Eight HYNICtide
hydrazones (three with aliphatic substituents and five with aromatic groups) were studied for their potential use as the final intermediate for preparation of
RP444, a new
radiopharmaceutical under development for imaging
thrombosis. The goal of this study is to screen various
hydrazones through stability testing and radiolabeling and find those which are able to remain stable without significant degradation in the manufacturing process and at the same time are reactive to produce enough free
hydrazine in situ for successful (99m)Tc-labeling. In an initial screening study, only
hydrazones 6 and 8, which contain aliphatic substituents, gave satisfactory (>/=90%) yields of
RP444 using 50 degrees C and 30 min of heating. However, their
solution instability excludes them from being used as commercial
reagents.
Hydrazones 1 and 4 gave >/=90% yields when the reaction mixtures were heated at 80 degrees C for 30 min. Both
hydrazone 1 and
hydrazone 4 can be used as the final intermediate for preparation of
RP444. The combination of 40 mg of
tricine, 1-10 mg of TPPTS, 20-40 microg of
hydrazone 1 or 4 for 50 mCi of [(99m)Tc]
pertechnetate, 20-50 microg of
stannous chloride, pH 4.5 +/- 0.5, and heating at 80 degrees C for 30 min gives the best yield for
RP444. It is surprising that
hydrazones 1 and 4 have both the
solution stability with respect to decomposition and to reaction with
aldehydes and
ketones and yet are able to hydrolyze in situ to produce enough free HYNICtide for the (99m)Tc-labeling.