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A new class of amphiphilic peptidolipidyl-cyclodextrins is reported. The derivatives are chiral due to the presence of an L-leucine in the spacer arm that links a saccharide moiety and a grafted, saturated hydrocarbon chain. Self-assembly properties of the peptidolipidyl-cyclodextrins are characterized by quasi-elastic light scattering, turbidity and UV–visible absorption measurements. NMR experiments give insight into the intermolecular dipolar interactions as a function of temperature and concentration. N-dodecyl- N α -(6I-amidosuccinyl-61-deoxy-cyclomaltoheptaose)-L-leucine (1) is poorly soluble in aqueous media. N-dodecyl- N α -(6I-amidosuccinyl-6I-deoxy-2I,3I-di-O-methyl-hexakis-(2II-VII,3II-VII,6II-VII-tri-O-methyl)-cyclomaltoheptaose)-L-leucine (2) is found to be more soluble and self-assembles into stable supramolecular colloidal aggregates with nanometric dimensions above a critical aggregation concentration (CAC). It has a propensity for solubilization of hydrophobic species revealing a micellar-like behavior, which is compared to that of the non-ionic detergent octyl glucoside. On the contrary, compound 1 precipitates in a crystalline phase beyond its water solubility limit, and it does not display any solubilizing capacity. The observed behavior corroborates at the molecular level with the NMR results.

The direct coupling via succinyl-diamide links of a difunctionalised cyclodextrin (CD) to di- and tetra-functionalised calix[4]arene-crown-6 (CAL) leads to tubular calixarene–cyclodextrin species. The product structures were characterised by high resolution 1H and 13C NMR and MALDI-TOF spectroscopies.

The coupling of two or four mono-6-amino β-cyclodextrin (amino-CD) units, (unprotected or permethylated hydroxyls), to diisopropoxycalix[4]arene crown-6 (CAL) was realised using the N , N ′-succinyldiamide linker. The resulting molecules in two series were characterised with the help of mass and NMR spectroscopies. The yields of all coupling products were improved for permethylated sugar series compared to the hydroxylated CD series or to our previous studies. The two β-cyclodextrin (β-CD) residues coupled to disubstituted CAL were orientated from the same side of the crown ether.

Novel molecules, composed of a β-cyclodextrin coupled via a succinic diamide linker to di-n-octyl-calix[4]arene monocrown-6 or to biscrown-6-calix[4]arene, were synthesized by two independent routes: from mono-6′-deoxy-6′-amino-β-cyclodextrin, and from tetraaminocalix[4]arene derivatives. Key words: β-cyclodextrin–calix[4]arene coupling, aminosuccinate-β-CD, aminosuccinate-calix[4]arene, octyloxy-calix[4]arene–monocrown-6, calix[4]arene–biscrown-6.

Cyclodextrins (D. Duchene (ed.): New Trends in Cyclodextrins and Derivatives (1991)) have long been shown to be capable of modifying the water solubility of a number of hydrophobic guests through the formation of inclusion complexes. Among the three natural cyclodextrins (α, β and γ-cyclodextrins containing 6, 7 and 8 d-glucopyranose units, respectively), β-cyclodextrin is by far the most commonly used although it exhibits a weaker solubility in water (and therefore a weaker solubilization power). This specific feature has encouraged the synthesis of derivatives exhibiting an increased solubility in water. Methylated cyclodextrins are amongst the simplest derivatives, and their properties regarding the solubility and the solubilization power for hydrophobic guests are well documented especially concerning Heptakis (2,6-di-Omethyl)-cyclodextrin (DIMEB) and Heptakis (2,3,6-tri-Omethyl)-cyclodextrin (TRIMEB) K. Koizumi et al.:J. Chromatogr. 368, 329–337 (1986). In order to avoid the use of human serum albumin (HSA), this property has been applied here to the solubilization of a very sparingly water-soluble fatty acid derivative (16-iodo-3-methylhexadecanoic acid), which is known to localise in viable myocardial cells, allowing the generation of functional images reflecting the viability of the cardiac tissue through the use of radiolabeled analog (Demaison et al.: J. Nucl-Med. 29, 1230–1236 (1998)). Nuclear magnetic resonance (NMR) was used throughout this study to evidence that the observed solubilization and stabilisation (under conditions required for sterilisation) induced by cyclodextrins are due to the formation of a true inclusion complex and not to non-specific interactions; This technique further allows to derive thermodynamic as well as structural informations for this complex. On one hand, the inclusion complex prevents thermal degradation during sterilisation process compared to HSA. On the other hand, NMR displacement experiments against HSA showed that the complex likely dissociates in vivo.

Using per(3,6-anhydro)cyclodextrin derivatives [per(3,6-anhydro)CD], it was possible to produce new lanthanide chelates by careful choice of the size and functional groups. Heptakis(3,6-anhydro-2-O-methyl)cyclomaltoheptaose fulfils the best criteria for complexation of lanthanide ions. Nuclear magnetic resonance was used to derive the association constants and the stoichiometries of these new complexes. Finally, a three-dimensional structure of these complexes consistent with the NMR data is proposed, to ascertain the position of lanthanide in the cavity of the per(3,6-anhydro)CD. For the present purposes, heptakis(2-O-acetyl-3,6-anhydro)cyclomaltoheptaose, octakis(2-O-acetyl-3,6-anhydro)cyclomaltooctaose, heptakis(3,6-anhydro-2-O-methyl)cyclomaltoheptaose and octakis(3,6-anhydro-2-O-methyl)cyclomaltooctaose have been synthesized and purified.

In order to visualize and quantify dopamine transporters, the synthesis of two novel ligands labelled with technetium-99 m (99mTc) 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 99mTc has been studied and the results make them good candidates for SPECT imaging. Copyright © 2002 John Wiley & Sons, Ltd.

In order to simplify preparation of [123I]PE2I, iodogen and hydrogen peroxide were examined as oxidants for the preparation of radioiodinated PE2I, e.g. (E)-N-(3-iodoprop-2-enyl)-2β-carbomethoxy-3β-(4′-tolyl) nortropane). Among the oxidizing compounds assayed, iodogen appears to afford the best results for this purpose (high radiochemical yield, high chemical purity and a reasonable reaction time). A simplified and efficient method is described here for the preparation of [123I]PE2I based on the exchange of a 123I tributyl tin analogue in oxidative conditions followed by purification by solid phase extraction (SPE). Using this method, [123I]PE2I was obtained with a radio-pharmaceutical yield over 60%, with chemical and radiochemical purities higher than 95% without the addition of a carrier (Na127I) (2G Bq/nmol) or with a specific activity adjusted to 85–90 MBq/nmol in the presence of the carrier. Copyright © 2002 John Wiley & Sons, Ltd.

PE2I ((E)-N-(3-iodoprop-2-enyl)-2β-(4′-tolyl) nortropane) is a cocaine derivative belonging to a new generation of selective dopamine transporter inhibitors. Labelled with iodine-123 (half-life: 13·1 hours), PE2I has been dedicated to the diagnostics of neurodegenerative diseases such as Parkinson's disease in humans using single photon emission computed tomography. Labelled with carbon-11 (half life: 20·4 minutes), it can be used in the absolute quantification of the dopamine transporter (DAT) using the high-resolution, sensitive and non-invasive quantitative imaging technique PET (positron emission tomography). In this paper, the radiosynthesis of carbon-11 labelled PE2I was investigated and oriented towards the preparation of multi milliCuries of radiotracer. Typically, 200 to 300 mCi (7·4–11·1 GBq) of [11C]PE2I were routinely obtained within 25 minutes of radiosynthesis (including HPLC purification) with specific radioactivities ranging from 0·8 to 1·2 Ci/μmol (29·4–44·4 GBq/μmol). Based on the preliminary PET experiments, it can be assumed that this radioligand would permit quantification of the DAT using PET and mathematical compartmental ligand-transporter models. Copyright © 2000 John Wiley & Sons, Ltd.

AMI-9S was synthesized in the S configuration with an enantiomeric purity of over 97% and labelled with iodine-123 with a specific activity of 300 Ci/mmol. Enantiomeric purity was determined by 19 F NMR spectroscopy following derivatisation using (R)-2-fluorophenylacetylchloride. Radioiodination was carried out from a vinylic stannane in the presence of iodide and chloramine T.

A simplified and efficient method is described for the preparation of [ 123 I]2-iodolisuride. The radioiodination of 3-(9,10-didehydro-6methyl-8a-ergolinyl)-1,1-diethylurea (lisuride) is based on tributyltin to 123 I exchange in oxidative conditions. After optimization of the reaction parameters [ 123 I]2-iodolisuride was obtained without high performance liquid chromatography purification with radiochemical yields >90% and a radiochemical purity higher than 95%. The specific activity of the product was more than 500 MBq/nmol. In vitro binding studies on striatal membranes and ex vivo autoradiography in rats showed that [ 123 I] or [ 125 I]2-iodolisuride prepared using this method, have the same radiopharmacological characteristics as radioiodinated iodolisuride prepared using the Iodogen® method.

Iodobenzamide (IBZM) and iodolisuride (ILIS), which belong to different chemical families, are two radioligands used for SPECT imaging of dopamine D2 receptors. We have compared their cerebral biodistribution in control rats and their ability to detect quantitative modifications of D2 receptors in experimental models. IBZM and ILIS have a similar cerebral distribution in vivo in control rats and permitted the detection of upregulation of striatal dopamine D2 receptors in a model of chronic haloperidol treatment. Moreover, we observed that 1 h after injection of a saturating dose of haloperidol, IBZM uptake was 72% displaced from the striatum, while ILIS uptake was 50% displaced. In an experimental model of excitotoxic striatal lesion, the in vivo accumulation of IBZM was 30% decreased on the lesioned side, in agreement with a decrease in dopamine D2 receptor density. By contrast, the accumulation of ILIS was identical in the lesioned and in the intact striatum. From the results, it appears that IBZM and ILIS, which are both used to image dopamine D2 receptors in vivo, behave differently in pathological experimental models. The ligand for human exploration should then be chosen according to the suspected pathology.

The syntheses and characterizations of five differently hydrosoluble monosubstituted aryl porphyrins are reported. Their metallation with indium-111 was achieved and provided tracers with strong specific activities. The covalent coupling between indium-111 porphyrins and BSA served as a model reaction for the definition of the best experimental coupling conditions; the transposition to the labeling of anti-CEA monoclonal antibody was realized. The conjugates exhibited an in vitro good mAb-labeling efficiency, as well as a good preservation of immunoreactivity.

Two novel series of iodinated N-substituted analogs of 2beta-carbomethoxy-3beta-(4'-iodophenyl)tropane (beta-CIT) and N-(3-iodoprop-(2E)-enyl)-2beta-carbomethoxy-3beta-(3',4'-dis ubstituted phenyl)nortropane were synthesized. They were evaluated for their inhibitory properties on dopamine (DA(T)), serotonin (5-HT(T)), and norepinephrine (NE(T)) transporters in rat brain homogenates using [3H]GBR-12935, [3H]paroxetine, and [3H]nisoxetine as specific ligands. All new N-substituted analogs of beta-CIT exhibited higher DAT selectivity over both 5-HT(T) and NE(T) than beta-CIT. Moreover compounds with the N-substituents propynyl (6), crotyl (4), 2-bromoprop-(2E)-enyl (5), and 3-iodoprop-(2E)-enyl (3d) showed similar to higher DA(T) affinities than beta-CIT (respectively 14, 15, 30, and 30 nM vs 27 nM). Compound 3d was found to be the most selective DA(T) agent of this series (5-HTT/DA(T) = 32.0 vs 0.1 for beta-CIT). The N-(3-iodoprop-(2E)-enyl) chain linked to the tropane nitrogen was therefore maintained on the tropane structure, and phenyl substitution was carried out in order to improve DA(T) affinity. K(i) values of N-(3-iodoprop-(2E)-enyl)-2beta-carbomethoxy-3beta-(3',4'-dis ubstituted phenyl)nortropanes revealed that phenyl, 4'-isopropyl, and 4'-n-propyl derivatives weakly inhibited specific binding to DA(T), whereas phenyl substitution with 4'-methyl (3c), 3',4'-dichloro (3b), and 4'-iodo (3d) yielded high-DA(T) reuptake agents with increased DA(T) selectivity compared to beta-CIT. These results demonstrate that the combination of a nitrogen and a phenyl substitution yields compounds with high affinity and selectivity for the dopamine transporter which are usable as SPECT markers for DA neurons.

Methylated 6A,6D-diamino 6A,6D-dideoxy β-cyclodextrin 4 was coupled with three cholesterol substituted glutaric or succinic acids 5 – 7 to give amphiphilic cyclodextrins 1 – 3 with good yields. The succinic acid derivative 1 , a typical member of this new family, has shown good compatibility with phosphatidyl choline monolayer and bilayer as confirmed by deuterium magnetic nuclear resonance ( 2 H NMR).

A study of the metallation of meso 10-(4′-N-pyridyl)-5,15,20-triphenylporphyrin with indium is reported. The crystal structure of the title compound has been determined by single-crystal X-ray diffraction. The complex crystallizes in the space group P 2 1 / n with Z = 4 and a = 10.146(2), b = 16.096(4), c = 20.861(2) A, β = 90.33 (1)° and V = 3407 A 3 . The crystal structure was refined to a conventional r (F) = 0.059 for 6355 out of 8613 reflections having δ( I )/I < 0.5. The indium-chlorine distance is 2.374(2) A, whereas the indium atom lies 0.608 and 0.7214 A from the plane of the four porphyrin nitrogens and the 24-atom porphyrin plane, respectively. The four outer-sphere aromatic substituents exhibit some degree of distributional disorder.

Methylated 6A,6D-diamino 6A,6D-dideoxy β-cyclodextrin 4 was coupled with three cholesterol substituted glutaric or succinic acids 5 – 7 to give amphiphilic cyclodextrins 1 – 3 with good yields. The succinic acid derivative 1 , a typical member of this new family, has shown good compatibility with phosphatidyl choline monolayer and bilayer as confirmed by deuterium magnetic nuclear resonance ( 2 H NMR).

International audience; Selective dealkylation of dialkyl calix(4)arene monocrown-6 and calix(4)arene biscrown-6 was achieved using laser irradiation. The resulting phenolic compounds structures,studied by NMR (1H and 13C) and ESI-MS (Cs+ spiking), probably originated from theirpartial photo-Claisen rearrangement.

For the diagnosis and follow-up of neurodegenerative diseases, many cocaine derivatives have been proposed as radioligands to explore the dopamine transporter. As none of them have all the criteria of specificity and kinetics for human use, we have developed a new derivative, ( E )- N -(3-iodoprop-2-enyl)-2β-carbomethoxy-3β-(4′-methylphenyl)nortropane (PE2I), which displays promising properties. We report the characterization of PE2I in vitro on rat striatal membranes and in vivo in rats and in monkeys. PE2I had a high affinity (Kd = 0.09 ± 0.01 nM) and high specificity for the dopamine transporter. In rats we observed a high accumulation in the striatum; by contrast, a very low fixation was measured in the cortex. Moreover, a preinjection of a saturating dose of GBR 12909 prevented the striatal accumulation of PE2I by 74%. These results confirmed the specificity of PE2I for the dopamine transporter. In vivo in monkeys, SPECT studies showed a high accumulation in striatum. Moreover, an equilibrium state was obtained 1 h after injection. PE2I seemed to be the most promising ligand for the dopamine transporter exploration by SPECT using a single-day protocol.

The iodine-123 labelled selective ligand N-(3-iodoprop-2E-enyl)-2-beta-carbomethoxy-3beta-(4-methylphenyl) nortropane ([123I]PE2I) was evaluated as a probe for in vivo dopamine transporter imaging in the human brain. Six healthy subjects were imaged with a high-resolution single-photon emission tomography scanner. Striatal radioactivity peaked at 1 h after injection. The background radioactivity was low. The volume of distribution in the striatum was 94+/-24 ml/ml. The results were compared with those of [123I]beta-CIT imaging. There was no significant uptake of [123I]PE2I in serotonin-rich regions such as the midbrain, hypothalamus and anterior gingulus, suggesting that in vivo binding is specific for the dopamine transporter. One main polar metabolite of [123I]PE2I was found in plasma, and the parent plasma concentration decayed rapidly. Radiation exposure to the study subject is 0.022+/-0.004 mSv/MBq (effective dose). The preliminary results suggest that [123I]PE2I is a selective SPET ligand for imaging striatal dopamine transporter density.

Two novel series of iodinated N-substituted analogs of 2beta-carbomethoxy-3beta-(4'-iodophenyl)tropane (beta-CIT) and N-(3-iodoprop-(2E)-enyl)-2beta-carbomethoxy-3beta-(3',4'-dis ubstituted phenyl)nortropane were synthesized. They were evaluated for their inhibitory properties on dopamine (DA(T)), serotonin (5-HT(T)), and norepinephrine (NE(T)) transporters in rat brain homogenates using [3H]GBR-12935, [3H]paroxetine, and [3H]nisoxetine as specific ligands. All new N-substituted analogs of beta-CIT exhibited higher DAT selectivity over both 5-HT(T) and NE(T) than beta-CIT. Moreover compounds with the N-substituents propynyl (6), crotyl (4), 2-bromoprop-(2E)-enyl (5), and 3-iodoprop-(2E)-enyl (3d) showed similar to higher DA(T) affinities than beta-CIT (respectively 14, 15, 30, and 30 nM vs 27 nM). Compound 3d was found to be the most selective DA(T) agent of this series (5-HTT/DA(T) = 32.0 vs 0.1 for beta-CIT). The N-(3-iodoprop-(2E)-enyl) chain linked to the tropane nitrogen was therefore maintained on the tropane structure, and phenyl substitution was carried out in order to improve DA(T) affinity. K(i) values of N-(3-iodoprop-(2E)-enyl)-2beta-carbomethoxy-3beta-(3',4'-dis ubstituted phenyl)nortropanes revealed that phenyl, 4'-isopropyl, and 4'-n-propyl derivatives weakly inhibited specific binding to DA(T), whereas phenyl substitution with 4'-methyl (3c), 3',4'-dichloro (3b), and 4'-iodo (3d) yielded high-DA(T) reuptake agents with increased DA(T) selectivity compared to beta-CIT. These results demonstrate that the combination of a nitrogen and a phenyl substitution yields compounds with high affinity and selectivity for the dopamine transporter which are usable as SPECT markers for DA neurons.

Ortho substituted porphyrins are able to complex copper (+II) in a neutral aqueous medium containing an excess of bovine albumine.