Modular Medical Imaging Agents Based on Azide-Alkyne Huisgen Cycloadditions:Synthesis and Pre-Clinical Evaluation of(18)F-Labeled PSMA-Tracers for Prostate Cancer Imaging

Since the seminal contribution of Rolf Huisgen to develop the [3+2] cycloaddition of 1,3-dipolar compounds, its azide–alkyne variant has established itself as the key step in numerous organic syntheses and bioorthogonal processes in materials science and chemical biology. In the present study, the copper(I)-catalyzed azide–alkyne cycloaddition was applied for the development of a modular molecular platform for medical imaging of the prostate-specific membrane antigen (PSMA), using positron emission tomography. This process is shown from molecular design, through synthesis automation and in vitro studies, all the way to pre-clinical in vivo evaluation of fluorine-18- labeled PSMA-targeting ‘F-PSMA-MIC’ radiotracers (t1/2=109.7 min). Pre-clinical data indicate that the modular PSMA-scaffold has similar binding affinity and imaging properties to the clinically used [68Ga]PSMA-11. Furthermore, we demonstrated that targeting the arene-binding in PSMA, facilitated through the [3+2]cycloaddition, can improve binding affinity, which was rationalized by molecular modeling. The here presented PSMA-binding scaffold potentially facilitates easy coupling to other medical imaging moieties, enabling future developments of new modular imaging agents

Non-heme iron complexes as supramolecular oxidation catalysts.

In recent years non-heme iron complexes have been shown to be promising catalysts in the oxidation of alkanes and alkenes. These complexes are capable of mimicking iron oxygenases 1,2,3. As was mentioned in Chapter 1 the aim of the research described in this thesis was the investigation of non-heme iron complexes as catalysts for oxidation reactions like epoxidation and dihydroxylation. Investigations have been carried out to combine the substrate binding site of cyclodextrin with the catalyctic site of iron complexes in order to prepare a supramolecular catalyst with enhanced selectivity. ... Zie: Summary

Non-heme Iron Catalysts For The Benzylic Oxidation: A Parallel Ligand Screening Approach

Ethylbenzene and 4-ethylanisole were used as model substrates for benzylic oxidation with H2 O2 or O2 using a range of non-heme iron catalysts following a parallel ligand screening approach. Effective oxidation was found for Fe complexes based on tetra- and pentadentate nitrogen ligands affording the corresponding benzylic alcohol and ketone.

Non-heme Iron Complexes For Stereoselective Oxidation: Tuning Of The Selectivity In Dihydroxylation Using Different Solvents

A new class of functional models for non-heme iron-based dioxygenases, including [(N3Py-Me)Fe(CH3 CN)2 ](ClO4 )2 and [(N3Py-Bn)Fe(CH3 CN)2 ](ClO4 )2 {N3Py-Me = [di(2-pyrid-yl) methyl]methyl(2-pyridyl)methylamine; N3Py-Bn = [di(2- pyridyl)methyl]benzyl(2-pyridyl)methylamine}, is presented here. NMR, UV and X-ray analyses revealed that six-coord-inate low-spin Fe II complexes with the pyridine N-atoms and the tertiary amine functionality of the ligand bound to Fe are formed. The two remaining coordination sites located cis to each other are occupied by labile CH3 CN groups that are easily exchanged by other ligands. We demonstrate that the reactivity and stereoselectivity of the complexes investigated depend on the choice of the solvent. The complexes have been examined as catalysts for the oxidation of both alkanes and olefins in CH3 CN. In this solvent alkanes are oxidized to alcohols and ketones and olefins to the corresponding cis- epoxides and cis-diols. In acetone as solvent a different react-ivity pattern was found, with, as the most striking example, the trans-dihydroxylation of cis-olefins. 18 O-labeling studies in CH3 CN establish incorporation of 18 O from H2 18 O2 and H2 18 O in both the epoxide and the diol implicating an HO-Fe V = 18 O active intermediate originating from an H2 18 O-Fe III OOH species. These results are in full agreement with mechanistic schemes derived for other dioxygenase model systems. Based on labeling studies in acetone an additional oxidation mechanism is proposed for this solvent, in which the solvent acetone is involved. This is the first example of a catalyst that can give cis- or trans-dihydroxylation products, just by changing the solvent.

CCDC 213726: Experimental Crystal Structure Determination

Related Article: M.Klopstra, G.Roelfes, R.Hage, R.M.Kellogg, B.L.Feringa|2004|Eur.J.Inorg.Chem.||846|doi:10.1002/ejic.200300667,An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.