Synthesis of stable hydrazones of a hydrazinonicotinyl-modified peptide for the preparation of 99mTc-labeled radiopharmaceuticals

Bioconjug Chem. 1999 Sep-Oct;10(5):808-14. doi: 10.1021/bc9900237.

Abstract

Hydrazones of a 6-hydrazinonicotinyl-modified cyclic peptide IIb/IIIa receptor antagonist were prepared in order to protect the hydrazine moiety from reaction with trace aldehyde and ketone impurities encountered during the process of manufacturing and compounding lyophilized kits used in radiolabeling with (99m)Tc. Hydrazones were prepared by either a direct reaction of the 6-hydrazinonicotinyl-modified cyclic peptide with carbonyl compounds or by conjugation of the cyclic peptide with hydrazones of succinimidyl 6-hydrazinonicotinate. Stability of the hydrazones was evaluated by treatment with formaldehyde. Hydrazones derived from simple aliphatic aldehydes underwent an exchange reaction with formaldehyde, while hydrazones of aromatic aldehydes and ketones provided the greatest level of stability when challenged with formaldehyde. We have been successful in protecting 6-hydrazinonicotinyl-modified cyclic peptides from reacting with formaldehyde, while still allowing sufficient reactivity for radiolabeling with (99m)Tc. The hydrazones of succinimidyl 6-hydrazinonicotinate are convenient and general reagents for forming 6-hydrazinonicotinyl conjugates with amino-functionalized bioactive molecules.

MeSH terms

  • Chromatography, High Pressure Liquid
  • Drug Stability
  • Formaldehyde / chemistry
  • Hydrazones / chemical synthesis*
  • Isotope Labeling / methods
  • Niacinamide / analogs & derivatives*
  • Niacinamide / chemistry
  • Organophosphorus Compounds / chemistry
  • Organotechnetium Compounds / chemical synthesis*
  • Peptides, Cyclic / chemical synthesis*
  • Peptides, Cyclic / chemistry*
  • Platelet Glycoprotein GPIIb-IIIa Complex / antagonists & inhibitors
  • Radiopharmaceuticals / chemical synthesis*
  • Sodium Pertechnetate Tc 99m / chemistry
  • Succinimides / chemistry
  • Sulfonic Acids / chemistry

Substances

  • 99mTc(HYNICtide)(tricine)(TPPTS)
  • Hydrazones
  • Organophosphorus Compounds
  • Organotechnetium Compounds
  • Peptides, Cyclic
  • Platelet Glycoprotein GPIIb-IIIa Complex
  • Radiopharmaceuticals
  • Succinimides
  • Sulfonic Acids
  • triphenylphosphine-3,3',3''-trisulfonic acid
  • Formaldehyde
  • Niacinamide
  • Sodium Pertechnetate Tc 99m