Naphthalene Exchange in [Re(η6 -napht)2 ]+ with Pharmaceuticals Leads to Highly Functionalized Sandwich Complexes [M(η6 -pharm)2 ]+ (M=Re/99m Tc).

Bis-arene sandwich complexes are generally prepared by the Fischer-Hafner reaction, which conditions are incompatible with most O- and N- functional groups. We report a new way for the synthesis of sandwich type complexes [Re(η6 -arene)2 ]+ and [Re(η6 -arene)(η6 -benzene)]+ from [Re(η6 -napht)2 ]+ and [Re(η6 -napht)(η6 -benzene)]+ , with functionalized arenes and pharmaceuticals. N-methylpyrrolidine (NMP) facilitates the substitution of naphthalene with the incoming arene. A series of fully characterized rhenium sandwich complexes with simple arenes, such as aniline, as well as with active compounds like lidocaine and melatonin are presented. With these rhenium compounds in hand, the radioactive sandwich complexes [99m Tc(η6 -pharm)2 ]+ (pharm=pharmaceutical) can be unambiguously confirmed. The direct labelling of pharmaceuticals with 99m Tc through η6 -coordination to phenyl rings and the confirmation of the structures with the rhenium homologues opens a path into molecular theranostics.

Fully Solvated, Monomeric ReII Complexes: Insights into the Chemistry of [Re(NCCH3)6]2.

The oxidation of [Re(η6-C10H8)2]+ with AgI in acetonitrile yields [Re(NCCH3)6]2+. This fully solvated ReII compound was characterized by spectroscopic methods and X-ray structure analyses. We show that [Re(NCCH3)6]2+ acts as a precursor complex for a variety of substitution reactions. Treatment with monodentate triphenylphosphine (PPh3) and bidentate 1,2-bis(diphenylphosphino)ethane (dppe) yields the complexes [trans-Re(PPh3)2(NCCH3)4]2+ and [trans-Re(dppe)2(NCCH3)2]+, respectively. [trans-Re(dppe)2(NCCH3)2]+ is oxidized under mild conditions by AgI to its ReII analogue [trans-Re(dppe)2(NCCH3)2]2+. Reactions of [Re(NCCH3)6]2+ with a halide mixture consisting of NaX and AgX (X = Cl, I) result in the formation of the corresponding ReIII complexes [trans-ReX2(NCCH3)4]+. [trans-ReBr2(NCCH3)4]+ can be obtained directly from [Re(η6-C10H8)2]+ by oxidation with FeBr3 in acetonitrile. The title compound is thus a convenient starting material for ReII and ReIII complexes by simple solvent exchange, which are otherwise difficult to access.

Bioorganometallic Technetium and Rhenium Chemistry: Fundamentals for Applications.

Due to its long half-life of 2.111×105 y, technetium, i.e. 99Tc, offers the excellent opportunity of combining fundamental and ' classical ' organometallic or coordination chemistry with all methodologies of radiochemistry. Technetium chemistry is inspired by the applications of its short-lived metastable isomer 99mTc in molecular imaging and radiopharmacy. We present in this article examples about these contexts and the impact of purely basic oriented research on practical applications. This review shows how the chemistry of this element in the middle of the periodic system inspires the chemistry of neighboring elements such as rhenium. Reasons are given for the frequent observation that the chemistries of 99Tc and 99mTc are often not identical, i.e. compounds accessible for 99mTc, under certain conditions, are not accessible for 99Tc. The article emphasizes the importance of macroscopic technetium chemistry not only for research but also for advanced education in the general fields of radiochemistry.

To Sandwich Technetium: Highly Functionalized Bis-Arene Complexes [99m Tc(η6 -arene)2 ]+ Directly from Water and [99m TcO4 ].

The labeling of (bio)molecules with metallic radionuclides such as 99m Tc demands conjugated, multidentate chelators. However, this is not always necessary since phenyl rings can directly serve as integrated, organometallic ligands. Bis-arene sandwich complexes are generally prepared by the Fischer-Hafner reaction. In extension of this, we show that [99m Tc(η6 -C6 R6 )2 ]+ -type complexes are directly accessible from water and [99m TcO4 ]- , even using arenes incompatible with Fischer-Hafner conditions. To unambiguously confirm the nature of these unprecedented 99m Tc complexes, their rhenium homologous have been prepared by substituting naphthalene ligands in [Re(η6 -C10 H8 )2 ]+ with the corresponding phenyl groups. The ease with which highly stable [99m Tc(η6 -C6 R6 )2 ]+ complexes are formed under standard labeling conditions enables a multitude of new potential imaging agents based on commercial pharmaceuticals or lead structures.

Cyclic-RGD penta-peptides cRGDyK derivatized with cyclopentadienyl complexes of technetium and rhenium as radiopharmaceutical probes.

The present study reports the syntheses of half-sandwich complexes of the type [M(η5 -C5 H4 CONH-R)(CO)3 ] (M═Re,99m Tc;R═cyclic RGD peptide (cRGDyK) for potential imaging of αv ß3 integrin expression. The 99m Tc complex was prepared directly from the reaction of [99m Tc(OH2 )3 (CO)3 ]+ with cRGDyK, doubly conjugated to Thiele's acid [(C5 H5 COOH)2 ] in water. This approach extends the viability of metal-mediated retro Diels-Alder reactions for the preparation of small molecules such as linear tripeptides to a more complex cyclic peptide carrying a [(η5 -C5 H4 )99m Tc(CO)3 ] tag. The Diels-Alder product [(C5 H5 CONH-cRGDyK)2 ] was prepared from Thiele's acid via double peptide coupling. The Re-complex [Re(η5 -C5 H4 CONH-cRGDyK)(CO)3 ] was obtained by attaching [Re(η5 -C5 H4 COOH)(CO)3 ] directly to the N-terminus of cRGDyK. The identity of the 99m Tc-complex is confirmed by chromatographic comparison with the corresponding rhenium complex, fully characterized by spectroscopic techniques.

Synthesis of tripeptide derivatized cyclopentadienyl complexes of technetium and rhenium as radiopharmaceutical probes.

We describe the syntheses of half-sandwich complexes of the type [(η(5)-Cp(CONH-R))M(CO)3] with M = Re or (99m)Tc. The R group represents different tri-peptides (tpe) which display high binding affinities for oligopeptide transporters PEPT2. The (99m)Tc complexes were prepared directly from [(99m)Tc(OH2)3(CO)3](+) and Diels-Alder dimerized, cyclopentadienyl derivatized peptides in water. This approach corroborates the feasibility of metal-mediated retro Diels-Alder reactions for the preparation of not only small molecules but also peptides carrying a [(η(5)-Cp)(99m)Tc(CO)3] tag. We synthesized the Diels-Alder product [(HCpCONH-tpe)2] from Thiele's acid [(η(5)-HCpCOOH)2] via double peptide coupling. The Re-complexes [(η(5)-CpCONH-tpe)Re(CO)3] were obtained by attaching [(Cp-COOH)Re(CO)3] directly to the N-terminus of peptides as received from SPPS. The authenticity of the (99m)Tc-complexes is confirmed by chromatographic comparison with the corresponding rhenium complexes, fully characterized by spectroscopic techniques.

Synthesis, characterization and bioevaluation of technetium-99m labeled N-(2-Hydroxybenzyl)-2-amino-2-deoxy-D-glucose as a tumor imaging agent.

N-(2-Hydroxybenzyl)-2-amino-2-deoxy-D-glucose (NHADG) was synthesized by conjugation of salicylaldehyde to glucosamine. The obtained compound was well characterized via different analytical techniques. Labeling of the synthesized compound with technetium-99m ((99m)Tc) in pertechnetate form ((99m)Tc O4-) was carried out via chelation reaction in the presence of stannous chloride dihydrate. Maximum radiochemical yield of (99m)Tc-NHADG complex (99%) was obtained by using 1 mg NHADG, 200 µg SnCl2.2H2O, at pH 9.5 and reaction time of 15 min. The radiochemical purity of the (99m)Tc-NHADG complex was measured by instant thin layer chromatography (ITLC) and paper chromatography (PC), without any notable decomposition at room temperature over a period of 4h. The biological evaluation results show that the (99m)Tc labeled NHADG conjugate is able to specifically target mammary carcinoma in mice models, thus highlighting its potential as an effective (99m)Tc labeled glucose-derived agent for tumor imaging.

An isoindoline bridged [M(η6-arene)2]+ (M = Re, 99mTc) ansa-arenophane and its dinuclear macrocycles with axial chirality.

This work presents a straightforward method for the preparation of an isoindoline bridged [M(arene)2]+ (M = Re, 99mTc) ansa-[3]arenophane. This intramolecular formation of an ansa-complex is accompanied by the intermolecular formation of a pair of isoindoline bridged macrocyclic dinuclear sandwich complexes, one of which exhibits axial chirality.

Dynamic dimer-monomer equilibrium in a cycloruthenated complex of [Re(η6-C6H6)2].

Cycloruthenation is a well known process in organometallic ruthenium chemistry. In this work, we report unprecedented cycloruthenated rhenium bis-arene compounds with planar chirality. In a two-step process, the reaction of acetyl-pyridine with [Re(η6-C6H6)2]+ introduced a pyridinyl-methanol ligand at one of the arene rings. Coordination of [Ru(CO)2Cl2] led to cycloruthenation, and the products were obtained as two diastereomeric pairs of enantiomers. Under basic pH conditions, the two pairs of enantiomers undergo spontaneous and reversible dimerization. The cycloruthenated monomers were fully characterized, and the dimerization process was studied by NMR, IR spectroscopy, and DFT calculations.

Assessment of Lagrangian particle dispersion model "LAPMOD" through short range field tracer test in complex terrain.

In this paper the mesoscale application of the 3D Lagrangian particle dispersion model LAPMOD has been assessed for a field tracer test performed in a short-range complex terrain. The meteorological input was provided through the diagnostic model CALMET, the meteorological pre-processor of the CALPUFF model. The CALMET/LAPMOD coupled system was used to simulate the hourly averaged ground level concentration at 47 discrete receptors. The LAPMOD model has a general tendency to slightly underestimate the hourly averaged ground-level concentrations. A Q-Q plot shows that the predicted concentration distribution has a good comparison with observed one. The Robust Highest Concentration (RHC) indicates that the LAPMOD model slightly underestimates the simulated peak concentration in short-term release conditions. The Fractional Bias (FB), Normalized Mean Squared Error (NMSE), Factor of Two (FAC2), Factor of Four (FAC4) and Factor of Exceedance (FOEX) statistical indices were calculated. The predicted results by LAPMOD are generally in good agreement with observed ones and the model is justified for the use in complex terrain for short-term near-field applications.