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

Hydrazones of a 6-hydrazinonicotinyl-modified cyclic peptide IIb/IIIa recep tor antagonist were prepared in order to protect the hydrazine moiety from reaction with trace aldehyde and ketone impurities encountered during the p rocess of manufacturing and compounding lyophilized kits used in radiolabel ing with Tc-99m. Hydrazones were prepared by either a direct reaction of th e 6-hydrazinonicotinyl-modified cyclic peptide with carbonyl compounds or b y conjugation of the cyclic peptide with hydrazones of succinimidyl 6-hydra zinonicotinate. 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 aldeh ydes and ketones provided the greatest level of stability when challenged w ith formaldehyde. We have been successful in protecting 6-hydrazinonicotiny l-modified cyclic peptides from reacting with formaldehyde, while still all owing sufficient reactivity for radiolabeling with Tc-99m. The hydrazones o f succinimidyl 6-hydrazinonicotinate are convenient and general reagents fo r forming 6-hydrazinonicotinyl conjugates with amino-functionalized bioacti ve molecules.