title: Effect of cyclodextrin complexation on the in vivo disposition of the brain imaging radiopharmaceutical 99mTechnetium ethyl cysteinate dimer (99mTc-ECD).
abstract: The brain imaging radiopharmaceutical, 99mTechnetium ethyl cysteinate dimer (99mTc-ECD, 99mTc-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 bioavailability 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 99mTc-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 99mTc-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--99mTc-ECD complexation on normal cerebral blood flow patterns, using two different cyclodextrins, i.e., gamma-cyclodextrin (CAS 17465-86-0) and beta-trimethylcyclodextrin (CAS 55216-11-0). The effect of incubation of 99mTc-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 99mTc-ECD was further determined. The current study has shown that cyclodextrin complexation of 99mTc-ECD indeed offers a useful approach to improve the stability of the radiopharmaceutical against peripheral metabolism. The acetylcholine shows also potential to protect 99mTc-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 99mTc-ECD when complexed with beta-trimethylcyclodextrin. The plasma incubation procedures showed that gamma-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 99mTc-ECD form.
authors.affiliation: Faculty Health Sciences, Pharmacology, Potchefstroom University for Christian Higher Education, Potchefstroom, Republic of South Africa. fkldwo@puknet.puk.ac.za
authors.forename: D W
authors.initials: DW
authors.lastname: Oliver
authors.forename: I C
authors.initials: IC
authors.lastname: Dormehl
authors.forename: W
authors.initials: W
authors.lastname: Louw
authors.forename: E
authors.initials: E
authors.lastname: Kilian
authors.forename: V
authors.initials: V
authors.lastname: de Beco
authors.forename: J L
authors.initials: JL
authors.lastname: Morretti
mesh_terms: D000778:Anesthetics, Dissociative / Q000493:pharmacokinetics; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging*; D003505:Cyclodextrins / Q000737:chemistry*; D003545:Cysteine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D007649:Ketamine / Q000493:pharmacokinetics; D008297:Male; D009778:Occipital Lobe / Q000000981:diagnostic imaging; D015609:Organotechnetium Compounds / Q000737:chemistry* / Q000493:pharmacokinetics; D010215:Papio; D019275:Radiopharmaceuticals / Q000737:chemistry* / Q000493:pharmacokinetics; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: D000778:Anesthetics, Dissociative; D003505:Cyclodextrins; D015609:Organotechnetium Compounds; D019275:Radiopharmaceuticals; D007649:Ketamine; C059659:technetium Tc 99m bicisate; D003545:Cysteine