Digilio Giuseppe, Tuccinardi Tiziano, Casalini Francesca, Cassino Claudio, Dias David M, Geraldes Carlos F G C, Catanzaro Valeria, Maiocchi Alessandro, Rossello Armando
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.
Eur J Med Chem. 2014 May 22;79:13-23. doi: 10.1016/j.ejmech.2014.03.064. Epub 2014 Mar 22.
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.
基于芳基砜的氟化基质金属蛋白酶（MMP）抑制剂已被用于[（18）F]放射性标记形式，作为正电子发射断层扫描（PET）中靶向MMP-2/9的放射性示踪剂。尽管它们显示出可接受的肿瘤摄取，但特异性相当低。为了进一步深入了解特异性低的原因，研究了这些化合物与人血清白蛋白（HSA）的结合相互作用。（19）F核磁共振光谱表明，所有考虑的化合物在多个HSA结合位点之间分配，其特征在于慢交换动力学（Ka约为10（5）M（-1））和快交换动力学（Ka约为10（4）M（-1））。对于2-（2-（4'-（2-氟乙氧基）联苯-4-基磺酰基）苯基）乙酸（1a）和2-（2-（4'-（2-氟乙酰胺基）联苯-4-基磺酰基）苯基）乙酸（1c），这些慢交换和快交换结合位点可分别映射到Sudlow位点I和II。结果表明，高亲和力白蛋白结合构成了MMP抑制剂作为癌症成像中MMP靶向PET示踪剂可实现特异性的理论限制，因为在肿瘤中非特异性积累的白蛋白会降低放射性示踪剂的结合潜力。
