François Guérard

The term “relativistic effects” originates from the history of quantum mechanics and refers to the discrepancies between values calculated by models that consider relativity and those that do not. We introduce a methodology that opens up the possibility of analyzing the mechanisms by which relativistic effects combine in molecular structures containing multiple heavy elements. Through an n-body decomposition of relativistic effects, the individual contributions of each heavy element are revealed, along with collective contributions that can be either cooperative or anticooperative. Illustrations are given of the effects of spin–orbit coupling on total energy, electron density, and the intricate mechanisms by which these effects are transferred through space to the molecular electrostatic potential or the strength of intermolecular interactions. Near a heavy atom, such properties can be significantly more affected by the spin–orbit coupling effects produced by other distant heavy atoms, not bonded to the atom of interest or to each other. For molecular properties, it is shown that the influence of collective components (two-body, three-body, etc.) account for about one-tenth of the total effect of spin–orbit coupling.

²¹¹At is a radionuclide of great interest in nuclear medicine for cancer therapy, provided it is firmly bound to an appropriate targeting agent. In recent years, original ²¹¹At-labeled compounds have shown promising in vivo stability, without the underlying logic being identified. Herein, molecular modeling (two-component relativistic density functional theory) is used to assess the hypothesis that the degradation mechanism(s), leading to the release of free ²¹¹At, is related to the ability of labeled compounds to form halogen-bond interactions involving astatine. We highlight inhibition phenomena at play for a variety of compounds, in line with observations of enhanced stability, paving the way for a potentially applicable strategy to access robust radiopharmaceuticals.

At is a radionuclide of great interest in nuclear medicine for cancer therapy, provided it is firmly bound to an appropriate targeting agent. In recent year, original 211 At-labeled compounds have shown promising in vivo stability, without the underlying logic being identified. Herein, molecular modeling (two-component relativistic DFT) is used to assess the hypothesis that the degradation mechanism(s), leading to the release of free 211 At, is related to the ability of labeled compounds to form halogen-bond interactions involving astatine. We highlight inhibition phenomena at play for a variety of compounds, in line with observations of enhanced stability, paving the way for a potentially applicable strategy to access robust radiopharmaceuticals.

The fine fit between astatine and gold illuminated by quantum chemical topology.

Bambusuril, BU, is reported as host molecule to strongly chelate astatide (At⁻) through 12 C–H⋯At non-covalent interactions, stabilizing At⁻ within its cavity. This complex will open the way to new ²¹¹At-labeling methods and radiopharmaceuticals.

²¹¹At-labeled (hetero)aryl compounds were obtained from arylsulfonium salt in high RCY with a short reaction time. Benzothiophenium salts appear to be superior to triarylsulfonium salts with a high efficiency demonstrated on electronically enriched or depleted phenyl rings and an ortho-substituted substrate. As a potential application, a ²¹¹At-labeled benzylazide prosthetic group was produced and conjugated to octreotate by SPAAC. This procedure offers an alternative to previous approaches that generally require toxic or unstable precursors and/or catalysts, and/or lead to inseparable products.

Targeted alpha therapy appears to be a promising approach in nuclear medicine for the treatment of cancers. Thanks to its appropriate physical properties, ²¹¹At is an ideal candidate compared with other alpha emitters. Because of its enigmatic nature, the chemical element astatine is the subject of growing interest to better understand its radiochemistry. The application of ²¹¹At in the clinic, which has shown good therapeutic results, is however still hampered. Stability issues of ²¹¹At-radiolabeling were quickly encountered in early preclinical trials and later confirmed in the clinic that mainly studied ²¹¹At-radiopharmaceuticals labeled by formation of an astatobenzamide derivative. Recent studies have shed light on the deastatination mechanisms encountered in vivo, in particular potential oxidative mechanisms that may weaken the carbon-astatine bond formed during the radiolabeling. In this work, we show that ortho-functionalization of astatoaryl compounds with benzyl alcohols protects radiolabeling from deastatination in a strongly oxidizing and acidic medium, as well as in liver microsomal media reproducing in vivo deastatination via cytochrome P450 (CYP450) mediated mechanisms. Our results open the way to the rational design of new ²¹¹At-aryl-based compounds with improved stability.

With the purpose of exploring alternatives to the poorly stable astatoaryl bond found in most ²¹¹At‐labeled radiopharmaceuticals, the coordination between astatine and metal‐NHC (NHC = N‐heterocyclic carbene) complexes was investigated. To orient this work, relativistic DFT calculations were performed, highlighting a superiority of gold(I) over rhodium(I) and iridium(I), both regarding the strength of the metal‐astatine bond and the metal's preference for astatine over other halogens. The DFT calculations also revealed a more stable metal‐astatine bond with electron‐withdrawing NHCs. Accordingly, two Au(I) complexes, [AuCl(IPr)] (IPr = N,N’‐bis[2,6‐(di‐isopropyl)phenyl]imidazol‐2‐ylidene) and [AuCl(IAd)] (IAd = N,N’‐bis[adamantyl]imidazol‐2‐ylidene) were radiolabeled by halide exchange in excellent radiochemical yields with iodine‐125 and astatine‐211 in a water/acetonitrile mixture with a reducing agent. While the adamantyl‐substituted complex was not investigated further due to its lack of solubility in aqueous or semi aqueous media, the stability of [Au²¹¹At(IPr)] in the presence of phosphate‐buffered saline was evaluated and proved excellent (96% after two half‐lives), encouraging further studies with relevant cancer‐targeting vectors.

Introduction: Recently, alpha-emitting radionuclides like astatine-211 have offered promising results in clinical development. Non-muscle-invasive bladder cancer (NMIBC) presents a need for novel therapies. One promising approach is radioimmunotherapy targeting Carbonic Anhydrase IX (CA-IX), which is supported by preclinical and clinical evidence. The aim of our preclinical and clinical studies was to evaluate the [²¹¹At]At-anti-CA-IX antibody (ATO-101™) for future use in NMIBC patient care. Methods: The anti-CA-IX antibody, girentuximab (TLX250), was labeled with lutetium-177 and astatine-211 for in vitro studies. Affinity constant measurements of [²¹¹At]At-girentuximab in RT-112 cells were taken, and toxicity evaluations were conducted in vitro and in healthy mice. Additionally, a clinical proof-of-concept study, PERTINENCE, that used [⁸⁹Zr]Zr-girentuximab for PET/CT imaging in bladder cancer patients was conducted. Results: The measurement of the affinity constant of [²¹¹At]At-girentuximab in RT112 cells revealed high binding affinity and significant cytotoxicity compared to [177Lu]Lu-girentuximab. Biodistribution studies in healthy mice indicated low systemic radioactivity uptake, and a bladder post-instillation examination showed no abnormalities in bladder mucosa, suggesting safety. In the PERTINENCE study, which involved patients with NMIBC tumors expressing CA-IX, [⁸⁹Zr]Zr-girentuximab PET/CT showed no extravesical leakage. Wall bladder uptake spots correlated with recurrence or inflammatory reaction. A dosimetric study suggested the potential efficacy and favorable safety profile of intravesical alpha therapy with the [²¹¹At]At-anti-CA-IX antibody (ATO-101™) in NMIBC treatment. Conclusions: Preclinical and clinical data demonstrate the promising therapeutic role of ²¹¹At-targeted alpha agents in NMIBC, and the [²¹¹At]At-anti-CA-IX antibody (ATO-101™) could fulfill this role. A phase I FIH clinical trial is in preparation, and results are expected within the next years.