Preparation and in vivo evaluation of a novel stabilized linker for 211At labeling of protein

• Published in: Nuclear medicine and biology Vol. 33; no. 4; pp. 469 - 480
• Main Authors: Talanov, Vladimir S., Garmestani, Kayhan, Regino, Celeste A.S., Milenic, Diane E., Plascjak, Paul S., Waldmann, Thomas A., Brechbiel, Martin W.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-05-2006
• Subjects: 211At; Adenocarcinoma - metabolism; Adenocarcinoma - radiotherapy; Animals; Antibodies, Monoclonal - chemistry; Antibodies, Monoclonal - pharmacokinetics; Antibodies, Monoclonal - therapeutic use; Astatine; Astatine - chemistry; Astatine - pharmacokinetics; Astatine - therapeutic use; Cell Line, Tumor; Colonic Neoplasms - metabolism; Colonic Neoplasms - radiotherapy; Cross-Linking Reagents - chemistry; Drug Stability; Excipients - chemistry; Humans; Isotope Labeling; Isotopes - chemistry; Isotopes - pharmacokinetics; Isotopes - therapeutic use; Metabolic Clearance Rate; Methyl-SAPS; Mice; Mice, Nude; Monoclonal antibody; Organ Specificity; Protein Binding; Radioimmunotherapy; Radiopharmaceuticals - chemical synthesis; Radiopharmaceuticals - pharmacokinetics; Radiopharmaceuticals - therapeutic use; SAPS; SPEMS; Tissue Distribution; α-Particle; Methyl-SAPS; 211At; Astatine; SAPS; Radioimmunotherapy; SPEMS; α-Particle; Monoclonal antibody
• ISSN: 0969-8051; 1872-9614
• DOI: 10.1016/j.nucmedbio.2006.03.001

Significant improvement of in vivo stability of
211At-labeled radioimmunoconjugates achieved upon employment of a recently reported new linker, succinimidyl
N-2-(4-[
211At]astatophenethyl)succinamate (SAPS), prompted additional studies of its chemistry. The
211At radiolabeling of succinimidyl
N-2-(4-tributylstannylphenethyl)succinamate (
1) was noted to decline after storage at −15°C for greater than 6 months. Compound
1 was found to degrade via a ring closure reaction with the formation of
N-2-(4-tributylstannylphenethyl)succinimide (
3), and a modified procedure for the preparation of
1 was developed. The
N-methyl structural analog of
1, succinimidyl
N-2-(4-tributylstannylphenethyl)-
N-methyl succinamate (SPEMS), was synthesized to investigate the possibility of improving the stability of reagent–protein linkage chemistry. Radiolabeling of SPEMS with
211At generates succinimidyl
N-2-(4-[
211At]astatophenethyl)-
N-methyl succinamate (Methyl-SAPS), with yields being consistent for greater than 1 year. Radiolabelings of
1 and SPEMS with
125I generated succinimidyl
N-2-(4-[
125I]iodophenethyl)succinamate (SIPS) and succinimidyl
N-2-(4-[
125I]iodophenethyl)-
N-methyl succinamate (Methyl-SIPS), respectively, and showed no decline in yields. Methyl-SAPS, SAPS, Methyl-SIPS and SIPS were conjugated to Herceptin for a comparative assessment in LS-174T xenograft-bearing mice. The conjugates of Herceptin with Methyl-SAPS or Methyl-SIPS demonstrated immunoreactivity equivalent to if not superior to the SAPS and SIPS paired analogs. The in vivo studies also revealed that the
N-methyl modification resulted in a superior statinated product.