Study of the binding interaction between fluorinated matrix metalloproteinase inhibitors and Human Serum Albumin.
Fluorinated, arylsulfone-based inhibitors of Matrix Metalloproteinases (MMP) have been used, in the [(18)F]-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. (19)F 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 10(5) M(-1)) and fast-exchange kinetics (with Ka in the order of 10(4) 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.
Department of Science and Technological Innovation, Università del Piemonte Orientale "Amedeo Avogadro", Viale T. Michel 11, I-15121 Alessandria, Italy. Electronic address: giuseppe.digilio@mfn.unipmn.it.
Giuseppe
G
Digilio
Department of Pharmacy, University of Pisa, Via Bonanno 6, I-56126 Pisa, Italy.
Tiziano
T
Tuccinardi
Department of Science and Technological Innovation, Università del Piemonte Orientale "Amedeo Avogadro", Viale T. Michel 11, I-15121 Alessandria, Italy; Department of Pharmacy, University of Pisa, Via Bonanno 6, I-56126 Pisa, Italy.
Francesca
F
Casalini
Department of Science and Technological Innovation, Università del Piemonte Orientale "Amedeo Avogadro", Viale T. Michel 11, I-15121 Alessandria, Italy.
Claudio
C
Cassino
Center for Neurosciences and Cell Biology of Coimbra, Coimbra, Portugal; Department of Life Sciences, Faculty of Science and Technology University of Coimbra, Coimbra, Portugal.
David M
DM
Dias
Center for Neurosciences and Cell Biology of Coimbra, Coimbra, Portugal; Department of Life Sciences, Faculty of Science and Technology University of Coimbra, Coimbra, Portugal; Coimbra Chemistry Centre, University of Coimbra, Coimbra, Portugal.
Carlos F G C
CF
Geraldes
Department of Science and Technological Innovation, Università del Piemonte Orientale "Amedeo Avogadro", Viale T. Michel 11, I-15121 Alessandria, Italy; Istituto di Ricerca Diagnostica e Nucleare SDN, Via Gianturco 113, Napoli 80143, Italy.
Valeria
V
Catanzaro
CRB Bracco Imaging SpA, Via Ribes 5, I-10010 Colleretto Giacosa, TO, Italy.
Alessandro
A
Maiocchi
Department of Pharmacy, University of Pisa, Via Bonanno 6, I-56126 Pisa, Italy.
Armando
A
Rossello
D001665:Binding Sites / Q000187:drug effects; D005461:Fluorine / Q000737:chemistry; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D007700:Kinetics; D061965:Matrix Metalloproteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D012709:Serum Albumin / Q000737:chemistry*; D013450:Sulfones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
D006845:Hydrocarbons, Fluorinated; D061965:Matrix Metalloproteinase Inhibitors; D012709:Serum Albumin; D013450:Sulfones; D005461:Fluorine; D020782:Matrix Metalloproteinases
(19)F NMR; Albumin; Binding affinity; Fluorine; Matrix metalloproteinase inhibitor; Molecular dynamics; Saturation Transfer Difference