TY - JOUR
T1 - Study of the binding interaction between fluorinated matrix metalloproteinase inhibitors and Human Serum Albumin
AU - Digilio, Giuseppe
AU - Tuccinardi, Tiziano
AU - Casalini, Francesca
AU - Cassino, Claudio
AU - Dias, David M.
AU - Geraldes, Carlos F.G.C.
AU - Catanzaro, Valeria
AU - Maiocchi, Alessandro
AU - Rossello, Armando
N1 - Funding Information:
Economic and scientific support from Regione Piemonte (Bando CIPE 2007 “Converging Technologies”, project “BIO_THER) and from MIUR (PRIN 2010 n° 2010B5B2NL). This work was also financially supported by FEDER and Fundação para a Ciência e a Tecnologia (Portugal) through a PhD grant to DMD (SFRH/BD/81735/2011) and Rede Nacional de RMN (REDE/1517/RMN/2005) for the acquisition of the Varian VNMRS 600 NMR spectrometer in Coimbra. This work was performed within the EU COST TD1004 Action “Theragnostics Imaging and Therapy”. GD wishes to thank the students of the “Bioorganic Chemistry Lab” course for technical assistance.
PY - 2014/5/22
Y1 - 2014/5/22
N2 - Fluorinated, arylsulfone-based inhibitors of Matrix Metalloproteinases (MMP) have been used, in the [18F]-radiolabelled version, as radiotracers targeted to MMP-2/9 for Positron Emission Tomography (PET). Although they showed acceptable tumour uptake, specificity was rather low. To get further insights into the reason of low specificity, the binding interaction of these compounds with Human Serum Albumin (HSA) has been investigated. 19F NMR spectroscopy showed that all compounds considered partition between multiple HSA binding sites, being characterized by either slow-exchange kinetics (with Ka in the order of 105 M-1) and fast-exchange kinetics (with Ka in the order of 104 M -1). For 2-(2-(4′-(2-fluoroethoxy)biphenyl-4-ylsulfonyl)phenyl) acetic acid (1a) and 2-(2-(4′-(2-fluoroacetamido)biphenyl-4-ylsulfonyl) phenyl)acetic acid (1c), these slow and fast-exchanging binding sites could be mapped to Sudlow's site I and II, respectively. It is shown that high affinity albumin binding constitutes a theoretical limitation for the specificity achievable by MMP-inhibitors as MMP-targeted PET tracers in cancer imaging, because albumin accumulating aspecifically in tumours lowers the binding potential of radiotracers.
AB - Fluorinated, arylsulfone-based inhibitors of Matrix Metalloproteinases (MMP) have been used, in the [18F]-radiolabelled version, as radiotracers targeted to MMP-2/9 for Positron Emission Tomography (PET). Although they showed acceptable tumour uptake, specificity was rather low. To get further insights into the reason of low specificity, the binding interaction of these compounds with Human Serum Albumin (HSA) has been investigated. 19F NMR spectroscopy showed that all compounds considered partition between multiple HSA binding sites, being characterized by either slow-exchange kinetics (with Ka in the order of 105 M-1) and fast-exchange kinetics (with Ka in the order of 104 M -1). For 2-(2-(4′-(2-fluoroethoxy)biphenyl-4-ylsulfonyl)phenyl) acetic acid (1a) and 2-(2-(4′-(2-fluoroacetamido)biphenyl-4-ylsulfonyl) phenyl)acetic acid (1c), these slow and fast-exchanging binding sites could be mapped to Sudlow's site I and II, respectively. It is shown that high affinity albumin binding constitutes a theoretical limitation for the specificity achievable by MMP-inhibitors as MMP-targeted PET tracers in cancer imaging, because albumin accumulating aspecifically in tumours lowers the binding potential of radiotracers.
KW - Albumin
KW - Binding affinity
KW - Fluorine
KW - Matrix metalloproteinase inhibitor
KW - Molecular dynamics
KW - Saturation Transfer Difference
UR - https://www.scopus.com/pages/publications/84898757497
U2 - 10.1016/j.ejmech.2014.03.064
DO - 10.1016/j.ejmech.2014.03.064
M3 - Article
SN - 0223-5234
VL - 79
SP - 13
EP - 23
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
ER -
