title: Synthesis and in vitro characterization of organometallic rhenium and technetium glucose complexes against Glut 1 and hexokinase.
abstract: A series of nine organometallic technetium-99m and rhenium complexes of glucose are presented and characterized in vitro regarding their potential as surrogates of [18F]-2-fluoro-desoxy glucose ([18F]-FDG). The glucose derivatives are functionalized at positions C-1, C-2, C-3, and C-6. Different spacer lengths and chelating systems have been introduced at these sites. For the (radio)labeling, the organometallic precursors [99mTc(H2O)3(CO)3]+ and [ReBr3(CO)3](2-) respectively have been used. The resulting complexes have been characterized chemically and radiochemically. The formation of uniform products has been observed on the macroscopic (Re) and no-carrier-added level (99mTc). The Tc-99m complexes revealed good inertness against ligand exchange (Cys and His) and excellent stability in physiological buffered saline as well as in human plasma over a period of 24 h at 37 degrees C. The rhenium complexes have been tested for competitive inhibition of the (yeast) hexokinase. Only for C-2 derivatized glucose complexes with extended spacer functionalities Ki values in the millimolar and sub-millimolar range have been observed. In silico molecular docking experiments supported these experimental findings. However, the competitive inhibitors are not recognized as a pseudosubstrate of hexokinase. The cellular uptake of all 99mTc-complexes into HT-29 colon carcinoma cells via Glut1 was generally low and unspecific independent of the position at the hexose ring, the chelating systems, or the overall charge of the corresponding metal complexes. The current results seem to preclude the use of these compounds as [18F]-FDG surrogates primarily due to the low cellular uptake via Glut1.
authors.affiliation: Center for Radiopharmaceutical Science, ETH-PSI-USZ, Paul Scherrer Institute, 5232 Villigen PSI, Switzerland. roger.schibli@psi.ch
authors.forename: Roger
authors.initials: R
authors.lastname: Schibli
authors.forename: Cécile
authors.initials: C
authors.lastname: Dumas
authors.forename: Jeannine
authors.initials: J
authors.lastname: Petrig
authors.forename: Loredana
authors.initials: L
authors.lastname: Spadola
authors.forename: Leonardo
authors.initials: L
authors.lastname: Scapozza
authors.forename: Elisa
authors.initials: E
authors.lastname: Garcia-Garayoa
authors.forename: P August
authors.initials: PA
authors.lastname: Schubiger
mesh_terms: D001667:Binding, Competitive; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000737:chemistry; D003110:Colonic Neoplasms / Q000378:metabolism; D004355:Drug Stability; D005656:Fungal Proteins / Q000737:chemistry; D005947:Glucose / Q000737:chemistry*; D051272:Glucose Transporter Type 1; D006593:Hexokinase / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008956:Models, Chemical; D009004:Monosaccharide Transport Proteins / Q000378:metabolism*; D015609:Organotechnetium Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000494:pharmacology; D012211:Rhenium / Q000737:chemistry*; D019690:Technetium Tc 99m Exametazime / Q000737:chemistry
chemical_list: D002614:Chelating Agents; D005656:Fungal Proteins; D051272:Glucose Transporter Type 1; D008024:Ligands; D009004:Monosaccharide Transport Proteins; D015609:Organotechnetium Compounds; D019275:Radiopharmaceuticals; C495677:SLC2A1 protein, human; D019690:Technetium Tc 99m Exametazime; D012211:Rhenium; D006593:Hexokinase; D005947:Glucose