Author/Authors :
Carpinelli, Assunta Institute of Molecular Bioimaging and Physiology of CNR - Segrate, Italy , Rainone, Paolo Doctorate School of Molecular and Translational Medicine - University of Milan - Milan, Italy , Belloli, Sara Institute of Molecular Bioimaging and Physiology of CNR - Segrate, Italy , Reale, Annalisa Department of Biotechnology - Chemistry - and Pharmacy - University of Siena - Siena, Italy , Cappelli, Andrea Department of Biotechnology - Chemistry - and Pharmacy - University of Siena - Siena, Italy , Germano, Giuliani Department of Biotechnology - Chemistry - and Pharmacy - University of Siena - Siena, Italy , Murtaj, Valentina Institute of Molecular Bioimaging and Physiology of CNR - Segrate, Italy , Coliva, Angela Nuclear Medicine Unit - San Raffaele Scientific Institute - Milan, Italy , Di Grigoli, Giuseppe Institute of Molecular Bioimaging and Physiology of CNR - Segrate, Italy , Valeri, Angela Department of Biotechnology - Chemistry - and Pharmacy - University of Siena - Siena, Italy , Carla Gilardi, Maria Institute of Molecular Bioimaging and Physiology of CNR - Segrate, Italy , Gianolli, Luigi Nuclear Medicine Unit - San Raffaele Scientific Institute - Milan, Italy , Anzini, Maurizio Department of Biotechnology - Chemistry - and Pharmacy - University of Siena - Siena, Italy , Moresco, Rosa Maria Institute of Molecular Bioimaging and Physiology of CNR - Segrate, Italy
Abstract :
Cyclooxygenase-2 (COX-2) is involved in the inflammatory response, and its recurrent overexpression in cancers as well as in neurodegenerative disorders has made it an important target for therapy. For this reason, noninvasive imaging of COX-2 expression may
represent an important diagnostic tool. In this work, a COX-2 inhibitor analogue, VA426 [1-(4-fluorophenyl)-3-(2-methoxyethyl)-2-
methyl-5-(4-(methylsulfonil)phenyl)-1H-pyrrole], was synthesized and radiolabelled with the 11C radioisotope. The ex vivo biodistribution profile of 11C-VA426 was evaluated in the brain and periphery of healthy rats and mice and in brain and periphery of
inflammation models, based on the administration of LPS. 11C-VA426 synthesis with the tBuOK base showed optimal radiochemical yield
(15±2%) based on triflate activity, molar activity (range 37–148 GBq/μmol), and radiochemical purity (>95%). Ex vivo biodistribution
studies showed a fast uptake of radioactivity but a rapid washout, except in regions expressing COX-2 (lungs, liver, and kidney) both in rats
and in mice, with maximum values at 30 and 10minutes p.i., respectively. LPS administration did not show significant e¢ect on radioactivity accumulation. Celecoxib competition experiments performed in rats and mice treated with LPS produced a general target
unrelated reduction of radioactivity concentration in all peripheral tissues and brain areas examined. Finally, in agreement with the
negative results obtained from biodistribution experiments, radiometabolites analysis revealed that 11C-VA426 is highly unstable in vivo.
This study indicates that the compound 11C-VA426 is not currently suitable to be used as radiopharmaceutical for PET imaging. This
family of compounds needs further implementation in order to improve in vivo stability.
