Realizing Clinical Trials with Astatine-211: The Chemistry Infrastructure

Abstract

Despite the consensus around the clinical potential of the a-emitting radionuclide astatine-211 (211 At), there are only a limited number of research facilities that work with this nuclide. There are three main reasons for this: (1) Scarce availability of the nuclide. Despite a relatively large number of globally existing cyclotrons capable of producing 211 At, few cyclotron facilities produce the nuclide on a regular basis. (2) Lack of a chemical infrastructure, that is, isolation of 211 At from irradiated targets and the subsequent synthesis of an astatinated product. At present, the research groups that work with 211 At depend on custom systems for recovering 211 At from the irradiated targets. Setting up and implementing such custom units require long lead times to provide a proper working system. (3) The chemistry of 211 At. Compared with radiometals there are no well-established and generally accepted synthesis methods for forming sufficiently stable bonds between 211 At and the tumor-specific vector to allow for systemic applications. Herein we present an overview of the infrastructure of producing 211 At radiopharmaceuticals, from target to radiolabeled product including chemical strategies to overcome hurdles for advancement into clinical trials with 211 At.

Preclinical and Clinical Status of PSMA-Targeted Alpha Therapy for Metastatic Castration-Resistant Prostate Cancer

“…It decays by electron capture (58.3%) to 211 Po (t1/2 = 0.52 s), which decays to stable 207 Pb by emitting an α particle (7.45 MeV, 100%). Additionally, its daughter 211 Po emits K X-rays in the range of 77 to 92 keV that allows the quantification of 211 At radioactivity and scintigraphic imaging of 211 At in vivo [169]. In 2009, modified anti-PSMA antibody 107-1A4 was labeled with 211 At [86].…”

Targeted Alpha Therapy: Current Clinical Applications

“…Nevertheless, in vivo instability of the labeled compound and scarce availability of the radionuclide remain major challenges with 211 At. 42 Elgqvist et al investigated the therapeutic efficacy of 211 At labeled with a fragment of an mAb in a preclinical model of ovarian cancer. 45,46 The results of these studies showed that dosimetry to the cell nuclei is strongly dependent on the tumor size-while in small tumors (radius <30 lm), all cells are eradicated, in tumors with radii >75 lm, there is a small fraction of unirradiated cells in the core that explain the low tumor-free fraction, despite the high mean absorbed dose in the tumor [>22 Gy for an injected activity of 400 kBq of 211 A-MX35 F(ab¢) 2 ].…”

“…52 There is also an ongoing phase I/II clinical study using 211 At labeled to anti-CD45 antibody for the treatment of acute myeloid leukemia (AML) and acute lymphoblastic leukemia, before bone stem cell transplant. 42…”

Biomedical Research Programs at Present and Future High-Energy Particle Accelerators

“…This will be achieved through the optimization of isotope production processes, research in radiochemistry, radiolabeling, and preclinical radiobiological studies on newly developed radiopharmaceuticals. In the coming years, a strong focus will go to the development of new theranostic radiopharmaceuticals and the production of astatine-211, a promising isotope for targeted α-particle therapy [ 52 ].…”