Differential effects of cyclodextrins and derivatives on the biological behavior of the myocardial perfusion imaging agent 99mTcN-NOET.
In addition to improving drug solubilization, cyclodextrins (CDs) also affect the biological behavior of the included compound. We evaluated the effects of two natural CDs beta-CD and gamma-CD, and six beta-CD derivatives, Dimeb, Trimeb, SBb, 2-HP, 6AD, and 6 MTU on the biological behavior of (99m)TcN-NOET, a technetium-99m-labeled, lipophilic compound readily detectable through radioactivity assessment. Determination of CDs' affinities for (99m)TcN-NOET indicated that the cavity size of gamma-CD was not suitable for (99m)TcN-NOET inclusion, and that beta-CD derivatization mostly resulted in decreased CDs affinities for (99m)TcN-NOET to various extents compared with the natural beta-CD. In vitro and ex vivo experiments performed on newborn rat cardiomyocytes and isolated perfused rat hearts, respectively, showed 1.7- and 2.3-fold maximal differences in (99m)TcN-NOET cellular and tissue activities. Regression analyzes indicated no significant correlation between these observed biological differences and the affinities of the eight CDs tested for (99m)TcN-NOET or for cellular membranes. In conclusion, CD derivatization often resulted in impaired affinity of the derivatives for the lipophilic compound (99m)TcN-NOET. Moreover, the in vitro and ex vivo biological behavior of (99m)TcN-NOET was greatly affected depending on the CD used for inclusion of the tracer.
Riou
Laurent
L
INSERM E0340 Radiopharmaceutiques Biocliniques, Faculté de Médecine de Grenoble, Domaine de la Merci, La Tronche, France. laurent.riou@ujf-grenoble.fr
Ghezzi
Catherine
C
Wouessidjewe
Denis
D
Law
Ho
H
Mathieu
Jean-Paul
JP
Defaye
Jacques
J
Bontron
René
R
Pasqualini
Roberto
R
Fagret
Daniel
D
D000818:Animals; D000831:Animals, Newborn; D003505:Cyclodextrins / Q000737:chemistry* / Q000493:pharmacokinetics; D004285:Dogs; D006321:Heart / Q000000981:diagnostic imaging*; D066298:In Vitro Techniques; D016014:Linear Models; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D015609:Organotechnetium Compounds / Q000737:chemistry / Q000493:pharmacokinetics*; D011877:Radionuclide Imaging; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D013859:Thiocarbamates / Q000737:chemistry / Q000493:pharmacokinetics*
D003505:Cyclodextrins; D015609:Organotechnetium Compounds; D013859:Thiocarbamates; C093922:technetium Tc 99m, bis(N-ethoxy-N-ethyldithiocarbamato)nitrido-