Design and synthesis of 225Ac radioimmunopharmaceuticals.
Abstract
The alpha-particle-emitting radionuclides 213Bi, 211At, 224Ra are under investigation for the treatment of leukemias, gliomas, and ankylosing spondylitis, respectively. 213Bi and 211At were attached to monoclonal antibodies and used as targeted immunotherapeutic agents while unconjugated 224Ra chloride selectively seeks bone. 225Ac possesses favorable physical properties for radioimmunotherapy (10d half-life and 4 net alpha particles), but has a history of unfavorable radiolabeling chemistry and poor metal-chelate stability. We selected functionalized derivatives of DOTA as the most promising to pursue from out of a group of potential 225Ac chelate compounds. A two-step synthetic process employing either MeO-DOTA-NCS or 2B-DOTA-NCS as the chelating moiety was developed to attach 225Ac to monoclonal antibodies. This method was tested using several different IgG systems. The chelation reaction yield in the first step was 93+/-8% radiochemically pure (n=26). The second step yielded 225Ac-DOTA-IgG constructs that were 95+/-5% radiochemically pure (n=27) and the mean percent immunoreactivity ranged from 25% to 81%, depending on the antibody used. This process has yielded several potential novel targeted 225Ac-labeled immunotherapeutic agents that may now be evaluated in appropriate model systems and ultimately in humans.
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Only DOTA and DOTMP showed chelation of 225Ac after 2 h at 37°C, with radiochemical yields of >99% and 78%, respectively.
“McDevitt et al. presented a comparison of 225Ac radiolabeling efficiency and in vitro stability of multiple chelators including DTPA, DOTA, TETA, DOTPA, TETPA, and DOTMP (116), and concluded that only DOTA and DOTMP showed chelation of 225Ac after 2 h at 37°C with radiochemical yields of >99 and 78%, respectively.”
From Alpha-peptide receptor radionuclide therapy using actinium-225 labeled somatostatin receptor agonists and antagonists (2022) · cites this paper as [116]
Chelation of 225Ac is a slow reaction demanding extensive heating and a high amount of ligand for an adequate yield.
“Moreover, chelation of 225Ac is a slow reaction demanding extensive heating and high amount of ligand for an adequate yield (77, 116, 117).”
From Alpha-peptide receptor radionuclide therapy using actinium-225 labeled somatostatin receptor agonists and antagonists (2022) · cites this paper as [116]
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- Authors
- McDevitt, M. R., Ma, D., Simon, J., Frank, R. K., & Scheinberg, D. A.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Dow Chemical (United States) (US)
- Corresponding author
- Scheinberg, David A.
- Venue
- Applied Radiation and Isotopes
- Publisher
- Elsevier BV
- Published
- 2002-12
- Volume
- 57
- Issue
- 6
- Pages
- 841-847
- ISSN
- 0969-8043 (ISSN-L)
- OpenAlex
- W1978689317
- Cited by
- 225
- References
- 17
- Citations by year
- 2026: 10 · 2025: 12 · 2024: 12 · 2023: 12 · 2022: 13 · 2021: 21 · 2020: 15 · 2019: 13 · 2018: 15 · 2017: 5 · 2016: 7 · 2015: 9 · 2014: 11 · 2013: 9 · 2012: 6
- FWCI
- 4.83
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Applied Radiation and Isotopes (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (R01CA055349, P01CA033049)
- Topics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Radiopharmaceutical Chemistry and Applications
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Chemical Reactions and Isotopes
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Keywords
- actinium-225, alpha-emitting radionuclides, radioimmunotherapy, DOTA chelator, monoclonal antibodies, radium-224, 213Bi, 211At
- MeSH terms
- Actinium, Antibodies, Monoclonal, Radioimmunotherapy, Radiopharmaceuticals
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