Dataset Information

Pyridine-containing octadentate ligand NE3TA-PY for formation of neutral complex with ¹⁷⁷Lu(III) and ⁹⁰Y(III) for radiopharmaceutical applications: Synthesis, DFT calculation, radiolabeling, and in vitro complex stability.

ABSTRACT: Targeted radionuclide therapy is a developing therapeutic modality for cancer and employs a cytotoxic radionuclide bound to a chelating agent and a bioactive molecule with high binding affinity for a specific biomarker in tumors. An optimal chelator is one of the critical components to control therapeutic efficacy and toxicity of targeted radionuclide therapy. We designed a new octadentate ligand NE3TA-PY (7-[2-[(carboxymethyl)(2-pyridylmethyl)amino]ethyl]-1,4,7-triazacyclononane-1,4-diacetic acid) for β-particle-emitting ¹⁷⁷Lu and ⁹⁰Y with targeted radionuclide therapy applications. The pyridine-containing polyaminocarboxylate ligand was proposed to form a neutral complex with Lu(III) and Y(III). The new chelator NE3TA-PY was synthesized and experimentally and theorectically studied for complexation with ¹⁷⁷Lu(III) and ⁹⁰Y(III). DFT-optimized structures of Y(III)-NE3TA-PY and Lu(III)-NE3TA-PY complexes were predicted. NE3TA-PY displayed excellent radiolabeling efficiency with both ¹⁷⁷Lu and ⁹⁰Y. The new chelator (NE3TA-PY) bound to ¹⁷⁷Lu was more stable in human serum and better tolerated when challenged by EDTA than ⁹⁰Y-labeled NE3TA-PY. Our findings suggest that the new chelator (NE3TA-PY) produced excellent Lu-177 radiolabeling and in vitro complex stability profiles.

SUBMITTER: Chong HS

PROVIDER: S-EPMC8344049 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Pyridine-containing octadentate ligand NE3TA-PY for formation of neutral complex with <sup>177</sup>Lu(III) and <sup>90</sup>Y(III) for radiopharmaceutical applications: Synthesis, DFT calculation, radiolabeling, and in vitro complex stability.

Chong Hyun-Soon HS Chen Yunwei Y Kang Chi Soo CS Sin Inseok I Zhang Shuyuan S Wang Haixing H

Journal of inorganic biochemistry 20210424

Targeted radionuclide therapy is a developing therapeutic modality for cancer and employs a cytotoxic radionuclide bound to a chelating agent and a bioactive molecule with high binding affinity for a specific biomarker in tumors. An optimal chelator is one of the critical components to control therapeutic efficacy and toxicity of targeted radionuclide therapy. We designed a new octadentate ligand NE3TA-PY (7-[2-[(carboxymethyl)(2-pyridylmethyl)amino]ethyl]-1,4,7-triazacyclononane-1,4-diacetic ac ...[more]

PMID: 33971521

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Project description:AimOver recent years, [225Ac]Ac-PSMA and [177Lu]Lu-PSMA radiopharmaceutical therapy have evolved as a promising treatment option for advanced prostate cancer. Especially for alpha particle emitter treatments, there is still a need for improving dosimetry, which requires accurate values of relative biological effectiveness (RBE). To achieve that, consideration of DNA damages in the cell nucleus and knowledge of the energy deposition in the location of the DNA at the nanometer scale are required. Monte Carlo particle track structure simulations provide access to interactions at this level. The aim of this study was to estimate the RBE of 225Ac compared to 177Lu. The initial damage distribution after radionuclide decay and the residual damage after DNA repair were considered.MethodsThis study employed the TOol for PArtcile Simulation (TOPAS) based on the Geant4 simulation toolkit. Simulation of the nuclear DNA and damage scoring were performed using the TOPAS-nBio extension of TOPAS. DNA repair was modeled utilizing the Python-based program MEDRAS (Mechanistic DNA Repair and Survival). Five different cell geometries of equal volume and two radionuclide internalization assumptions as well as two cell arrangement scenarios were investigated. The radionuclide activity (number of source points) was adopted based on SPECT images of patients undergoing the above-mentioned therapies.ResultsBased on the simulated dose-effect curves, the RBE of 225Ac compared to 177Lu was determined in a wide range of absorbed doses to the nucleus. In the case of spherical geometry, 3D cell arrangement and full radionuclide internalization, the RBE based on the initial damage had a constant value of approximately 2.14. Accounting for damage repair resulted in RBE values ranging between 9.38 and 1.46 for 225Ac absorbed doses to the nucleus between 0 and 50 Gy, respectively.ConclusionIn this work, the consideration of DNA repair of the damage from [225Ac]Ac-PSMA and [177Lu]Lu-PSMA revealed a dose dependency of the RBE. Hence, this work suggested that DNA repair is an important aspect to understand response to different radiation qualities.

Project description:PurposeAccurate dosimetry is critical for ensuring the safety and efficacy of radiopharmaceutical therapies. In current clinical dosimetry practice, MIRD formalisms are widely employed. However, with the rapid advancement of deep learning (DL) algorithms, there has been an increasing interest in leveraging the calculation speed and automation capabilities for different tasks. We aimed to develop a hybrid transformer-based deep learning (DL) model that incorporates a multiple voxel S-value (MSV) approach for voxel-level dosimetry in [177Lu]Lu-DOTATATE therapy. The goal was to enhance the performance of the model to achieve accuracy levels closely aligned with Monte Carlo (MC) simulations, considered as the standard of reference. We extended our analysis to include MIRD formalisms (SSV and MSV), thereby conducting a comprehensive dosimetry study.MethodsWe used a dataset consisting of 22 patients undergoing up to 4 cycles of [177Lu]Lu-DOTATATE therapy. MC simulations were used to generate reference absorbed dose maps. In addition, MIRD formalism approaches, namely, single S-value (SSV) and MSV techniques, were performed. A UNEt TRansformer (UNETR) DL architecture was trained using five-fold cross-validation to generate MC-based dose maps. Co-registered CT images were fed into the network as input, whereas the difference between MC and MSV (MC-MSV) was set as output. DL results are then integrated to MSV to revive the MC dose maps. Finally, the dose maps generated by MSV, SSV, and DL were quantitatively compared to the MC reference at both voxel level and organ level (organs at risk and lesions).ResultsThe DL approach showed slightly better performance (voxel relative absolute error (RAE) = 5.28 ± 1.32) compared to MSV (voxel RAE = 5.54 ± 1.4) and outperformed SSV (voxel RAE = 7.8 ± 3.02). Gamma analysis pass rates were 99.0 ± 1.2%, 98.8 ± 1.3%, and 98.7 ± 1.52% for DL, MSV, and SSV approaches, respectively. The computational time for MC was the highest (~2 days for a single-bed SPECT study) compared to MSV, SSV, and DL, whereas the DL-based approach outperformed the other approaches in terms of time efficiency (3 s for a single-bed SPECT). Organ-wise analysis showed absolute percent errors of 1.44 ± 3.05%, 1.18 ± 2.65%, and 1.15 ± 2.5% for SSV, MSV, and DL approaches, respectively, in lesion-absorbed doses.ConclusionA hybrid transformer-based deep learning model was developed for fast and accurate dose map generation, outperforming the MIRD approaches, specifically in heterogenous regions. The model achieved accuracy close to MC gold standard and has potential for clinical implementation for use on large-scale datasets.

Project description:BackgroundDead-time correction is required for accurate quantitative SPECT-based dosimetry in the context of personalised 177Lu radiopharmaceutical therapy. We aimed to evaluate the impact of applying dead-time correction on the reconstructed SPECT image versus on the acquisition projections before reconstruction.MethodsData from 16 SPECT/CT acquisitions of a decaying 177Lu-filled phantom (up to 20.75 GBq) and dual-timepoint SPECT/CT in 14 patients treated with personalised 177Lu peptide receptor radionuclide therapy were analysed. Dead time was determined based on the acquisition wide-spectrum count rate for each projection and averaged for the entire acquisition. Three dead-time correction methods (DTCMs) were used: the per-projection correction, where each projection was individually corrected before reconstruction (DTCM1, the standard of reference), and two per-volume methods using the average dead-time correction factor of the acquisition applied to all projections before reconstruction (DTCM2) or to the SPECT image after reconstruction (DTCM3). Relative differences in quantification were assessed for various volumes of interest (VOIs) on the phantom and patient SPECT images. In patients, the resulting dosimetry estimates for tissues of interest were also compared between DTCMs.ResultsBoth per-volume DTCMs (DTCM2 and DTCM3) were found to be equivalent, with VOI count differences not exceeding 0.8%. When comparing the per-volume post-reconstruction DTCM3 versus the per-projection pre-reconstruction DTCM1, differences in VOI counts and absorbed dose estimates did not exceed 2%, with very few exceptions. The largest absorbed dose deviation was observed for a kidney at 3.5%.ConclusionWhile per-projection dead-time correction appears ideal for QSPECT, post-reconstruction correction is an acceptable alternative that is more practical to implement in the clinics, and that results in minimal deviations in quantitative accuracy and dosimetry estimates, as compared to the per-projection correction.

Project description:BackgroundRadiohybrid PSMA-targeted ligands (rhPSMA) have been introduced as a novel platform for theranostic applications. Among a variety of rhPSMA-ligands developed for radioligand therapy, two stereoisomers [177Lu]Lu-rhPSMA-10.1 and -10.2 have been synthesized and initially characterized in preclinical experiments with the aim to provide an optimized binding profile to human serum albumin, a reduction of charge, and thus accelerated kidney excretion, and unaffected or even improved tumor uptake. As both isomers showed similar in vitro characteristics and tumor uptake at 24 h post injection in tumor bearing mice and in order to identify the isomer with the most favorable pharmacokinetics for radioligand therapy, we carried out in-depth biodistribution and dosimetry studies in tumor-bearing and healthy mice.ResultsrhPSMA-10.1 and -10.2 were radiolabeled with lutetium-177 according to the established procedures of other DOTA-based PSMA ligands and displayed a high and comparable stability in all buffers and human serum (> 97%, 24 h). Biodistribution studies revealed fast clearance from the blood pool (0.3-0.6%ID/g at 1 h) and other background tissues within 48 h. Distinctive differences were found in the kidneys, where [177Lu]Lu-rhPSMA-10.1 displayed lower initial uptake and faster excretion kinetics compared to [177Lu]Lu-rhPSMA-10.2 expressed by a 1.5-fold and ninefold lower uptake value at 1 h and 24 h in healthy animals, respectively. Tumor uptake was comparable and in the range of 8.6-11.6%ID/g for both isomers over 24 h and was maintained up to 168 h at a level of 2.2 ± 0.8 and 4.1 ± 1.4%ID/g for [177Lu]Lu-rhPSMA-10.1 and [177Lu]Lu-rhPSMA-10.2, respectively.ConclusionOur preclinical data on biodistribution and dosimetry indicate a more favorable profile of [177Lu]Lu-rhPSMA-10.1 compared to [177Lu]Lu-rhPSMA-10.2 for PSMA-targeted radioligand therapy. [177Lu]Lu-rhPSMA-10.1 shows fast kidney clearance kinetics resulting in excellent tumor-to-organ ratios over a therapy relevant time course. Meanwhile, [177Lu]Lu-rhPSMA-10.1 is currently being investigated in clinical phase I/II studies in patients with mCRPC (NCT05413850), in patients with high-risk localized PC (NCT06066437, Nautilus Trial) and after external beam radiotherapy (NCT06105918).

Project description:BackgroundIndividualized dosimetry is recommended for [177Lu]Lu-PSMA radioligand therapy (RLT) which is resource-intensive and protocols are often not optimized. Therefore, a simulation study was performed focusing on the determination of efficient optimal sampling schedules (OSS) for renal and tumour dosimetry by investigating different numbers of time points (TPs).MethodsSampling schedules with 1-4 TPs were investigated. Time-activity curves of the kidneys and two tumour lesions were generated based on a physiologically based pharmacokinetic (PBPK) model and biokinetic data of 13 patients who have undergone [177Lu]Lu-PSMA I&T therapy. Systematic and stochastic noise of different ratios was considered when modelling time-activity data sets. Time-integrated activity coefficients (TIACs) were estimated by simulating the hybrid planar/SPECT method for schedules comprising at least two TPs. TIACs based on one single SPECT/CT measurement were estimated using an approximation for reducing the number of fitted parameters. For each sampling schedule, the root-mean-squared error (RMSE) of the deviations of the simulated TIACs from the ground truths for 1000 replications was used as a measure for accuracy and precision.ResultsAll determined OSS included a late measurement at 192 h p.i., which was necessary for accurate and precise tumour TIACs. OSS with three TPs were identified to be 3-4, 96-100 and 192 h with an additional SPECT/CT measurement at the penultimate TP. Kidney and tumour RMSE of 6.4 to 7.7% and 6.3 to 7.8% were obtained, respectively. Shortening the total time for dosimetry to e.g. 96 h resulted in kidney and tumour RMSE of 6.8 to 8.3% and 9.1 to 11%, respectively. OSS with four TPs showed similar results as with three TPs. Planar images at 4 and 68 h and a SPECT/CT shortly after the 68 h measurement led to kidney and tumour RMSE of 8.4 to 12% and 12 to 16%, respectively. One single SPECT/CT measurement at 52 h yielded good approximations for the kidney TIACs (RMSE of 7.0%), but led to biased tumour TIACs.ConclusionOSS allow improvements in accuracy and precision of renal and tumour dosimetry for [177Lu]Lu-PSMA therapy with potentially less effort. A late TP is important regarding accurate tumour TIACs.

Dataset Information

Pyridine-containing octadentate ligand NE3TA-PY for formation of neutral complex with ¹⁷⁷Lu(III) and ⁹⁰Y(III) for radiopharmaceutical applications: Synthesis, DFT calculation, radiolabeling, and in vitro complex stability.

Publications

Pyridine-containing octadentate ligand NE3TA-PY for formation of neutral complex with <sup>177</sup>Lu(III) and <sup>90</sup>Y(III) for radiopharmaceutical applications: Synthesis, DFT calculation, radiolabeling, and in vitro complex stability.

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Dataset Information

Pyridine-containing octadentate ligand NE3TA-PY for formation of neutral complex with 177Lu(III) and 90Y(III) for radiopharmaceutical applications: Synthesis, DFT calculation, radiolabeling, and in vitro complex stability.

Publications

Pyridine-containing octadentate ligand NE3TA-PY for formation of neutral complex with <sup>177</sup>Lu(III) and <sup>90</sup>Y(III) for radiopharmaceutical applications: Synthesis, DFT calculation, radiolabeling, and in vitro complex stability.

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OmicsDI is part of the ELIXIR infrastructure

Tweets

Pyridine-containing octadentate ligand NE3TA-PY for formation of neutral complex with ¹⁷⁷Lu(III) and ⁹⁰Y(III) for radiopharmaceutical applications: Synthesis, DFT calculation, radiolabeling, and in vitro complex stability.