Labeling Monoclonal Antibody with α-emitting At at High Activity Levels via a Tin Precursor.

In a previous clinical study, the authors evaluated the potential of antitenascin C monoclonal antibody (mAb) 81C6 labeled with At via the prosthetic agent -succinimidyl 3-[At]astatobenzoate (SAB) for the treatment of primary brain tumors. Although encouraging results were obtained, labeling chemistry failed while attempting to escalate the dose to 370 MBq. The goal of the current study was to develop a revised procedure less susceptible to radiolysis-mediated effects on At labeling that would be suitable for use at higher activity levels of this α-emitter.

Radiopharmaceutical chemistry of targeted radiotherapeutics, part 4: Strategies for At labeling at high activities and radiation doses of At α-particles.

Introduction: Alpha particles are radiation of high energy and short range, properties that can lead to radiolysis-mediated complications in labeling chemistry at the high radioactivity levels required for clinical application. In previous papers in this series, we have shown that radiation dose has a profound effect on the astatine species that are present in the labeling reaction and their suitability for the synthesis of N-succinimidyl 3-[At]astatobenzoate. The purpose of this study was to evaluate the effects of adding N-chlorosuccinimide (NCS) to the methanol solution used for initial isolation of At after distillation, a process referred to as At stabilization, on At chemistry after exposure to high radiation doses.

Engineered modular recombinant transporters: application of new platform for targeted radiotherapeutic agents to alpha-particle emitting 211 At.

Purpose: To generate and evaluate a modular recombinant transporter (MRT) for targeting 211 At to cancer cells overexpressing the epidermal growth factor receptor (EGFR).

Methods And Materials: The MRT was produced with four functional modules: (1) human epidermal growth factor as the internalizable ligand, (2) the optimized nuclear localization sequence of simian vacuolating virus 40 (SV40) large T-antigen, (3) a translocation domain of diphtheria toxin as an endosomolytic module, and (4) the Escherichia coli hemoglobin-like protein (HMP) as a carrier module. MRT was labeled using N-succinimidyl 3-[211 At]astato-5-guanidinomethylbenzoate (SAGMB), its 125 I analogue SGMIB, or with 131 I using Iodogen.

Targeted alpha-particle radiotherapy with 211At-labeled monoclonal antibodies.

An attractive feature of targeted radionuclide therapy is the ability to select radionuclides and targeting vehicles with characteristics that are best suited for a particular clinical application. One combination that has been receiving increasing attention is the use of monoclonal antibodies (mAbs) specifically reactive to receptors and antigens that are expressed in tumor cells to selectively deliver the alpha-particle-emitting radiohalogen astatine-211 (211At) to malignant cell populations. Promising results have been obtained in preclinical models with multiple 211At-labeled mAbs; however, translation of the concept to the clinic has been slow.

Radiopharmaceutical chemistry of targeted radiotherapeutics, Part 3: alpha-particle-induced radiolytic effects on the chemical behavior of (211)At.

Unlabelled: Two characteristics of alpha-particles that enhance their potential for targeted radiotherapy are their high energy and approximately cellular range. Unfortunately, these properties also can have negative consequences, confounding the production of clinically relevant levels of radiopharmaceutical because of radiolytic effects. The purpose of this study was to evaluate the effect of radiation dose on the astatine species present before initiation of a labeling reaction and the potential role of these molecules in the efficiency of N-succinimidyl 3-(211)At-astatobenzoate (SAB) synthesis.

Influence of prosthetic radioiodination on the chemical and biological behavior of chemotactic peptides labeled at high specific activity.

The influence of radioiodination made through prosthetic group N-succinimidyl-3-[131I]iodo-benzoate ([131I]SIB) on the behavior of small peptides was investigated using as model the chemotactic hexapeptide Nalpha-for-Nle-Leu-Phe-Nle-Tyr-Lys. No carrier added labeled peptide was isolated by reverse-phase HPLC (RP-HPLC) with coupling efficiencies up to 59-75%. Biodistribution in normal and infected C57 mice showed mainly a hepatobiliary clearance, a very low thyroid uptake and the highest uptake at the infection site was within 1h of injection.

Iodide benzamides for the in-vivo detection of melanoma and metastases.

The aim of this work was to synthesize, label and evaluate in vivo [I]N-(2-diethylaminoethyl)-3-iodo-4-methoxybenzamide ([I]IMBA) as a radiotracer for B16-F0 melanoma cells, in C57 mice bearing a subcutaneous melanoma tumour and experimentally induced lung metastases. The average radio-iodination yield achieved, after labelling and Sep-Pak purification, was 65%, with a radiochemical purity of > or = 96%. Biodistribution studies using [I]IMBA (2.

Radiopharmaceutical chemistry of targeted radiotherapeutics, Part 2: radiolytic effects of 211At alpha-particles influence N-succinimidyl 3-211AT-astatobenzoate synthesis.

Unlabelled: A variety of promising targeted radiotherapeutics labeled with alpha-emitters have been developed. Clinical investigation of these radiopharmaceuticals requires the production of high activity levels, which can be hindered by alpha-particle-mediated radiolytic effects on labeling chemistry. The purpose of this study was to investigate the effects of radiation dose on the synthesis of N-succinimidyl 3-(211)At-astatobenzoate (SAB), a compound used in our clinical trials for labeling antibodies with alpha-particle-emitting (211)At.

Radiopharmaceutical chemistry of targeted radiotherapeutics, part 1: effects of solvent on the degradation of radiohalogenation precursors by 211At alpha-particles.

Unlabelled: The high energy and short range of alpha-particles make them attractive for targeted radiotherapy. However, these properties can be problematic when the production of high activity levels of alpha-particle-emitting radiotherapeutics is required. For example, difficulties were encountered in the production of N-succinimidyl 3-[211At]-astatobenzoate (SAB), when 370-MBq doses of 211At-labeled antibody were required.