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.
INSERM E0340 Radiopharmaceutiques Biocliniques, Faculté de Médecine de Grenoble, Domaine de la Merci, La Tronche, France. laurent.riou@ujf-grenoble.fr
Laurent
L
Riou
Catherine
C
Ghezzi
Denis
D
Wouessidjewe
Ho
H
Law
Jean-Paul
JP
Mathieu
Jacques
J
Defaye
René
R
Bontron
Roberto
R
Pasqualini
Daniel
D
Fagret
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-