Preclinical Validation of [211At]mABG, Synthesized via GMP-Friendly Electrophilic Astatodeboronylation Chemistry
5 affiliations
- 1Division Imaging & Oncology, Department of Radiology and Nuclear Medicine, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
- 2Department of Solid Tumors, Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands
- 3Department of Clinical Physiology and Nuclear Medicine, Cyclotron and Radiochemistry Unit, Rigshospitalet, 2100 Copenhagen, Denmark
- 4Department of Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands
- 5Department of Nuclear Medicine, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands
Abstract
Introduction: Neuroblastoma is a highly malignant pediatric tumor with a high membrane expression of the norepinephrinetransporter (NET). Iodine-131-labeled meta-iodobenzylguanidine (mIBG) as a substrate for the norepinephrine transporter can be used as treatment for neuroblastoma. However, [131I]MIBG has a limited therapeutic effect and requires 4–6 day isolation to shield parents and families from unwanted irradiation. Recently, the alpha emitter-based derivative meta-astatobenzylguanidine ([211At]mABG) has been suggested as a more potent antitumor agent and patient-friendly alternative. In this work, we selected and validated the preferred chemical method for [211At]mABG synthesis towards GMP production for clinical implementation to treat pediatric neuroblastoma patients. Methods: Astatine-211 was obtained by dry distillation using the Atley C100 module. Two different methodologies for the synthesis of [211At]mABG by electrophilic aromatic substitution on either a trimethylsilyl or boronic-acid precursor were compared. Time-dependent uptake was tested in transporter-positive (MaxNB293, SK-N-SH) and -low/negative (AMC691T, Kelly) neuroblastoma cells. Norepinephrine transporter specificity was tested by co-incubation with the transporter substrate norepinephrine or inhibitor desipramine. Cytotoxicity of [211At]mABG was determined by measuring cell viability in both NET-positive and -negative cells. Finally, a large [211At]mABG dose was synthesized and stability was monitored for up to 24 h. Results: Radiochemical conversion into [211At]mABG using a trimethylsilyl and boronic-acid precursor reached 78 ± 8% and 95 ± 1%, respectively (based on radioTLC analysis, (n = 3 for each condition). When [211At]mABG was synthesized from the boronic-acid precursor, the final formulated product was obtained in 79 ± 8% yield with a radiochemical purity > 95%. Time dependent and NET specific [211At]mABG uptake in neuroblastoma cells was observed with 268 ± 46 and 309 ± 58% of added activity/mg protein after 4 h incubation for the NET-positive cells MaxNB293 and SK-N-SH, respectively. Uptake in NET-negative cells AMC691T and Kelly only showed 31 ± 6 and 36 ± 9% of added activity/mg protein, respectively. Cell viability was NET expression-dependent, with an EC50 value of 0.036 kBq for SK-N-SH and 16 kBq for Kelly cells, as positive- and low-expressing cell lines. Ultimately, starting with 345 MBq of astatine-211, 236 MBq of [211At]mABG was afforded (68% non-decay-corrected, n = 1). Radiochemical purity of the formulated product remained >95%, over 24 h. Conclusions: We have developed a mild synthesis procedure for reliable and high-yielding production of [211At]mABG using GMP compatible reagents. Efforts towards fully automated and GMP compliant synthesis are underway.
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BibTeX
@article{sluijter2026preclinical,
title = {{Preclinical Validation of [211At]mABG, Synthesized via GMP-Friendly Electrophilic Astatodeboronylation Chemistry}},
author = {Daan A. Sluijter and Khaled Alkayal and Carlijn A. Vlaswinkel and Holger J. Jensen and Jan J. Molenaar and Arthur J. A. T. Braat and Max M. van Noesel and Alex J. Poot and Berend van der Wildt},
journal = {Biomolecules},
year = {2026},
month = nov,
doi = {10.3390/biom16111606},
url = {https://www.mdpi.com/2218-273X/16/11/1606},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Preclinical Validation of [211At]mABG, Synthesized via GMP-Friendly Electrophilic Astatodeboronylation Chemistry
AU - Daan A. Sluijter
AU - Khaled Alkayal
AU - Carlijn A. Vlaswinkel
AU - Holger J. Jensen
AU - Jan J. Molenaar
AU - Arthur J. A. T. Braat
AU - Max M. van Noesel
AU - Alex J. Poot
AU - Berend van der Wildt
PY - 2026
DA - 2026/11/04
JO - Biomolecules
DO - 10.3390/biom16111606
UR - https://www.mdpi.com/2218-273X/16/11/1606
AB - Introduction: Neuroblastoma is a highly malignant pediatric tumor with a high membrane expression of the norepinephrinetransporter (NET). Iodine-131-labeled meta-iodobenzylguanidine (mIBG) as a substrate for the norepinephrine transporter can be used as treatment for neuroblastoma. However, [131I]MIBG has a limited therapeutic effect and requires 4–6 day isolation to shield parents and families from unwanted irradiation. Recently, the alpha emitter-based derivative meta-astatobenzylguanidine ([211At]mABG) has been suggested as a more potent antitumor agent and patient-friendly alternative. In this work, we selected and validated the preferred chemical method for [211At]mABG synthesis towards GMP production for clinical implementation to treat pediatric neuroblastoma patients. Methods: Astatine-211 was obtained by dry distillation using the Atley C100 module. Two different methodologies for the synthesis of [211At]mABG by electrophilic aromatic substitution on either a trimethylsilyl or boronic-acid precursor were compared. Time-dependent uptake was tested in transporter-positive (MaxNB293, SK-N-SH) and -low/negative (AMC691T, Kelly) neuroblastoma cells. Norepinephrine transporter specificity was tested by co-incubation with the transporter substrate norepinephrine or inhibitor desipramine. Cytotoxicity of [211At]mABG was determined by measuring cell viability in both NET-positive and -negative cells. Finally, a large [211At]mABG dose was synthesized and stability was monitored for up to 24 h. Results: Radiochemical conversion into [211At]mABG using a trimethylsilyl and boronic-acid precursor reached 78 ± 8% and 95 ± 1%, respectively (based on radioTLC analysis, (n = 3 for each condition). When [211At]mABG was synthesized from the boronic-acid precursor, the final formulated product was obtained in 79 ± 8% yield with a radiochemical purity > 95%. Time dependent and NET specific [211At]mABG uptake in neuroblastoma cells was observed with 268 ± 46 and 309 ± 58% of added activity/mg protein after 4 h incubation for the NET-positive cells MaxNB293 and SK-N-SH, respectively. Uptake in NET-negative cells AMC691T and Kelly only showed 31 ± 6 and 36 ± 9% of added activity/mg protein, respectively. Cell viability was NET expression-dependent, with an EC50 value of 0.036 kBq for SK-N-SH and 16 kBq for Kelly cells, as positive- and low-expressing cell lines. Ultimately, starting with 345 MBq of astatine-211, 236 MBq of [211At]mABG was afforded (68% non-decay-corrected, n = 1). Radiochemical purity of the formulated product remained >95%, over 24 h. Conclusions: We have developed a mild synthesis procedure for reliable and high-yielding production of [211At]mABG using GMP compatible reagents. Efforts towards fully automated and GMP compliant synthesis are underway.
SN - 2218-273X
ER -