Effect of cyclodextrin complexation on the in vivo disposition of the brain imaging radiopharmaceutical (99m)Technetium ethyl cysteinate dimer (Tc-99m-ECD)

The brain imaging radiopharmaceutical, (99m)Technetium ethyl cysteinate dim er (Tc-99m-ECD, Tc-99m-bicisate) is the most recent addition to the availab le set of radiopharmaceuticals for measuring cerebral blood flow. Ideally r adiotracers should be trapped in the brain long enough so that their distri bution can be quantitated and should demonstrate good spatial resolution Fu rthermore, the stability (chemical and metabolic) and bioavailabity of radi opharmaceuticals have in general proved to be a challenge during developmen t and clinical administration. In view of these challenges and background, this study with Tc-99m-ECD is presented. The aims of this research program were to develop novel approaches to improve the chemical and metabolic stab ility and the bioavailability of Tc-99m-ECD across the blood brain barrier for cerebral blood flow determinations, using the well known non-human prim ate in vivo baboon model. These aims were addressed by investigating the in fluence of cyclodextrin - Tc-99m-ECD complexation on normal cerebral blood flow patterns, using two different cycrodextrins, i.e., gamma-cyclodextrin (CAS 17465-86-0) and beta-trimethylcyclodextrin (CAS 55216-11-0). The effec t of incubation of Tc-99m-ECD (with or without cyclodextrin complexation) i n plasma, on metabolic esterase action, was also investigated. Possible pro tection against plasma esterase by acetylcholine (CAS 51-84-3) of Tc-99m-EC D was further determined. The current study has shown that cyclodextrin com plexation of Tc-99m-ECD indeed offers a useful approach to improve the stab ility of the radiopharmaceutical against peripheral metabolism. The acetylc holine shows also potential to protect Tc-99m-ECD. However, it is clear Fro m the current data that the choice of cyclodextrin is of utmost importance, as has been observed from significantly reduced the bioavailability of Tc- 99m-ECD when complexed with beta-trimethylcyclodextrin. The plasma incubati on procedures showed that gamma-cyclodextrin offers protection with only sl ightly reduced bioavailability. This study has indicated that novel approac hes, such as cyclodextrin technologies, indeed show potential to modify the performance in its currently available Tc-99m-ECD form.