Implementation of new radionuclides for Targeted Alpha Therapy (TαT)


With the overall survival benefit conferred by Ra-223 treatment and its subsequent approval for bone-predominant mCRPC (metastatic castration-resistant prostate cancer), interest in the therapeutic potential of α–emitting radionuclides is increasing. Other α-emitters being investigated in preclinical and clinical studies include Th-227, Ac-225, Bi-213, At-211, and Pb-212, as pointed out in a recently published review article.


It is expected that these radionuclides will be applied in nuclear medical therapy in near future. Because of this reason these new  radionuclides have been implemented in the 9th update in order to enable the user to establish nuclide specific monitoring programs and to evaluate the monitoring results, respectively.



Features of new radionuclides




Thorium-227 is an α-emitter with a physical half-life of 18.7 days. The Th-227 decay scheme is initiated by its α-decay into Ra-223, which subsequently follows the decay chain of Ra-223. As Th-227 decays to stable Pb-207, 5 α-particles are released, making Th-227 an attractive candidate for TαT. Targeted Th-227 conjugates are being investigated in several preclinical and phase 1 studies across tumortypes, including prostate cancer, colorectal cancer, gastric cancer, ovarian cancer, non-Hodgkin lymphoma, and leukemia.




The decay of Ac-225 results in the emission of 4 α-particles, which marks Ac-225 as an attractive and potent choice for TαT. Actinium-225 has a physical half-life of 9.92 days and yields 3 daughter radionuclides that each emit an α-particle on their decay. As with Ra-223, the relatively long half-life of Ac-225 allows for centralized production, distribution, and administration of Ac-225 TαT. Another distinct advantage of Ac-225–based TαT is the emission of a 440-keV γ-ray after the decay of the Bi-213 daughter radionuclide, which can be used for imaging to determine biodistribution. An ongoing phase 1/2 trial of Ac-225–lintuzumab targeting CD33-positive myeloid leukemia cells in patients with acute myeloid leukemia has shown that treatment is safe.





Bismuth-213 has a short physical half-life of 45.6 minutes and is prepared for therapeutic use in an Ac-225 and Bi-213-generator. The generator produces Bi-213 that is clinically useful for 10 days. Bismuth-213 decays to stable Bi-209 through the emission of an α-particle and 2 beta particles. Bismuth-213 is readily conjugated to mAbs, peptides, and small molecules and has been investigated as a TαT in several clinical trials. However, its short half-life and conjugation chemistry restrict the use of Bi-213 for patients. Despite these practical limitations, clinical trials have shown promising efficacy of Bi-213.





Astatine-211 has a physical half-life of 7.2 hours and decays through a branched pathway, with each decay path producing an α-particle as it decays to stable Pb-207. Astatine-211 has several attractive features for use as a TαT, including no long-lived α-particle–emitting daughter radionuclides, 18 photon emission that allows imaging, and compatibility for conjugation with several carrier molecules to allow targeted delivery. The availability of At-211 is limited by its short half-life, which makes it difficult to deliver sufficient quantities of At-211 to distant treatment centers and has limited the number of preclinical and clinical studies of this radionuclide.





Lead-212 is a β-particle emitter with a physical half-life of 10.2 hours; it is the immediate parental radionuclide of Bi-212. Bismuth-212 decays to stable Pb-208 through the emission of 1 α-particle and 1 β-particle.