title: Radiolabeled hydroxamate-based matrix metalloproteinase inhibitors: How chemical modifications affect pharmacokinetics and metabolic stability.
abstract: Dysregulated MMP expression or activation is associated with several diseases. To study MMP activity in vivo by means of PET a radiolabeled MMP inhibitor (MMPI) functioning as radiotracer has been developed by our group based on the lead structure CGS 25966.
  
  
  
  Aiming at the modification of the pharmacokinetics of this lipophilic model tracer a new class of MMPIs has been discovered, consisting of additional fluorinated hydrophilic substructures, such as mini-PEG and/or 1,2,3-triazole units. To identify the best candidate for further clinical applications, radiofluorinated compounds of each subgroup have been (radio) synthesized and evaluated regarding their biodistribution behavior and their metabolic stability.
  
  
  
  Radiosyntheses of different triazole based MMPIs could be realized using two step "click chemistry" procedures. Compared to lead structure [(18)F]FEtO-CGS 25966 ([(18)F]1e, log D(exp) =2.02, IC50=2-50nM) all selected candidates showed increased hydrophilicities and inhibition potencies (log D(exp) =0.23-1.25, IC50=0.006-6nM). Interestingly, despite different hydrophilicities most triazole based MMPIs showed no significant differences in their in vivo biodistribution behavior and were cleared predominantly via the hepatobiliary excretion route. Biostability and metabolism studies in vitro and in vivo revealed significant higher metabolic stability for the triazole moiety compared to the benzyl ring in the lead structure. Cleavage of ethylene glycol subunits of the mini-PEG chain led to a faster metabolism of mini-PEG containing MMPIs.
  
  
  
  The introduction of hydrophilic groups such as mini-PEG and 1,2,3-triazole units did not lead to a significant shift of the hepatobiliary elimination towards renal clearance. Particularly the introduction of mini-PEG chains led to an intense metabolic decomposition. Substitution of the benzyl moiety in lead structure 1e by a 1,2,3-trizole ring resulted in an increased metabolic stability. Therefore, the 1,2,3-triazole-1-yl-methyl substituted MMPI [(18)F]3a was found to be the most stable candidate in this series and should be chosen for further preclinical evaluation.
authors.affiliation: Department of Nuclear Medicine, University Hospital Münster, Albert-Schweitzer-Campus 1, Building A1, D-48149, Münster, Germany; European Institute for Molecular Imaging, University of Münster, Waldeyerstraße 15, D-48149, Münster, Germany. Electronic address: verena.hugenberg@gmx.de.
authors.forename: Verena
authors.initials: V
authors.lastname: Hugenberg
authors.affiliation: European Institute for Molecular Imaging, University of Münster, Waldeyerstraße 15, D-48149, Münster, Germany; DFG EXC 1003 Cluster of Excellence 'Cells in Motion', University of Münster, Münster, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Hermann
authors.affiliation: Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, Corrensstraße 48, D-48149, Münster, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Galla
authors.affiliation: Department of Nuclear Medicine, University Hospital Münster, Albert-Schweitzer-Campus 1, Building A1, D-48149, Münster, Germany; European Institute for Molecular Imaging, University of Münster, Waldeyerstraße 15, D-48149, Münster, Germany; DFG EXC 1003 Cluster of Excellence 'Cells in Motion', University of Münster, Münster, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Schäfers
authors.affiliation: Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, Corrensstraße 48, D-48149, Münster, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Wünsch
authors.affiliation: Siemens Medical Solutions USA, Inc., 6140 Bristol Parkway, Culver City, CA, 90230, USA.
authors.forename: Hartmuth C
authors.initials: HC
authors.lastname: Kolb
authors.affiliation: Siemens Medical Solutions USA, Inc., 6140 Bristol Parkway, Culver City, CA, 90230, USA.
authors.forename: Katrin
authors.initials: K
authors.lastname: Szardenings
authors.affiliation: Siemens Medical Solutions USA, Inc., 6140 Bristol Parkway, Culver City, CA, 90230, USA.
authors.forename: Artem
authors.initials: A
authors.lastname: Lebedev
authors.affiliation: Siemens Medical Solutions USA, Inc., 6140 Bristol Parkway, Culver City, CA, 90230, USA.
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Walsh
authors.affiliation: Siemens Medical Solutions USA, Inc., 6140 Bristol Parkway, Culver City, CA, 90230, USA.
authors.forename: Vani P
authors.initials: VP
authors.lastname: Mocharla
authors.affiliation: Siemens Medical Solutions USA, Inc., 6140 Bristol Parkway, Culver City, CA, 90230, USA.
authors.forename: Umesh B
authors.initials: UB
authors.lastname: Gangadharmath
authors.affiliation: Department of Nuclear Medicine, University Hospital Münster, Albert-Schweitzer-Campus 1, Building A1, D-48149, Münster, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Kopka
authors.affiliation: Department of Nuclear Medicine, University Hospital Münster, Albert-Schweitzer-Campus 1, Building A1, D-48149, Münster, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Wagner
mesh_terms: D000818:Animals; D004355:Drug Stability; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry*; D007553:Isotope Labeling; D061965:Matrix Metalloproteinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D049268:Positron-Emission Tomography; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors
keywords: MMP radioligand; Matrix metalloproteinase inhibitors; Pharmacokinetics; Positron emission tomography; Radiotracer; Triazole-substituted hydroxamates