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.

Water-stable fac-{TcO3}+ Complexes – A New Field of Technetium Chemistry

“…Glucose is a particularly interesting biomolecule due to the search for a 99m Tc-based carbohydrate as a complement to 2-deoxy-2-( 18 F)fluoro-d-glucose ( 18 F-FDG). [11,39,40] These reactions demonstrate the flexibility and suitability of this new labeling strategy. In vivo studies with these new compounds and the preparation of other new radiopharmaceuticals derived from this core are currently under way.…”

Conjugation of glucosamine with Gd3+-based nanoporous silica using a heterobifunctional ANB-NOS crosslinker for imaging of cancer cells

“…Via nitrene, some amino groups in glucosamine can be crosslinked to form amides. Nitrene is a very reactive functional group, so its participation in the cross-linking process takes less than 10 −4 of a second, 37 which minimizes nonspecific binding.…”

“…36,37 Blood glucose levels A statistically insignificant (P , 0.05) increase in blood glucose levels was observed after intravenous injection of MSN-Gd 3+ -DG at the various doses. 36 Coadministration of MSN-Gd 3+ -DG and insulin caused a marked decrease in blood glucose levels.…”

“…Most recently, surface-functionalized MSNs using cancer-specific agents have also been used for selectively targeting cancer cells. 15 Antibodies, peptides, aptamers, 16 carbohydrates, 17 and folic acid 18 are some of these agents. Glucose analogs are excellent agents for diagnosis of cancer, showing excessive cellular uptake of glucose due to overexpression of glucose transporters in cancer cells.…”

Metal-based glycoconjugates and their potential in targeted anticancer chemotherapy

“…Schibli and co-workers generated a series of technetium-99m (and the corresponding "cold" rheniumbased analogues) tricarbonyl complexes bearing different tridentate chelating moieties (including iminodiacetate, N-(2-pyridylmethyl)glycine and N aliphatic -tethered histidine) bound to glucose at the C(1), C(2), C(3) and C(6) position [167,168]. All complexes showed high stability in vitro but cellular uptake proved rather low and not mediated by a GLUT1-dependent process.…”