Effect of cyclodextrin complexation on the in vivo disposition of the brain imaging radiopharmaceutical 99mTechnetium ethyl cysteinate dimer (99mTc-ECD).

The brain imaging radiopharmaceutical, 99m Technetium ethyl cysteinate dimer ( 99m Tc-ECD, 99m Tc-bicisate) is the most recent addition to the available set of radiopharmaceuticals for measuring cerebral blood flow. Ideally radiotracers should be trapped in the brain long enough so that their distribution can be quantitated and should demonstrate good spatial resolution. Furthermore, the stability (chemical and metabolic) and bioavailabily of radiopharmaceuticals have in general proved to be a challenge during development and clinical administration. In view of these challenges and background, this study with 99m Tc-ECD is presented. The aims of this research program were to develop novel approaches to improve the chemical and metabolic stability and the bioavailability of 99m Tc-ECD across the blood brain barrier for cerebral blood flow determinations, using the well known non-human primate in vivo baboon model. These aims were addressed by investigating the influence of cyclodextrin - 99m Tc-ECD complexation on normal cerebral blood flow patterns, using two different cyclodextrins, i.e., γ-cyclodextrin (CAS 17465-86-0) and β-trimethylcyclodextrin (CAS 55216-11-0). The effect of incubation of 99m Tc-ECD (with or without cyclodextrin complexation) in plasma, on metabolic esterase action, was also investigated. Possible protection against plasma esterase by acetylcholine (CAS 51-84-3) of 99m Tc-ECD was further determined. The current study has shown that cyclodextrin complexation of 99m Tc-ECD indeed offers a useful approach to improve the stability of the radiopharmaceutical against peripheral metabolism. The acetylcholine shows also potential to protect 99m Tc-ECD. However, it is clear from the current data that the choice of cyclodextrin is of utmost importance, as has been observed from significantly reduced the bioavailability of 99m Tc-ECD when complexed with β-trimethylcyclodextrin. The plasma incubation procedures showed that γ-cyclodextrin offers protection with only slightly reduced bioavailability. This study has indicated that novel approaches, such as cyclodextrin technologies, indeed show potential to modify the performance in its currently available 99m Tc-ECD form.