The particular role of radiopharmacy within bioorganometallic chemistry

This article will emphasize the particular role of organometallic radiopharmaceutical chemistry, namely the need for syntheses from water and the emerging implications for other (bio)organometallic fields. After some basic insights into the different directions of bioorganometallic chemistry, some facets of the [M(CO)₃]⁺ (M = Tc, Re) moiety are reviewed and discussed in the respective context. The mechanism for the synthesis of [M(OH₂)₃(CO)₃]⁺ which is still little understood, will be touched. The formation of additional M-C bonds is exemplified with cyclopentadienyl chemistry, the potential impact on targeted molecular imaging with the labelling of amino acids and the reactivity towards essential biomolecules such as guanine is shown. Future perspectives and implications for organometallic radiopharmaceutical chemistry will close this article.     

Synthesis of homoleptic Re(I) complexes of isocyano-carboranes and the X-ray structure of hexakis(p-carboran-1-yl-isonitrile)Re(I)

Two homoleptic Re(I) complexes of ortho and para-carborane isocyanide ligands were prepared as the first examples of a new class of metal-based BNCT and BNCS agents. The target compounds were prepared in low yield through the reaction of [Re₂(O₂CPh)₄Cl₂] and [Re₂(OAc)₄Cl₂] with 3-isocyano-1,2-dicarba-closo-dodecaborane and a para-carborane azetidine derivative respectively. The desired product from the latter reaction was characterized crystallographically and is only the second reported molecular structure of a homoleptic Re(I) isonitrile complex.     

Tricarbonyl complexes of rhenium(I) and technetium(I) with thiourea derivatives

fac-[M(CO)₃X₃]²⁻ complexes (M=Re, X=Br; M=Tc, X=Cl) react with thiourea derivatives under formation of stable rhenium(I) and technetium(I) complexes. The composition of the products can be controlled by the steric requirements of the ligands and their ability to form chelates.The products of reactions with tetramethylthiourea, Me₄tu (I), N,N-diethylthiocarbamoylbenzamidine, H₂Et₂tcb (II), and morpholinylthiocarbamoylbenzamidine, H₂morphtcb (III), have been studied by X-ray crystallography showing that the products belong to three different structural types. A mononuclear complex of the composition fac-[Re(CO)₃Br(Me₄tu)₂] has been isolated with tetramethylthiourea, whereas the thiocarbamoylbenzamidines deprotonate and act as N,S-chelating ligands. This results in the formation of a dimeric [Tc(CO)₃(HEt₂tcb-N,S)]₂ complex with a central, almost square Tc₂S₂ unit and a monomeric compound of the composition [Tc(CO)₃(Hmorphtcb-N,S)(H₂morphtcb-S)]. The latter compound contains a neutral, S-bonded morpholinylthiocarbamoylbenzamidine in the unusual imine form in addition to a chelate-bonded Hmorphtcb⁻ ligand.     

Comparison of tridentate ligands in competition experiments for their ability to form a [Tc(CO)3] complex

In this study we have compared different ligands containing three or more hetero-atoms (N, O and/or S) with respect to their ability to form tridentate complexes with a Tc-tricarbonyl moiety. Comparison of each ligand in a competition reaction with histidine first and then with each other compound allowed to rank the ligands according to their ability of complex formation with the [^99mTc(CO)₃]⁺ precursor from diethylenetriamine (most efficient of the studied ligands) to nitrilotriacetic acid (weakest complexing properties). The results provide insight in the structural requirements for the formation of stable Tc-tricarbonyl complexes and suggest preferred combinations and arrangements of the hetero-atoms involved in the complex formation. They also give a good indication which type of ligand is most appropriate to modify biomolecules for an efficient and stable labelling with a Tc-tricarbonyl moiety.     

Synthese,EPR und Röntgenkristallstrukturanalyse von mer-Trichloro(2,2′-bipyridin)nitridotechnetium(VI), einem neuen Nitridokomplex des Technetium(VI)

Synthesis, EPR and X-Ray Structure of mer-Trichloro(2,2′-bipyridine)nitridotechnetium(VI) — a new Technetium(VI) Nitrido Complex mer-Trichloro(2,2′-bipyridine)nitridotechnetium(VI) has been prepared by the reaction of (NBu₄)[TcNCl₄] with 2,2′-bipyridine in acetonitrile, whereas the same procedure gives in methanol the technetium(V) cation [TcNCl(bipy)₂]⁺. The EPR spectrum of [TcNCl₃(bipy)] suggests a meridional coordination of the three chloro ligands. [TcNCl₃(bipy)] crystallizes monoclinic in the space group P2₁/n; a = 8.572(1), b = 15.462(1), c = 10.110(1) Å, β = 104.21(1)°, Z = 4. The R value converged at 0.034 on the basis of 3 040 reflections. The technetium atom is distorted octahedrally coordinated with the chloro ligands meridionally cis with respect to the nitrido nitrogen. The Tc? N(1) bond length is 1.669(4) Å, and the Tc? N(3) bond (2.371(4) Å) is significantly lengthened due to the structural trans labilizing influence of the “N^3?” ligand.     

Rhenium‐Dicarbonyl‐Nitrosyl‐Komplexe mit Imidazol

Rhenium Dicarbonyl‐Nitrosyl Complexes with Imidazole Different rhenium‐dicarbonyl‐nitrosyl complexes with imidazole (Im) as monodentate ligand have been synthesized and characterized, starting from [NEt₄][ReCl₃(CO)₂(NO)] and [ReCl(μ?Cl)(CO)₂(NO)]₂. Whereas the complexes [ReCl₂(Im)(CO)₂(NO)] and [ReCl(Im)₂(CO)₂(NO)]⁺ were achieved in high yields, the complex [Re(Im)₃(CO)₂(NO)]²⁺ with three imidazole ligands could only be isolated after complete removal of all halide ions (with AgBF₄) in low yield. The synthesis of a corresponding ^99mTc‐dicarbonyl‐nitrosyl complex with imidazole opens a new perspective for such compounds as potential radiopharmaceuticals and alternatives to the already established ^99mTc‐tricarbonyl complexes.     

To Sandwich Technetium: Highly Functionalized Bis-Arene Complexes [99mTc(η6-arene)2]+ Directly from Water and [99mTcO4]−

The labeling of (bio)molecules with metallic radionuclides such as ^99mTc 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 [^99mTc(η⁶-C₆R₆)₂]⁺-type complexes are directly accessible from water and [^99mTcO₄]⁻, even using arenes incompatible with Fischer–Hafner conditions. To unambiguously confirm the nature of these unprecedented ^99mTc complexes, their rhenium homologous have been prepared by substituting naphthalene ligands in [Re(η⁶-C₁₀H₈)₂]⁺ with the corresponding phenyl groups. The ease with which highly stable [^99mTc(η⁶-C₆R₆)₂]⁺ complexes are formed under standard labeling conditions enables a multitude of new potential imaging agents based on commercial pharmaceuticals or lead structures.     

New paradigms for synthetic pathways inspired by bioorganometallic chemistry

Two series of particular examples of reactions used in bioorganometallic chemistry are described. One based on a decomplexation-complexation reaction, indicates how, starting from a cymantrenyl derivative, a range of organometallic complexes bearing various metals can be prepared. The second one refers to the easy synthesis in water of the very versatile Alberto's reagent, which leads to new organometallic radiopharmaceuticals of Tc and Re.     

The Reaction of Cs2[Tc(NO)F5] with BF3 in Acetonitrile: Formation and Structure of [{Tc(NO)(CH3CN)4}2(μ‐F)](BF4)3

The deep blue, paramagnetic Cs₂[Tc^II(NO)F₅] is formed during reactions of pertechnetate, acetohydroxamic acid, and CsF in aqueous HF. A reaction of Cs₂[Tc(NO)F₅] with BF₃ · MeOH in acetonitrile gives yellow blocks of the fluorido‐bridged dimer [{Tc^I(NO)(CH₃CN)₄}₂F](BF₄)₃. The compound is stable as solid and in acetonitrile solutions. The complex cation contains a bent μ‐F^– ligand and two linear nitrosyl groups.