Kurzbeschreibung
(Englisch)
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It is a strong incentive in medicinal inorganic or radiopharmaceutical chemistry to prepare small biomolecules labelled with 99mTc which are still recognized by their receptors and being actively transported into the cell. Most promising are biomolecules such as estradiol, amino acids or glucose. While data on structure-activity relationships are available for a few cold cyclopentadienyl-rhenium containing compounds, it is so far impossible to synthesise the homologues with technetium. This prevents their practical application in clinics. We aim in this project at finding novel routes towards the synthesis of half sandwich complexes with technetium from water and will apply these methods to the labelling of amino acids for targeting the L-type amino acid transporter LAT1. Since a thorough drug design is required to retain the action of these derivatives, cold rhenium containing analogues will be synthesized and biologically studied in parallel. The scientific results will find interest in the organometallic, the inorganic medicinal and the radiopharmaceutical community in general and for the other members of the WG 'Bioorganometallics' in particular.
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Partner und Internationale Organisationen
(Englisch)
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AT, BE, CH, CZ, DE, DK, ES, FR, GR, HU, IE, IL, IT, NL, NO, PL, PT, RO, SE, SI, TR, UK
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Abstract
(Englisch)
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The COST action D39 is dedicated towards Metallo-Drug Action and Design. Within this broad topics, the present project C06.0109 had the objective of preparing and evaluating cyclopentadienyl (Cp) complexes of technetium (99mTc), bearing a biologically active functionality at the Cp-ring. From a synthetic point of view, the primary aim was the preparation of cyclopentadienyl complexes from pertechnetate, directly in water and in one single step as required by future routine applications in hospitals. Within this objective, a focus was put on artificial amino acids, resembling the natural substrate of the L-type amino acid transporter LAT1, phenylalanine (phe). Phe is actively transported into rapidly proliferating cells such as cancer cells. Accumulation of activity at certain sites would allow an early diagnosis of cancerous tissues. With that goal in mind, we have prepared a Cp-analogue of phe with the CH2 group between the phenyl ring and the a-amino acid portion lacking. We found that this compound 'C0' has a higher affinity for LAT1 than phe itself and is actively transported into the cell. Thus, the focus has not been put on the true analogue but on a derivative. The objective of preparing cyclopentadienyl analogues of phe has been achieved. This artificial amino acid can be labelled and is recognized by its target transporter. The key compound in this project was Thiele's acid, the Diels-Alder product of [C5H6COOH]. Based on this synthetic concept, we exceeded what was originally planned with a number of further Cp-derivatised biomolecules. In collaboration with a group in Pakistan, we could show that the artificial peptide [Cp-(CONH-gly3)99mTc(CO)3] accumulated in the brain in unprecedented high concentrations. Thus, the phenyl-Cp analogy could be shown for a very different class of biomolecules. Given the fact that piano-stool complexes with rhenium and technetium can mimic phenyls, we consequently selected a number of further lead compounds, mainly melanoma targeting agents of the benzamide type, carbonic anhydrase (CA) inhibitors and histone deacteylase (HDAC) inhibitors. In collaboration with the Portugal group from COST action D39 it was shown that IC50 values of the rhenium compounds of HDAC inhibitors were in the same range (low micro molar) as their purely organic models (e.g. suberoic acid hydroxamate SAHA). Labelling of the HDAC inhibitors proved difficult due to the coordinating properties of the hydroxamate group. Studies to overcome this drawback are on the way. The CA inhibitors, on the other hand, were quantitatively labelled. In summary, the following major goals within COST action D39 have been achieved: i) Cyclopentadienyl analogues of amino acids have been synthesized and their rhenium complexes been prepared and fully characterized. ii) Cyclopentadienyl analogues of amino acids have been labelled with 99mTc as molecular imaging agents. iii) Cyclopentadienyl analogues of amino acids have been integrated in peptide chains and been labelled, opening an access to truly artificial peptides for molecular imaging. iv) Thiele's acid has been derivatised with a number of biologically active functionalities, their rhenium complexes are available and the parent Thiele's acid compound (partially) been labelled with 99mTc v) Attaching of the parent compounds to solid phase supports allows for the synthesis of no carrier added radiopharmaceuticals. vi) the cyclopentadienyl-phenyl analogy in pharmacophores has been shown for a variety of pharma ceuticals. vii) the experimental knowledge, elaborated during this project, did and will enable the labelling of biomolecules of interest from other participants in D39. The project reliably introduced a new class of radiopharmaceuticals in molecular imaging. Although the preparation of piano-stool complexes with the [99mTc(CO)3]+ core needs to be optimized from case to case, [(Cp-R)99mTc(CO)3] represents a novel building block with substantial advantages (mainly size and m.w.) over the common labelling strategy according to the bifunctional chelator approach with multidentate chelators. This extension will lead to novel opportunities in 99mTc based imaging but impacts also other fields such as (cold) rhenium-based therapy of various diseases since the two elements are chemical congeners. Thus, whereas the (cold) rhenium compounds can be taken as novel metallo-drugs, their 99mTc congeners are tools for imaging. Collaborations from within D39 are exceeding the end of this action.
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