In order to visualize and quantify dopamine transporters, the synthesis of two novel ligands labelled with technetium-99m (Tc-99m) has been investigated. A multi-step synthesis afforded two target ligands with a tropane skeleton and a macrocyclic complexing moiety. The choice and the position of substituents are in adequation with dopamine transporter structure. The radiolabelling of these ligands with Tc-99m has been studied and the results make them good candidates for SPECT imaging. Copyright (C) 2002 John Wiley Sons, Ltd.

Several Tc-99m complexes were synthesized, substituted with a nitroimidazole group, in order to visualize hypoxic tissues. The complexes were tested on rats (isolated hearts) and showed no significant uptake under hypoxic conditions.

Two anomeric analogues of glucose labelled with 123 iodine in position 6, proposed as tracers of glucose transport in vivo, have been synthesized: alpha- and beta-methyl-6-deoxy-6-iodo-D-glucopyranoside (alpha MDIG and beta MDIG). The aim of this study was to determine whether these molecules interact with the glucose transporter and whether they could be used as tracers of glucose transport in vivo. The biodistribution of alpha MDIG and beta MDIG was studied in the mouse in vivo. To determine if these two anomers enter the cell via the glucose transporter, their uptake was measured in isolated perfused rat hearts, in human erythrocytes in suspension, and in cardiomyocytes of neonatal rat in culture. Both alpha MDIG and beta MDIG had similar repartitions in the mouse: myocardial uptake averaged 7% of the injected dose/g of organ at 2 min postinjection and alpha MDIG competed with D-glucose to enter the cells. Insulin produced a 123% increase of its uptake in isolated perfused rat hearts and a 100% increase in cardiomyocytes of neonatal rat in culture. alpha MDIG uptake was lowered in the presence of glucose transport inhibitors in each experimental model. An interaction between beta MDIG and glucose transporters was observed only in human erythrocytes in suspension. Only alpha MDIG interacts with the glucose transporter, and thus could be used to estimate glucose transport in vivo.

A glucose analogue labelled with iodine-123 in position 6 has been synthesized: [123I]-6-deoxy-6-iodo-D-glucose (6DIG). The aim of this study was to examine its biological behaviour in order to assess whether it could be used to evaluate glucose transport with SPECT. To establish whether 6DIG enters the cells using the glucose transporter, four biological models have been used: human erythrocytes in suspension, neonatal rat cardiomyocytes in culture, isolated perfused rat hearts, and biodistribution in mice. 6DIG competed with D-glucose to enter the cells and its entry was increased by insulin and inhibited in the presence of cytochalasin B. The biological behaviour of 6DIG was similar to that of 3-O-methyl-D-glucose. 6DIG is a tracer of glucose transport which is very promising for clinical studies.

La synthèse de tétramines cycliques, de tétramines cycliques mono-et tétra-N-alkylées est développée ainsi que la complexation due technétium par ces ligands à partir de 99mTcO−4. Plusieurs réducteurs du pertechnétate sont étudiés ainsi que le rendement de complexation, la charge et la lipophilie des complexes. Leur étude biologique chez la souris (biodistribution) et chez le chien (scintigraphie) a permis de mettre en évidence une excellente captation hépatobiliaire du trans-99mTcO2(1-dodécyl-1,4,8,11-tétraazacylotétradécane).

This paper describes the synthesis of four new polyisocyanides (three diisocyanides and one triisocyanide). The complexation of 99mTc with these ligands is also studied through chromatography and revealed the formation of hexacoordinated 99mTc+1 complexes. Finally, biodistributions of these complexes in mice are given and compared. Heart captations are lower than the ones with [99mTc(MIBI)6]+ but remain constant and a satisfactory lungs clearance, probably due to the metabolization of the ligands, is observed.

The new diisocyanide ligand L possessing a polyether backbone was synthesized and its complexing ability towards metal such as 99mTc, Cu and Re was evaluated. Using the γ-emitting 99mTc isotope (at the non-carrier added level), L led to the formation of a cationic species whose biodistribution in Swiss mice revealed a moderate but lasting heart uptake. No redox properties of the ligand were observed by complexation since reaction with a CuII salt led to the formation of a CuII complex, characterized by EPR, IR and elemental analysis. Rhenium complexation gave two new chelates [ReIIICl3PPh3L] and [ReI3]BPh4, identified by IR NMR, elemental analysis and conductimetric studies. The usefulness of rhenium chemistry to approach 99mTc properties is discussed.

Analogues of glucose labeled with 123 iodine in positions 1, 2 or 3 have been synthesized. The aim of this study was to examine their biological behavior in four experimental models in order to assess whether they could be used to evaluate the uptake of glucose with single photon emission computed tomography (SPECT). The results obtained have shown that none of these molecules enters the cell using the glucose transporter. Therefore, they cannot be used as tracers of glucose uptake.

123-Iodine labelled 6-iodo-4-oxa-hexanoic acid, an analogue of 6-iodo-hexanoic acid, has been prepared and its radiochemical stability and in vivo distribution in mice evaluated. The β-iodoethoxyl group has been found to be suitable moiety for iodine radiolabelling.

The trans dioxo complexes [TcO2(L)]+ (L = 1,4,8,11-tetraazacyclotetradecane (cyclam), 1,4,8,11-tetraazacyclotetradecane-5-one, 1,4,8,11-tetraazacyclotetradecane-5,7-dione) have been prepared through a new alternative route involving the reaction of excess of the appropriate ligand with the complexes [TcCl4(PPh3)2] and [TcCl3(CH3CN)(PPh3)2] in CH3CN solution, at room temperature. The yields of formation of the final products obtained through this new synthetic method (30–55%) are significantly higher than that found in the synthesis of the complex [TcO2(cyclam)]+ (7%) obtained through a previously reported procedure involving pertechnetate reduction by Na2S2O3 in alkaline solution and in the presence of the ligand or by substitution reaction onto the mono-oxo complex [TcOCl4]−. The new synthetic method was also efficiently applied to the synthesis of the trans dioxo complexes [TcO2(L′)2]+ (L = enthylenediamine, 1,3-propanediamine) and [Tc2(tad)]+ (tad = 1,5,8,12-tetraazadodecane), containing bidentate and tetradentate chelating amines, giving final yields similar to those obtained using [TcOCl4]− as starting substrate. These results indicate that the complex [TcCl4(PPh3)2] and [TcCl3(CH3CN)(PPh3)2] are superior precursors for the synthesis, at macroscopic level, of trans dioxo Tc(V) complexes with tetraazamacrocylic ligands as compared to [TcO4]− and [TcOCl4]−. All the complexes have been characterized by elemental analysis, FTIR and mass spectra, and magnetic susceptibility measurements in solution.

In the preparation of gamma and beta- tracers for use in biomedical measurement, we have studied the reaction between two alkylated dioxophosphides and the o-xylene-alpha,alpha'-dichloride 5. The dioxophosphides are prepared by reaction of diisopropylethylenediphosphinate 1 or diisopropyltrimethylenediphosphinate 2 with sodium bis(methoxyethoxy)aluminohydride (vitride). The cycloaddition reactions give predominantly the 1/1 cyclocondensation compounds 6 and 9; 2/2 and 3/3 cyclocondensation products 7, 8, 10 are also-obtained but in significantly lower yield. The yield of the 1/1 product can be optimized when the reaction is monitored by P-31 NMR. The 1/1 products are mixtures of diastereoisomers which have been identified. The cyclic diphosphines 11 are obtained by reduction of the corresponding cyclic phosphine dioxides using LiAlH5-CeCl3.

The complex benzene-1,2,4,5-tetra(methylene-phosphonato)triferrate III 4, Fe3BTMP, is a contrast agent for liver MRI (magnetic resonance imaging). The stoichiometries 1:1 and 3:1 were found for FeBTMP 3 and Fe3BTMP 4 using polarography and P-31 NMR. At physiological pH and in aqueous solution these complexes are more stable than FeTTMP (5') and as stable as FeN3TMP (6'). It was found that 3 and 4 are polymers with linear and polydimensional structures respectively.

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With the aim of obtaining complexes of gamma-emitters and paramagnetic ions for use as imaging reagents and contrast agents, the synthesis of ligands was performed by cyclocondensation between dioxophosphids, alpha,omega-dihalogenoalkanes, and alkenes. These reactions lead to new cyclic P-alkylated polyphosphine polyoxides with saturated and unsaturated bridges. The 1:1 cyclocondensation products are obtained predominantly over the 2:2 and 3:3 cyclocondensation products. The formation of tetraphosphorated cycles becomes significant when it is allowed by the dihalide configuration. The origin of these orientations is discussed and a mechanism is also presented for these reactions.

Dans le cadre de la synthèse de traceurs γ et β − à finalité biomédicale nous avons étudié la réaction entre les dioxophosphures alkylés sur le phosphore obtenus par action du bis(méthoxy-éthoxy)aluminohydrure de sodium (vitride) sur l'éthylène-1,2-bis(méthylphosphinate d'isopropyle) 1 ou le triméthylène-1,3-bis(méthylphosphinate d'isopropyle, 2 et l′α,α'-dichloroorthoxyléne 5 . Cette réaction conduit essentiellement aux produits de cyclocondensation 1/1 6, 9 ; une faible proportion de cycles correspondant à une cycloaddition 2/2 voire 3/3 se forme également ( 7, 8, 10 ). Un suivi par RMN 31P de ce type de réaction mettant en oeuvre oxophosphures et halogénures, permet d'en optimiser le rendement. Les produits prépondérants sont des mélanges de diastéréoisomères qui ont été identifiés. La réduction des dioxydes de phosphines cycliques obtenus par LiAlH4-CeCl3 conduit aux diphosphines cycliques homologues. In the preparation of γ and β − tracers for use in biomedical measurement, we have studied the reaction between two alkylated dioxophosphides and the o-xylene-α,α'-dichloride 5 . The dioxophosphides are prepared by reaction of diisopropylethylenediphosphinate 1 or diisopropyltrimethylenediphosphinate 2 with sodium bis(methoxyethoxy)aluminohydride (vitride). The cycloaddition reactions give predominantly the 1/1 cyclocondensation compounds 6 and 9 ; 2/2 and 3/3 cyclocondensation products 7, 8, 10 are also-obtained but in significantly lower yield. The yield of the 1/1 product can be optimized when the reaction is monitored by 31P NMR. The 1/1 products are mixtures of diastereoisomers which have been identified. The cyclic diphosphines 11 are obtained by reduction of the corresponding cyclic phosphine dioxides using LiAlH4-CeCl3.

Les stabilités et thermodynamique des complexes [95mTcO2-oxocyclam] et [95mTcO2-dioxocyclam] ont été comparées à celles du complexe [95mTcO2-cyclam] par échange de ligands. La synthèse et l'utilisation de l'isotope 95mTc sous forme de pertechnétate de sodium a permis d'atteindre l'équilibre thermodynamique entre [95mTcO2-oxocyclam]/[95mTcO2-cyclam] d'une part et [95mTcO2-dioxocyclam]/[95mTcO2-cyclam] fid'autre part. Cette étude a permis de mettre en évidence la remarquable stabilité cinétique ou thermodynamique du complexe [95mTcO2-oxocyclam].

La complexation du coeur 99mTcO3+ par le 2,10-diméthyl-4,8-dithiaundécane-2,10-dithiol 1 a été réalisée en utilisant un sel d'étain comme réducteur et a conduit à la formation d'une espèce I stable et neutre. Avec le 5-butyl-3,7-dithianonane-1,9-dithiol 2, la même réaction conduit à la formation d'un complexe II instable difficile à isoler. Les études biologiques sur la souris Swiss ont montré que seul I était intéressant (fixation myocardique supérieure à celle du RP 30). Dans le cas des complexes à coeur TcN, on obtient chaque fois deux espèces neutres, soit à partir de [99mTcNCl4]−, soit à partir de 99mTcNCl2[P(CH2CH2CN)3]2; il est possible, selon les conditions opératoires, de favoriser la formation de l'une ou l'autre espèce et de les isoler par purification. Les résultats biologiques se sont avérés assez décevants.

Les conditions d'obtention exclusive de [99mTcNCl4]− à partir de 99mTcO4−, NaN3 et HCl ont été déterminées. Les conditions d'analyse chromatographique sur papier de cet ion ont été précisées (éluant, pH, type de papier). L'espèce obtenue a servi à préparer, par échange de ligandes, une série de complexes de type N2S2 à partir de diaminodithiols substitués ou non sur l'azote. L'échange a également été obtenu avec 99mTcNCl2[P(CH2CH2CN)3]2 comme précurseur. Suivant la structure du diaminodithiol de départ on obtient un ou deux complexes neutres. La séparation éventuelle des deux espèces (dans ce cas seule la plus lipophile est récupérée) et l'élimination de l'excès de ligande ont été effectuées par chromatographie sur papier. Les complexes ont donné lieu à une étude biologique sur la souris Swiss. La captation myocardique est peu satisfaisante. Par contre, dans certains cas et en particulier avec l'espèce obtenue à partir du 5,8-diaza-3,10-diéthyldodécane-3,10-dithiol 6 la captation cérébrale est au moins èquivalence à celle obtenue avec le HMPAO.