages: (a) Germanium-68 ( 68 Ge) ( t 1/2 , 271 days), a long-lived isotope, facilitates a widespread generator circulation; (b) physical properties of 68 Ga ( t 1/2 , 68 min; 89% β + ; 1.92 MeV max energy) are appropriate for PET imaging; (c) 68 Ge/ 68 Ga generators provide an easy distribution for obtaining a positron-emitting isotope without the need of a nearby cyclotron. , For radionuclide therapy, decay characteristics of 177 Lu ( t 1/2 = 6.71 days, β – (max) = 497 keV) are very attractive and they have been successfully applied in treatment of different cancers. Recently, Lu-177 DOTATATE (Lutathera) was approved by the FDA for the treatment of gastroenteropancreatic neuroendocrine tumors.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Evaluation of ⁶⁸Ga- and ¹⁷⁷Lu-Labeled (R)- vs (S)-DOTAGA Prostate-Specific Membrane Antigen-Targeting Derivatives

Zhao

Plöessl²,

Zha³

et al. 2020

Mol. Pharmaceutics

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Prostate-specific membrane antigen (PSMA) is overexpressed in prostate cancer cells and therefore is an attractive target for prostate cancer diagnosis and radionuclide therapy. Recently, published results from clinical studies using a new PSMA-targeting PET imaging agent, [68Ga]Ga-PSMA-093 ([68Ga]Ga-HBED-CC-O-carboxymethyl-Tyr-CO-NH-Glu), support the development of this agent for the diagnosis of prostate cancer. In this study, the HBED-CC chelating group in PSMA-093 was replaced by stereoselective (R)- or (S)-DOTAGA. This chelating group serves not only for chelating 68Ga but is also amendable for complexing other radioactive metals for radionuclide therapy. The corresponding optically pure (R)- and (S)-[68Ga/177Lu]-DOTAGA derivatives, (R)-[68Ga/177Lu]-13 and (S)-[68Ga/177Lu]-13, were successfully prepared. Comparison of radiolabeling, binding affinity, cell uptake, and biodistribution between the two isomers was performed. Radiolabeling of (R)-[177Lu]Lu-13 and (S)-[177Lu]Lu-13 at 50 °C suggested that rates of complex formation were time-dependent and the formation of (S)-[177Lu]Lu-13 was distinctly faster. The rates of complex formation for the corresponding 68Ga agents were comparable between structural isomers. The natGa and natLu equivalents showed high binding PSMA affinity (IC50 = 24–111 nM), comparable to that of the parent agent, [natGa]Ga-PSMA-093 (IC50 = 34.0 nM). Results of cell uptake and biodistribution studies in PSMA-expressing PC3-PIP tumor-bearing mice appeared to show no difference between the labeled (R)- and (S)-isomers. This is the first time that a pair of [68Ga/177Lu]-(R)- and (S)-DOTAGA isomers of PSMA agents were evaluated. Results of biological studies between the isomers showed no noticeable difference; however, the distinctions on the rate of Lu complex formation should be considered in the development of new 177Lu-DOTAGA-based radionuclide therapy agents in the future.

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Section: Introductionmentioning

confidence: 99%

Synthesis and Evaluation of ⁶⁸Ga- and ¹⁷⁷Lu-Labeled (R)- vs (S)-DOTAGA Prostate-Specific Membrane Antigen-Targeting Derivatives

Zhao

Plöessl²,

Zha³

et al. 2020

Mol. Pharmaceutics

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“…Another PSMA kit, THP-PSMA by Rotop, contains 40 µg THP-PSMA, sodium bicarbonate, mannitol and phosphate buffer (Derlin et al 2018 ). An example of translating a manual labeling process to a kit preparation is outlined in Prince et al, who reported the optimization of [ 68 Ga]Ga-DOTA-TATE kit formulation (Prince et al 2018 ).…”

Section: Ga Radiopharmaceutical Production Techniquesmentioning

confidence: 99%

Good practices for 68Ga radiopharmaceutical production

Nelson

Andersson

Wuest

et al. 2022

EJNMMI radiopharm. chem.

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Background The radiometal gallium-68 (68Ga) is increasingly used in diagnostic positron emission tomography (PET), with 68Ga-labeled radiopharmaceuticals developed as potential higher-resolution imaging alternatives to traditional 99mTc agents. In precision medicine, PET applications of 68Ga are widespread, with 68Ga radiolabeled to a variety of radiotracers that evaluate perfusion and organ function, and target specific biomarkers found on tumor lesions such as prostate-specific membrane antigen, somatostatin, fibroblast activation protein, bombesin, and melanocortin. Main body These 68Ga radiopharmaceuticals include agents such as [68Ga]Ga-macroaggregated albumin for myocardial perfusion evaluation, [68Ga]Ga-PLED for assessing renal function, [68Ga]Ga-t-butyl-HBED for assessing liver function, and [68Ga]Ga-PSMA for tumor imaging. The short half-life, favourable nuclear decay properties, ease of radiolabeling, and convenient availability through germanium-68 (68Ge) generators and cyclotron production routes strongly positions 68Ga for continued growth in clinical deployment. This progress motivates the development of a set of common guidelines and standards for the 68Ga radiopharmaceutical community, and recommendations for centers interested in establishing 68Ga radiopharmaceutical production. Conclusion This review outlines important aspects of 68Ga radiopharmacy, including 68Ga production routes using a 68Ge/68Ga generator or medical cyclotron, standardized 68Ga radiolabeling methods, quality control procedures for clinical 68Ga radiopharmaceuticals, and suggested best practices for centers with established or upcoming 68Ga radiopharmaceutical production. Finally, an outlook on 68Ga radiopharmaceuticals is presented to highlight potential challenges and opportunities facing the community.

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“…Therefore, there has been a strong focus on the development of novel tracer molecules with faster kinetics that allow an earlier imaging timepoint, reducing the radiation dose to healthy tissues and improving the overall imaging contrast. Antibody fragments [ 4 ], scaffold proteins [ 5 ], and peptides [ 6 ] have all been shown to be capable of this.…”

Section: Introductionmentioning

confidence: 99%

Decorating sdAbs with Chelators: Effect of Conjugation on Biodistribution and Functionality

et al. 2021

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Single domain antibodies (sdAbs) have proven to be valuable probes for molecular imaging. In order to produce such probes, one strategy is the functionalization of the reactive amine side chain of lysines with a chelator, resulting in a mixture of compounds with a different degree of conjugation. In this study, we implemented anion exchange chromatography (AEX) to separate the different compounds or fractions that were further characterized and evaluated to study the impact of the conjugation degree on pharmacokinetic properties and functionality. Anti-HER2 and anti-MMR sdAbs were functionalized with NOTA or DTPA chelator. Anion exchange chromatography was performed using 0.02 mol/L Tris pH 7.5 as the first solvent and 0.25 M or 0.4 M NaCl (in case of NOTA chelator or DTPA chelator, respectively) as the second solvent applied as a gradient. The fractions were characterized via mass spectrometry (MS), surface plasmon resonance (SPR), and isoelectric focusing gel electrophoresis (IEF), while in vivo studies were performed after radiolabeling with either 68Ga (NOTA) or 111In (DTPA) to assess the impact of the conjugation degree on pharmacokinetics. AEX could successfully be applied to separate fractions of (chelator)n-anti-HER2 and (chelator)n-anti-MMR sdAb constructs. MS confirmed the identity of different peaks obtained in the separation process. SPR measurement suggests a small loss of affinity for (chelator)3-anti-sdAb, while IEF revealed a correlated decrease in isoelectric point (pI) with the number of conjugated chelators. Interestingly, both the reduction in affinity and in pI was stronger with the DTPA chelator than with NOTA for both sdAbs. In vivo data showed no significant differences in organ uptake for any construct, except for (DTPA)n-anti-MMR, which showed a significantly higher liver uptake for (DTPA)1-anti-MMR compared to (DTPA)2-anti-MMR and (DTPA)3-anti-MMR. For all constructs in general, high kidney uptake was observed, due to the typical renal clearance of sdAb-based tracers. The kidney uptake showed significant differences between fractions of a same construct and indicates that a higher conjugation degree improves kidney clearance. AEX allows the separation of sdAbs with a different degree of conjugation and provides the opportunity to further characterize individual fractions. The conjugation of a chelator to sdAbs can alter some properties of the tracers, such as pI; however, the impact on the general biodistribution profile and tumor targeting was minimal.

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Optimization of a Labeling and Kit Preparation Method for Ga-68 Labeled DOTATATE, Using Cation Exchange Resin Purified Ga-68 Eluates Obtained from a Tin Dioxide 68Ge/68Ga Generator

Abstract: A labeling method using SCX-processed Ga-68 eluates was optimized. DOTATATE kits specifically for these SCX-processed Ga-68 eluates were successfully formulated. A post-labeling Sep-Pak C18 purification should be optional.

Cited by 10 publications

References 25 publications

Synthesis and Evaluation of ⁶⁸Ga- and ¹⁷⁷Lu-Labeled (R)- vs (S)-DOTAGA Prostate-Specific Membrane Antigen-Targeting Derivatives

Synthesis and Evaluation of ⁶⁸Ga- and ¹⁷⁷Lu-Labeled (R)- vs (S)-DOTAGA Prostate-Specific Membrane Antigen-Targeting Derivatives

Good practices for 68Ga radiopharmaceutical production

Decorating sdAbs with Chelators: Effect of Conjugation on Biodistribution and Functionality

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Optimization of a Labeling and Kit Preparation Method for Ga-68 Labeled DOTATATE, Using Cation Exchange Resin Purified Ga-68 Eluates Obtained from a Tin Dioxide 68Ge/68Ga Generator

Abstract: A labeling method using SCX-processed Ga-68 eluates was optimized. DOTATATE kits specifically for these SCX-processed Ga-68 eluates were successfully formulated. A post-labeling Sep-Pak C18 purification should be optional.

Cited by 10 publications

References 25 publications

Synthesis and Evaluation of 68Ga- and 177Lu-Labeled (R)- vs (S)-DOTAGA Prostate-Specific Membrane Antigen-Targeting Derivatives

Synthesis and Evaluation of 68Ga- and 177Lu-Labeled (R)- vs (S)-DOTAGA Prostate-Specific Membrane Antigen-Targeting Derivatives

Good practices for 68Ga radiopharmaceutical production

Decorating sdAbs with Chelators: Effect of Conjugation on Biodistribution and Functionality

Contact Info

Product

Resources

About

Synthesis and Evaluation of ⁶⁸Ga- and ¹⁷⁷Lu-Labeled (R)- vs (S)-DOTAGA Prostate-Specific Membrane Antigen-Targeting Derivatives

Synthesis and Evaluation of ⁶⁸Ga- and ¹⁷⁷Lu-Labeled (R)- vs (S)-DOTAGA Prostate-Specific Membrane Antigen-Targeting Derivatives