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Cyclopentadienyl-Based Amino Acids (Cp-aa) As Phenylalanine Analogues for Tumor Targeting: Syntheses and Biological Properties of [(Cp-aa)M(CO)3](M = Mn, Re, 99mTc)
Abstract
Due to an enhanced demand for amino acids, the l-type amino acid transporter 1 (LAT1) is overexpressed in many tumor cell lines. LAT1 represents therefore an attractive target for cancer therapy and diagnosis. On the basis of our reported aqueous synthesis of [(Cp-R)99mTc(CO)3]-type complexes,(1-5) we describe the preparation of unnatural amino acid analogues [(Cp-CH2CH(NH2)COOH)Mn(CO)3] and [(Cp-CH(NH2)COOH)M(CO)3] (M = Mn, Re, 99mTc). Starting from fully protected HC5H5-aa (aa = amino acid), [(Cp-aa)99mTc(CO)3] complexes are accessible in quantitative yields and in a one-step synthesis from [99mTcO4]−. The rhenium and manganese analogues were prepared and structurally characterized to confirm the authenticity of the 99mTc complex. The inhibition constant of natural phenylalanine (phe) for LAT1 is in the range 70 ± 10 μM. The Ki value of [(Cp-CH(NH2)COOH)Mn(CO)3] (1a) is 53 ± 11 μM, whereas Ki for the “true” phe analogue [(Cp-CH2CH(NH2)COOH)Mn(CO)3] (2) was surprisingly high at 277 ± 37 μM. Complex 1a caused efflux when exposed to cells, underlining its active transport by LAT1 into the cell. 99mTc analogues of small biological lead structures such as amino acids are generally not recognized anymore by their targets, in particular by trans-membrane transporters. The bioorganometallic analogues presented here are, however, actively transported and corroborate the importance of organometallic complexes as mimics of organic lead structures in life sciences.
... For this reason, dirhenium(I) hexacarbonyl complexes consisting of bridging bis(chelating) ligands have enjoyed significant attention in various fields such as photoluminescence, anti-cancer pharmaceuticals and catalysis [5][6][7][8][9][10]. However, these attributes are already well known in the chemistry of halogenated/aqueous tricarbonyl (fac-[M(CO) 3 ] + ) complexes of the group 7 transition elements (M = Mn, Tc and Re) [11,12]. By way of comparison, it is however evident that there is still much outstanding research on dirhenium complexes [6][7][8][9][10][11][12][13][14][15][16][17][18][19]. ...
... However, these attributes are already well known in the chemistry of halogenated/aqueous tricarbonyl (fac-[M(CO) 3 ] + ) complexes of the group 7 transition elements (M = Mn, Tc and Re) [11,12]. By way of comparison, it is however evident that there is still much outstanding research on dirhenium complexes [6][7][8][9][10][11][12][13][14][15][16][17][18][19]. Nonetheless, it has been suggested in literature that two heavy metals bridged with a chelating ligand enhances the emissive properties of the metal orbitals involved, suggesting that di-nuclear species might offer a greater advantage over their mono-nuclear counter parts. ...
C 42 H 45 NO 8 P 2 Re 2 , monoclinic, C 2/ c (no. 15), a = 24.1612(7) Å, b = 13.0229(3) Å, c = 14.9180(4) Å, β = 121.383(3)°, V = 4007.2(2) Å ³ , Z = 4, Rgt ( F ) = 0.0235, wRref ( F² ) = 0.0596, T = 173(2) K.
... Thus, [{R-Cp} 99m Tc(CO) 3 ] (R = organic part or biomolecule) were obtained in good yield by reacting the fac-[ 99m Tc(CO) 3 (H 2 O) 3 ] + core or directly the sodium pertechnetate, with Diels-Alder dimerized compounds like Thiele's acid [5,6]. Additionally, he exploited a similar procedure with monomeric Cp derivatives which yielded piano-stool complexes as well, after reaction with Tc(I) or Tc(VII) precursors in water [7]. The second and the oldest approach was first reported by Wenzel [8] and developed by Katzenellenbogen [9], Jaouen [10] and our group [11]. ...
... While Alberto reported that the metal-mediated retro Diels-Alder reaction is a convenient method to prepare cytectrenes in aqueous solution [5,7], we demonstrated recently the use of microwave heating gave a novel impetus to the double-ligand transfer reaction [13]. Thus, using these conditions, i.e. pertechnetate and [MnBr(CO) 5 ] as Tc and CO sources, respectively, and 5 microwave irradiation periods of 40 s, -substituted ferrocenecarboxamide derivatives lead to cytectrenes 99m Tc-2-99m Tc-5, from good to excellent radiochemical yield (Table 2). ...
The synthesis, characterization and biological evaluation of five neutral and lipophilic (99m)Tccomplexes, so-called cytectrenes, obtained from.. substitutedferrocenecarboxamide derivatives are reported. N-substitutedferrocenecarboxamide starting materials were obtained in two steps, with good yield and were fully characterized by classical spectroscopic methods including X-ray diffraction analysis for one of them. Using a microwave strategy for the Tc-99m-radiolabelling step, each cytectrene were obtained quickly (radiolabelling time < 5min), from modest to good yield. The Tc-99m-complexes, characterized by HPLC comparison with cold rhenium complex analogues, are stable, neutral and lipophilic (log P-o/w ranged between 1.8 and 2.9). Unfortunately, despite such suitable features, in vivo studies of two of them gave poor results, in terms of brain uptake. Both radiocompounds exhibited the maximum brain accumulation of 0.31% ID/g and 0.26% ID/g at 5min post-injection, respectively, followed by a very fast
... The three water ligands attached to the fac-[M(CO) 3 ] + core are labile and can be readily substituted by a variety of mono-, bi-and tridentate ligands. As a result, a number of complexes consisting of varying ligand systems coordinated to the fac-[M(CO) 3 ] + core have been investigated as potential models for developing novel radiopharmaceutical compounds [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15]. ...
The methanol substitution reactions in the manganese acetylacetonato complex, fac-[Mn(CO)3(acac)(CH3OH)], was kinetically investigated with a range of entering ligands including pyridine (Py), imidazole (Im) and 4-dimethylaminopyridine (DMAP). All the complexes were characterized by NMR, UV-vis and IR spectroscopy. Moreover, crystal structures of fac-[Mn(CO)3(acac)(CH3OH)] (1), fac-[Mn(CO)3(acac)(Py)] (2) and fac-[Mn(CO)3(acac)(DMAP)] (3) are reported. The substitution of methanol in fac-[Mn(CO)3(acac)(CH3OH)] (1) by DMAP is approximately 2 times faster than Py, and 1.7 times faster when compared to Im. The results correlate well with the pKa of the entering nucleophile where pyridine (Py) < imidazole (Im) < 4-dimethylaminopyridine (DMAP). The activation parameters for complex (1) were determined as ΔH≠=73.9 ± 0.6 kJ mol⁻¹ and the entropy of activation ΔS≠= -28 ± 2 JK⁻¹ indicating an interchange associative mechanism.
... [8][9][10] Our group corroborated the importance of cyclopentadiene conjugated to targeting molecules as a pendent ligand or as an integral part of lead structures in several examples. [11][12][13][14][15] The cyclopentadienyl motif does, however, not occur in pharmaceuticals or naturally occurring molecules. In contrast, phenyl groups are ubiquitous in such lead structures. ...
The labeling of (bio)molecules with metallic radionuclides such as 99mTc demands conjugated, multidentate chelators. 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, we show that [99mTc(η6‐C6R6)2]+ type complexes are directly accessible from water and [99mTcO4]‐, even with 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 phenyls. The ease with which highly stable [99mTc(η6‐C6R6)2]+ are formed under standard labeling conditions enables a multitude of new potential imaging agents, based on commercial pharmaceuticals or lead structures.
... In cell-based assays, compound 8 -but not the decomplexed chromium-free ligand -was identified as a specific inhibitor of NOD2mediated NF-kB activation in a dose dependent manner with inhibitory concentrations in the low micromolar range. The Alberto group reported an important study 78 Bioinorganic chemistry [28]. ...
This article reviews recent advances in the design and discovery of inert metal complexes as protein binders. In these metal-based probes or drug candidates, the metal is supposed to exert a purely structural role by organizing the coordinating ligands in the three dimensional space to achieve a shape and functional group complementarity with the targeted protein pockets. Presented examples of sandwich, half-sandwich and octahedral d(6)-metal complexes reinforce previous perceptions that metal complexes are highly promising scaffolds for the design of small-molecule protein binders and complement the molecular diversity of organic chemistry by opening untapped chemical space.
Studies concerning the development of radiopharmaceuticals based on the Tc(I) carbonyl core are considered from the coordination-chemical viewpoint. The coordination behavior of the fac-Tc(CO)3⁺ core (hard/soft acid properties, complexation kinetics and thermodynamics, coordination preferences, mutual influence of ligands) is discussed in detail. Particular attention is paid to possible coordination isomerism and stereoisomerism of the complexes—problems that often escape from researchers’ attention. Metal-mediated ligand transformations, which can play both positive and negative role in the synthesis, are summarized for the first time. A comparative analysis of possible labeling strategies (one-pot, prelabeling, postlabeling) is made with more detailed consideration of the click-to-chelate and chelate-then-click approaches. A summary of ligands and ligand systems used for tethering the fac-Tc(CO)3⁺ core to biomolecules is made, including typical complexation conditions, yields, and key characteristics of the bioconjugate stability. Alternative technetium carbonyl coordination cores (higher carbonyls, mer-Tc(CO)3⁺, Tc(CO)2(NO)²⁺, Tc(CO)2(phosphine, isonitrile)2⁺, Tc(CO)2(isonitrile)4⁺) are briefly discussed. Coordination-chemical problems deserving, in authors’ opinion, a more detailed study are pointed out.
This chapter reviews organometallic π complexes of manganese reported between 2005 and 2020, with a focus on their synthesis, structures, and reactivity. Acyclic π ligands in this review include alkene, alkyne, allene, ketene, quinone, butadiene, allyl, benzyl, propargyl, and pentadienyl ligands, as well as heteroatom-containing analogues. Cyclic π ligands include cyclopentadienyl and arene ligands, as well as related polycyclic and heteroatom-containing ligands.
Two bidentate PNP ligands N,N-bis(di-p-tolylphosphino)cyclohexylamine (Cy-pTolPNP) (1) and N,N-bis(di-p-tolylphosphino)cyclobutylamine (Cb-pTolPNP) (2) were synthesized and crystallized. Coordination to the fac-[MI(CO)3]+ core (M = Re, 99Tc) yielded fac-[Re(Cy-pTolPNP)(CO)3Br] (1A), fac-[99Tc(Cy-pTolPNP)(CO)3Cl] (1B), fac-[Re(Cb-pTolPNP)(CO)3Br] (2A) and fac-[99Tc(Cb-pTolPNP)(CO)3Cl] (2B) in relatively good yields (56 to 86%): The structures of 1, 2, 1A and 1B were studied by single crystal X-ray crystallography. Preliminary mitochondrial/antimicrobial evaluation of the free ligand (N,N-bis(di-p-tolylphosphino)-cyclohexylamine) (1) and its respective fac-[Re(CO)3]+ (1A) complex indicates that neither the free ligand nor the complex was active against selected fungi Eremothecium ashbyii and Nadsonia fulvescens. In addition, all four compounds were found to have no activity against Gram-positive and Gram-negative bacterial species. These biological results are essential to the understanding of how these types of complexes behave and show they are perfectly stable in the evaluated bio-environments. The results also indicate that these ligands and complexes may present themselves as excellent models for radiotoxicity studies using technetium-99m, but more specifically, rhenium Re-186 and Re-188.
A novel proof-of-concept is reported to modify the water solubility and potential biological effects of a bis(diphenylphosphino)alkylamine (PNP) ligand and the corresponding metal complex, by introducing an amine group on the outer periphery of the pendant ligand arm. Thus, a tertiary butoxycarbonyl protected N'-Boc-ethylenediamine-N,N-bis(diphenylphosphino) (N'-Boc-PNP) ligand (1) was synthesized by reacting the protected ethylenediamine and chlorodiphenylphosphine in a 1 : 2 molar ratio. The corresponding fac-[Re(CO)3(N'-Boc-PNP)Br] (1A) complex was then obtained by reacting N'-Boc-PNP (1) with (Et4N)2fac-[Re(CO)3Br3] in equimolar amounts in DCM at 50 °C. De-protection of the N'-Boc pendant amine group in 1A with TFA leads to fac-[Re(NH3+-PNP)(CO)3Br]·CF3COO- (1B) which is soluble in D2O (>0.05 M). Treating 1B with saturated aqueous NaHCO3 yields fac-[Re(NH2-PNP)(CO)3Br]·MeOH (1C) in near quantitative yield. Although both 1A and 1C are not soluble in D2O, addition of TFA easily generates 1B (31P NMR), confirming the formation of the protonated amine. Isolation of fac-[99Tc(CO)3(N-Boc-PNP)(Cl)] (1D) confirmed that the rhenium and technetium (99Tc) can be easily interchanged in this process. Reported are hence the unique rhenium series of compounds 1A, 1B and 1C and the corresponding technetium complex 1D, unequivocally characterized by single crystal XRD, as well as IR and 1H NMR spectroscopy. Preliminary antimicrobial evaluation indicates that ligand 1 and its respective rhenium complexes (1A-1C) were not active against selected fungi (Candida albicans and Cryptococcus neoformans) and bacteria (Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Staphylococcus aureus). These types of ligands and complexes therefore present themselves as excellent radio models for further evaluation using 186Re, 188Re and 99mTc to potentially study the radiotoxicity of appropriately designed complexes.
This section reviews progress in bioorganometallic chemistry with rhenium and technetium over the past two decades. It includes general considerations with respect to the concepts for which the compounds of the two elements described here are designed. The more specific subsections focus on the traditional field of receptor targeting with 99mTc radiopharmaceuticals and molecular imaging agents. More recently, non-radioactive, de novo rhenium complexes have emerged as versatile tools for various applications in life sciences. Progress in this respect is discussed for rhenium alone or in combination with 99mTc homologs where applicable. Some urgent disease targets such as Alzheimer's disease are given special attention. Future directions, incentives for research, are reviewed throughout. The objective of this section is to not only provide a comprehensive review on organometallic chemistry of rhenium and technetium in the life sciences, but also to give a scope for the field based on recent accomplishments.
This article focuses on organometallic chemistry of the isotope 99-technetium (⁹⁹Tc), summarizing the developments from the beginning until the year 2020. ⁹⁹Tc carbonyl, isocyanate, cyclopentadienyl, arene, alkyl, aryl, carbene and carbyne complexes are discussed. Where available, structural information is highlighted and links are made to research fields that go beyond pure fundamental organometallic ⁹⁹Tc chemistry.
The coordination chemistry of ruthenium, osmium, technetium and rhenium with carbon-based ligands covering the literature from 2003 to 2018 is discussed. These metals form a vast number of coordination compounds with carbon-based ligands ranging from a single carbon atom (a carbido ligand) to polydentate hydrocarbon chains, and from monodentate organometallic ligands such as carbenes to multidentate ligands such as pincers and macrocycles. Particular focus of this review is given to syntheses, properties and applications of complexes with popular carbon-based ligands such as monodentate N-heterocyclic carbenes (NHCs), cyclometallated bidentate ligands, tridentate pincers and porphyrin-like macrocycles.
99mTc is one of the most frequently used isotopes in medicinal nuclear imaging. The two parts of this review summarize the chemistry of 99mTc-cytectrenes of the type [η⁵-(C5H5)99mTc(CO)3] and their syntheses. Various synthetic approaches such as the double ligand transfer (DLT), the single ligand transfer (SLT), the retro Diels-Alder and direct syntheses have been introduced over time and are discussed in detail and outlined in chronological order to underline the development of the field. In a second part, applications of the resulting cytectrenes in the imaging of the myocardium, the central nervous system, cancer, and infection sites are presented with comprehensive examples. In this way, the use of cytectrenes as structurally flexible imaging agents are highlighted.
[34822‐90‐9]
C5H5Tl
(MW 269.48)
InChI = 1S/C5H5.Tl/c1‐2‐4‐5‐3‐1;/h1‐5H;
InChIKey = RKLJDPOVAWGBSD‐UHFFFAOYSA‐N
(cyclopentadienyl ligand)
• Physical Data: mp >300 °C.
• Solubility: sol organic solvents.
• Form Supplied in: light yellow solid readily prepared from thallium hydroxide and dicyclopentadiene²; commercially available.
• Drying: purified by sublimation.
• Handling, Storage, and Precautions: stable for several months if stored under nitrogen in a Schlenk flask kept in the dark. All thallium compounds are extremely toxic to inhalation, skin contact, and ingestion. Toxicity is cumulative. Extreme caution should be used when handling these materials. Use in a fume hood.
The labeling of (bio)molecules with metallic radionuclides such as 99mTc demands conjugated, multidentate chelators. 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, we show that [99mTc(η6‐C6R6)2]+ type complexes are directly accessible from water and [99mTcO4]‐, even with 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 phenyls. The ease with which highly stable [99mTc(η6‐C6R6)2]+ are formed under standard labeling conditions enables a multitude of new potential imaging agents, based on commercial pharmaceuticals or lead structures.
Understanding fundamental Tc chemistry is important to both the remediation of nuclear waste and the reprocessing of nuclear fuel; however, current knowledge of the electronic structure and spectral signatures of low-valent Tc compounds significantly lags behind the remainder of the d-block elements. In particular, identification and treatment of Tc speciation in legacy nuclear waste is challenging due to the lack of reference data especially for Tc compounds in the less common oxidation states (I-VI). In an effort to establish a spectroscopic library corresponding to the relevant conditions of extremely high ionic strength typical for the legacy nuclear waste, compounds with the general formula of [ fac-Tc(CO)3(OH2)3- n(OH) n]1- n (where n = 0-3) were examined by a range of spectroscopic techniques including 99Tc/13C NMR, IR, XPS, and XAS. In the series of monomeric aqua species, stepwise hydrolysis results in the increase of the Tc metal center electron density and corresponding progressive decrease of the Tc-C bond distances, Tc electron binding energies, and carbonyl stretching frequencies in the order [ fac-Tc(CO)3(OH2)3]+ > [ fac-Tc(CO)3(OH2)2(OH)] > [ fac-Tc(CO)3(OH2)(OH)2]-. These results correlate with established trends of the 99Tc upfield chemical shift and carbonyl 13C downfield chemical shift. The lone exception is [ fac-Tc(CO)3(OH)]4 which exhibits a comparatively low electron density at the metal center attributed to the μ3-bridging nature of the -OH ligands causing less σ-donation and no π-donation. This work also reports the first observations of these compounds by XPS and [ fac-Tc(CO)3Cl3]2- by XAS. The unique and distinguishable spectral features of the aqua [ fac-Tc(CO)3]+ complexes lay the foundation for their identification in the complex aqueous matrixes.
Although suitable radiotracers are available for many clinical applications in emission tomography such as SPECT and PET, improved tracers are required for advanced nuclear medical imaging. But their development remains a challenge. The demand for new tracers arises from recent progress in the development of imaging techniques and innovations in isotope production. Particularly the latter has triggered an interest in hitherto less favored radionuclides for routine applications of nuclear medical imaging. Since most new tracers are radioactive metals, the coordination chemistry of some of the elements of interest needs to be extended to meet the specific requirements that apply to the preparation of radioactive pharmaceuticals.
Potentially tetradentate thiocarbamoylbenzamidine derivatives H4L have been synthesized from corresponding benzimidoyl chlorides and triglycine. They are suitable chelating agents for the oxidotechnetium(V) and oxidorhenium(V) cores and form stable, neutral [MO(HL)] complexes with an equatorial SN3 coordination sphere and an additional, uncoordinated carboxylic group, which can be used for bioconjugation. Representatives of the rhenium and 99Tc products have been isolated and analyzed with spectroscopic methods and X-ray diffraction. Bioconjugates of these complexes with angiotensin-II have been synthesized and structurally characterized. Analogous 99mTc complexes have been produced and tested in vitro and in vivo. The experiments confirm a considerable stability for the [99mTc(HL)] product as well as for its bioconjugate and recommend this class of compounds for further bioconjugation studies towards clinical applications.
Reactions between [Tc(I)(NO)X2(PPh3)2(CH3CN)] complexes (X = Cl, Br) and KCp form the pseudotetrahedral organotechnetium compounds [Tc(I)(NO)(Cp)(PPh3)X]. The halide ligands can readily be replaced by other halides or organometallic ligands giving access to a novel family of technetium(i) compounds with the robust {Tc(NO)(Cp)(PPh3)}(+) core.
Doxorubicin, a well-established chemotherapeutic agent, is known to accumulate in the cell nucleus. By using ICP-MS, we show that the conjugation of two small organometallic rhenium complexes to this structural motif results in a significant redirection of the conjugates from the nucleus to the mitochondria. Despite this relocation, the two bioconjugates display excellent toxicity toward HeLa cells. In addition, we carried out a preliminarily investigation of aspects of cytotoxicity and present evidence that the conjugates disrupt the mitochondrial membrane potential, are strong inhibitors of human Topoisomerase II, and induce apoptosis. Such derivatives may enhance the therapeutic index of the aggressive parent drug and overcome drug resistance by influencing nuclear and mitochondrial homeostasis.
A series of molybdenum complexes bearing new ligands is reported. The study covers a series of molybdenum compounds with the η5-coordinated indenyl ligand substituted with acyl-, ester- and amide-functions. This portfolio was extended by adding one representative with a η3-coordinated ester-substituted indenyl ligand. The functionalized indenes, necessary for the assembly, were prepared by convenient routes starting from inexpensive and readily available materials, enabling their production on a multigram scale. All structural types presented in this experimental study were supported by X-ray crystallographic data.
Cyclopentadienyl, hydrinedienyl, and indenyl glycines were synthesized using dienylaziridines as Nazarov cyclization precursors for the first time. Several substrates were synthesized to demonstrate the compatibility of this reaction. Asymmetric synthesis of these amino acids was also developed to show the additional scope of this method.
Complexes of the [(eta(5)-C5H4COOR)M(CO)(3)] type (M = (99)mTc, Re; R = targeting function) are basic bioorganometallic structures with the potential of combining molecular imaging ((99)mTc) with therapy (cold Re or (186)/Re-188). So far, the single carboxylate group on the cyclopentadienyl ring (C-p(-)) limited targeting to one function. The concept of C-p(-) as a scaffold for attaching biological molecules could be extended substantially with two or more functionalities bound to the C-p(-) ligand. Accordingly, the rarely studied bis-substituted cyclopentadienyl ligands [C5H3(1,2-COOMe)(2)](-) and [C5H3(1,3-COOMe)(2)](-) were synthesized and their coordination to the fac-{M(CO)(3)}(+) moiety was studied in water. Both ligands are deprotonated at physiological pH and do not undergo Diels-Alder reactions. In water, they react directly with [Re(OH2)(3)(CO)(3)](+) to form [(eta(5)-C5H3{1,2-COOMe}(2))Re(CO)(3)] and [(eta(5)-C5H3{1,3-COOMe}(2))Re(CO)(3)]. Controlled hydrolysis at neutral to alkaline pH gives the monoesters and fully hydrolyzed [(eta(5)-C5H3{1,2-COOH}(2))Re(CO)(3)] and [(eta(5)-C5H3{1,3-COOH}(2))Re(CO)(3)]. Thermal treatment leads to decarboxylation and formation of [(eta(5)-C5H4COOH)Re(CO)(3)]. The corresponding 99mTc homologues are directly accessible under slightly acidic conditions from [(99)mTcO(4)](-) in high yields. In the presented strategy, the C-p(-) ring acts as a scaffold for attaching multiple targeting agents or pharmacophores at the same time.
The discovery of the superfamily of nuclear receptors, represented first by the estrogen receptor (ERα) identified by E.V. Jensen in 1958, caused a veritable revolution in biology. Its repercussions are still with us, in the chemistry of steroids, synthetic selective steroid receptor modulators, and endocrine disruptors. These small molecules, including the group of steroids we will focus on here, can be linked to major diseases (e.g., cancers, osteoporosis, and diabetes), as well as issues relating to fertility and conception, birth control, and environmental diseases.After a brief description of the mechanism of action of the nuclear receptors we will address the issue of the organometallic versions of molecules that can potentially target these receptors, as well as their biological advantages. We have shown via radioactive labeling that certain organometallic hormone complexes have good targeting ability for nuclear receptors. The reversible binding of these complexes with specific receptors as well as the case of irreversible inhibition of estrogen receptors that can sometimes be obtained using carefully selected organometallic moieties will be discussed in this chapter. This work introduces the approach using SERMs, SARMs, and so on, which due to their large numbers are only touched on here. A section gives more complete details of organometallic radiopharmaceuticals, mostly steroidal. In broader strokes the current renaissance underway in the area of organometallic steroids is discussed with emphasis on biological aspects where known.Finally, some directions are indicated concerning new organometallic bioprobes obtained with SERMs and other endocrine disruptors that make new types of analysis possible. This combined with endocrine modulators possessing an additional organometallic function, for example of the redox type, points to a future that looks to be rich in promise.
Abstract Reported herein is the synthesis and evaluation of anticancer properties of a well-established organometallic protein kinase inhibitor scaffold in which the stereochemical complexity is increased. The investigated ruthenium η5-cyclopentadienyl half-sandwich complexes contain a bidentate pyridocarbazole and a monodentate CO ligand, thereby leading to four different stereoisomers due to the combined presence of ruthenium-centered chirality and planar chirality of the π -coordinated trisubstituted cyclopentadienyl moiety (two diastereomers as mixtures of enantiomers). While one of the two racemic diastereomers turns out to be nontoxic towards cancer cells, the second racemic diastereomer displays high cytotoxicities towards different cancer cell lines in vitro, thus demonstrating the intertwining of organometallic stereochemistry and biological activity.
A range of N,O-donor atom salicylidene complexes of the type fac-[M(O,N-Bid)(CO)3(L)](n) (O,N-Bid = anionic N,O-bidentate ligands; L = neutral coordinated ligand) have been studied. The unique feature of the complexes which crystallize in a monoclinic isostructural space group for complexes containing methanol in the sixth position (L = MeOH) is highlighted. The reactivity and stability of the complexes were evaluated by rapid stopped-flow techniques, and the methanol substitution by a range of pyridine type ligands indicates significant activation by the N,O-salicylidene type of bidentate ligands as observed from the variation in the second-order rate constants. In particular, following the introduction of the sterically demanding and electron rich cyclohexyl salicylidene moiety on the bidentate ligand, novel limiting kinetic behavior is displayed by all entering ligands, thus enabling a systematic probe and manipulation of the limiting kinetic constants. Clear evidence of an interchange type of intimate mechanism for the methanol substitution is produced. The equilibrium and rate constants (25 °C) for the two steps in the dissociative interchange mechanism for methanol substitution in fac-[Re(Sal-Cy)(CO)3(MeOH)] (5) by the pyridine type ligands 3-chloropyridine, pyridine, 4-picoline, and DMAP are k3 (s(-1)), 40 ± 4, 13 ± 2, 10.4 ± 0.7, and 2.11 ± 0.09, and K2 (M(-1)), 0.13 ± 0.01, 0.21 ± 0.03, 0.26 ± 0.02, and 1.8 ± 0.1, respectively.
A series of carbonyl metal complexes with anions of functional α-amino acids has been prepared: [M(CO) 3 (L-histidinate)] ⁻ (M = Cr. Mo, W), M(CO) 3 (L-histidinate) (M = Mn, Re), [Re(CO) 3 (NO)(L-histidinate)] ⁺ PF 6 ⁻ ,M(CO) 2 (η ³ -allyl)(L-histidinate) (M = Mo, W), Mo(CO) 2 (NO)(L-histidinate), [Mo(CO)(NO)(η ³ -methallyl)(L-histidinate)]PF 6 , Mo(CO) 2 (η ³ -methallyl)(L-histidineOMe)Cl, [M(CO) 3 ,(cysteinate)] ²⁻ (M = Mo. W), [Mo(CO) 3 (glyglyO)(H 2 O)] ⁻ , [Re(CO) 3 (L-ornithinate)(CH 3 CN)] and [Re(CO) 3 (L-lysinate)]. The IR and NMR data of the new complexes are reported.
A route to the organometallic complex 8 is described, along
with a study of its antiproliferative effects on breast cancer cell lines;
in the examples studied, 8 behaves in a very similar manner to tamoxifen,
suggesting new possibilities for applications in organometallic
chemistry.
The review, with 37 refs., describes recent developments in the chem. of first and second generation 99m-technetium-based imaging agents. The material is presented according to the biol. target for the agent, and where possible actual images are presented to indicate the type of information available to the clinician. Beta emitting isotopes of rhenium offer a possible method for the in situ treatment of cancerous tissue using analogous targeting strategies to those for technetium. Recent developments in the relevant coordination chem. of rhenium and their extension to in vitro and in vivo studies are presented. [on SciFinder(R)]
Large neutral l-amino acids are substrates of system L amino acid transporters. The level of one of these, LAT1, is increased in many tumors. Aromatic l-amino acids may also be substrates of aromatic l-amino acid decarboxylase (AADC), the level of which is enhanced in endocrine tumors. Increased amino acid uptake and subsequent decarboxylation result in the intracellular accumulation of the amino acid and its decarboxylation product. (18)F- and (11)C-labeled neutral aromatic amino acids, such as l-3,4-dihydroxy-6-(18)F-fluorophenylalanine ((18)F-FDOPA) and 5-hydroxy-l-[β-(11)C]tryptophan, are thus successfully used in PET to image endocrine tumors. However, 5-hydroxy-l-[β-(11)C]tryptophan has a relatively short physical half-life (20 min). In this work, we evaluated the in vitro and in vivo characteristics of the (18)F-labeled tryptophan analog 5-(2-(18)F-fluoroethoxy)-l-tryptophan ((18)F-l-FEHTP) as a PET probe for tumor imaging.
(18)F-l-FEHTP was synthesized by no-carrier-added (18)F fluorination of 5-hydroxy-l-tryptophan. In vitro cell uptake and efflux of (18)F-l-FEHTP and (18)F-FDOPA were studied with NCI-H69 endocrine small cell lung cancer cells, PC-3 pseudoendocrine prostate cancer cells, and MDA-MB-231 exocrine breast cancer cells. Small-animal PET was performed with the respective xenograft-bearing mice. Tissues were analyzed for potential metabolites.
(18)F-l-FEHTP specific activity and radiochemical purity were 50-150 GBq/μmol and greater than 95%, respectively. In vitro cell uptake of (18)F-l-FEHTP was between 48% and 113% of added radioactivity per milligram of protein within 60 min at 37°C and was blocked by greater than 95% in all tested cell lines by the LAT1/2 inhibitor 2-amino-2-norboranecarboxylic acid. (18)F-FDOPA uptake ranged from 26% to 53%/mg. PET studies revealed similar xenograft-to-reference tissue ratios for (18)F-l-FEHTP and (18)F-FDOPA at 30-45 min after injection. In contrast to the (18)F-FDOPA PET results, pretreatment with the AADC inhibitor S-carbidopa did not affect the (18)F-l-FEHTP PET results. No decarboxylation products of (18)F-l-FEHTP were detected in the xenograft homogenates.
(18)F-l-FEHTP accumulates in endocrine and nonendocrine tumor models via LAT1 transport but is not decarboxylated by AADC. (18)F-l-FEHTP may thus serve as a PET probe for tumor imaging and quantification of tumor LAT1 activity. These findings are of interest in view of the ongoing evaluation of LAT1 substrates and inhibitors for cancer therapy.
System L is a major nutrient transport system responsible for the transport of large neutral amino acids including several essential amino acids. We previously identified a transporter (L-type amino acid transporter 1: LAT1) subserving system L in C6 rat glioma cells and demonstrated that LAT1 requires 4F2 heavy chain (4F2hc) for its functional expression. Since its oncofetal expression was suggested in the rat liver, it has been proposed that LAT1 plays a critical role in cell growth and proliferation. In the present study, we have examined the function of human LAT1 (hLAT1) and its expression in human tissues and tumor cell lines. When expressed in Xenopus oocytes with human 4F2hc (h4F2hc), hLAT1 transports large neutral amino acids with high affinity (K(m)= approximately 15- approximately 50 microM) and L-glutamine and L-asparagine with low affinity (K(m)= approximately 1.5- approximately 2 mM). hLAT1 also transports D-amino acids such as D-leucine and D-phenylalanine. In addition, we show that hLAT1 accepts an amino acid-related anti-cancer agent melphalan. When loaded intracellularly, L-leucine and L-glutamine but not L-alanine are effluxed by extracellular substrates, confirming that hLAT1 mediates an amino acid exchange. hLAT1 mRNA is highly expressed in the human fetal liver, bone marrow, placenta, testis and brain. We have found that, while all the tumor cell lines examined express hLAT1 messages, the expression of h4F2hc is varied particularly in leukemia cell lines. In Western blot analysis, hLAT1 and h4F2hc have been confirmed to be linked to each other via a disulfide bond in T24 human bladder carcinoma cells. Finally, in in vitro translation, we show that hLAT1 is not a glycosylated protein even though an N-glycosylation site has been predicted in its extracellular loop, consistent with the property of the classical 4F2 light chain. The properties of the hLAT1/h4F2hc complex would support the roles of this transporter in providing cells with essential amino acids for cell growth and cellular responses, and in distributing amino acid-related compounds.
The application of 123I-3-iodo-alpha-methyltyrosine is limited to diagnosis of brain tumors due to its marked long-term uptake in kidneys. In vitro evaluation of 125I-2-iodo-L-phenylalanine showed high uptake in R1M cells by L-type amino acid transport system 1 (LAT1). This study evaluates 123I-2-iodo-L-phenylalanine as a new specific tumor tracer for SPECT.
123/125I-2-Iodo-L-phenylalanine is prepared as a one-pot kit using the Cu1+-assisted isotopic exchange method. The characteristics of 125I-2-iodo-L-phenylalanine were examined in vivo in R1M tumor-bearing athymic mice and in acute inflammation-bearing NMRI mice. The uptake of 123/125I-2-iodo-L-phenylalanine in tumor and other organs of interest was measured by dynamic planar imaging (DPI) and gamma-counting after dissection. Displacement of 123I-2-iodo-L-phenylalanine radioactivity by L-phenylalanine, L-methionine, and L-cysteine was measured. 123I-Iodo-human serum albumin planar imaging was performed to correct for blood-pool activity and MRI was performed to delineate the tumor in DPI. 18F-FDG uptake was measured with an animal PET scanner. 125I-2-Iodo-L-phenylalanine and 18F-FDG uptake in inflamed muscle were compared.
123/125I-2-Iodo-L-phenylalanine showed a high and fast tumor uptake and followed a reversible first-order pattern allowing calculation of the half-life and the time to reach equilibrium (t(R)). Net tumor-to-background ratios up to 6.7 at 60 min were obtained. This radioactivity was significantly displaced by L-phenylalanine, L-methionine, and L-cysteine, pointing to reversible LAT transport. When plotting t(R) of the tumor uptake as a function of tumor volume, a rectangular hyperbolic curve was obtained. The almost constant t(R) values at higher tumor volumes (>4 mL) could be linked to increased necrotic tissue. Fast blood clearance of the tracer through the kidneys to the bladder and low tracer activity in the abdomen and brain were observed. The inflamed muscle showed only a slight increase of 125I-2-iodo-L-phenylalanine uptake (inflammation-to-background ratio, RIB = 1.30 +/- 0.02), in contrast to the high 18F-FDG uptake (RIB = 11.1 +/- 1.7). The in vivo stability of 123/125I-2-iodo-L-phenylalanine was good: Only 7% of free radioiodide and no other labeled metabolites were observed after 90 min.
123/125I-2-Iodo-L-phenylalanine is quickly taken up by the overexpressed LAT1 system in R1M tumors with high tumor specificity. The availability of a kit and the specificity of the tracer make 123I-2-iodo-L-phenylalanine a promising tool for oncologic SPECT.
In vitro in the R1M cell model and in vivo in the R1M tumour-bearing athymic model, both [(123)I]-2-iodo-L: -phenylalanine and [(123)I]-2-iodo-D: -phenylalanine have shown promising results as tumour diagnostic agents for SPECT. In order to compare these two amino acid analogues and to examine whether the observed characteristics could be generalised, both isomers were evaluated in various tumour models.
Transport type characterisation in vitro in A549, A2058, C6, C32, Capan2, EF43fgf4, HT29 and R1M cells with [(123)I]-2-iodo-L: -phenylalanine was performed using the method described by Shotwell et al. Subsequently, [(123)I]-2-iodo-L: -phenylalanine and [(123)I]-2-iodo-D: -phenylalanine tumour uptake and biodistribution were evaluated using dynamic planar imaging and/or dissection in A549, A2058, C6, C32, Capan2, EF43fgf4, HT29 and R1M inoculated athymic mice. Two-compartment blood modelling of the imaging results was performed.
In vitro testing demonstrated that [(123)I]-2-iodo-L: -phenylalanine was transported in all tumour cell lines by LAT1. In all tumour models, the two amino acid analogues showed the same general biodistribution characteristics: high and specific tumour uptake and renal tracer clearance. Two-compartment modelling revealed that the D: -isomer showed a faster blood clearance together with a faster distribution to the peripheral compartment in comparison with [(123)I]-2-iodo-L: -phenylalanine.
[(123)I]-2-iodo-L: -phenylalanine and its D: -isomer are promising tumour diagnostic agents for dynamic planar imaging. They showed a high and similar uptake in all tested tumours. [(123)I]-2-iodo-D: -phenylalanine showed better tracer characteristics concerning radiation dose to other organs.
A number of human cancers are known to over-express the gastrin-releasing peptide receptor (GRPr) on cell surfaces. The high specificity and affinity of bombesin (BBN), an amphibian analogue of mammalian gastrin-releasing peptide, for the GRPr makes it an ideal candidate for delivery of diagnostic probes, such as 99mTc radiometal, to tumor sites. An optimized targeting agent possesses high tumor uptake with minimal uptake in normal tissues. In this study, 99mTc-targeting vectors of bombesin using various amino acid/aliphatic pharmacokinetic modifiers or linking groups were evaluated to determine the effect of the spacer on receptor binding affinity, internalization/externalization and biodistribution. Conjugates of the general type [DPR-X-BBN] (X = amino acid/aliphatic pharmacokinetic modifier) were synthesized by solid phase peptide synthesis (SPPS) and metallated with either low-valent, radioactive Tc-99m(I) or non-radioactive Re(I)-tricarbonyl precursors. All of the new non-metallated and metallated conjugates were characterized by electrospray ionization mass spectrometry (ESI-MS). Receptor binding affinity, internalization/externalization and biodistribution studies in normal (CF-1) and tumor (human prostate PC-3-bearing mice) are reported. The effectiveness of targeting xenografted PC-3 tumors in rodents for two of the new 99mTc-BBN conjugates is demonstrated herein using small animal single photon emission computed tomography (SPECT).
Synthetic strategies for the bifunctionalization of glucose and 2-deoxyglucose at position C-1 for transition metal coordination are reported. In particular organometallic technetium and rhenium complexes for potential use in diagnostic nuclear medicine were synthesized and investigated. Specifically, a common iminodiacetic acid (IDA) moiety was O-glycosidically connected through an ethylene spacer group to produce the pure α- (in case of 2-deoxyglucose) and β-anomer (in case of glucose). Reaction of the sugar derivatives with the organometallic precursor [M(H2O)3(CO)3]+ (M=99mTc, Re) produced single products in high yield, which are water-soluble and water-stable. The displacement of the three water molecules of the metal precursor and thus the tridentate coordination of the metal-tricarbonyl core exclusively via the amine and the two carboxylic acid functionalities of the IDA chelate was verified by means of 1D and 2D 1H NMR spectroscopy, mass spectrometry, and IR spectroscopy. The radioactive-labeled products (99mTc) proved their excellent stability in vitro in physiological phosphate buffer (pH=7.4) and human plasma over a period of 24 h at 37 °C.
IntroductionSelected Examples: Therapeutic RadiopharmaceuticalsDiagnostic Metal-Based RadiopharmaceuticalsPerspectives and Conclusion
Twelve [ReIL(CO)3]n+ complexes with various carbohydrate-pendant ligands L have been prepared and their uptake into HeLa S3 cells were investigated. The ligand library includes: (i) glucose/galactose as the carbohydrate group; (ii) bis(2-pyridylmethyl)amine (DPA), bis(2-quinolylmethyl)amine (DQA), or N-(2-pyridylmethyl)glycine (NPG) as the metal binding component; and (iii) an ethylene chain as a linker between the metal binding site and the O/C-glycosides. Microwave induced plasma mass spectroscopy (MIP-MS) measurements revealed that all complexes were extensively incorporated into the HeLa cells over a 24 h period, and the DQA complexes showed the highest uptake of all the complexes in the series. However, in comparison to the corresponding Re complexes without the pendant carbohydrate functions (prepared with the related ligands LDPA, LDQA, and LNPG), only the NPG complexes exhibited carbohydrate enhanced cellular uptake. Considering their water solubility and cellular uptake properties, the NPG complexes containing an O-glycoside group (L1 and L′1) are the best candidates for enhancing cellular uptake of metal ions. Microscopic analysis with PC-12 cells in the presence of thefluorescent complex [Re(L′7)(CO)3]Cl, revealed that the complex stays in the cell cytosol and cannot penetrate into the nucleus.
The syntheses of two new metallocenic analogues of phenylalanine: D,L-β-cymantrenyl alanine and D,L-β-tricarbonyl(cyclobutadienylalanine)iron are described.
Syntheses of DL-ferrocenylalanine from ferrocenecarboxyaldehyde by the azlactone method, and, more efficiently, from (ferrocenylmethyl) trimethylammonium iodide via (ferrocenylmethyl)formamidomalonic ester are described. The latter starting material has also been converted into ferrocenyl-acetic and -propionic acid.
The complexes 17α-[(C≡CC5H4)M(CO)3]-estradi o l, M = Re (17) and Mn (18), were prepared either by reaction of (LiC≡CC5H4)M(CO)3 with estrone or by the Pd-catalyzed coupling reaction of 17α-ethynylestradiol with (C5H4I)Re(CO)3. Analogously, 11β-(chloromethyl)-17α-[(C≡CC5H4)Re ( CO)3]-estradiol (19) was prepared from (LiC≡CC5H4)Re(CO)3 and 11β-(chloromethyl)estrone. 19 was characterized by X-ray crystallography: spece group P212121 (orthorhombic), a = 8.189(2) Å, b = 15.247(6) Å, c = 20.549(9) Å, V = 2566(2) Å3, Z = 4. The complexes 17α-[(CH2C5H4)M(CO)3]-es t radiol, M = Re (22) and Mn (23), were prepared by reaction of (C5H4Li)M(CO)3 with spiro[oxirane-2,17β'-estra-1,3,5(10)-trien-3-ol]. The relative binding affinities (RBA's) of these complexes for the estradiol-specific receptor are compared to that of the natural hormone. The low RBA values for 22 (0.8%) and 23 (2.5%) are rationalized on the basis of the flexible character of their bulky 17α substituents; in contrast, the alkynyl derivatives 17 and 18 adopt conformations in which the organometallic fragments lie beneath the steroidal D ring, as in the X-ray structure of 19, and their relative binding affinities are reasonably good (16% and 15%, respectively). It is proposed that the extraordinarily high RBA for 19 (172% at 25°C) can be accounted for in terms of an interaction of the 11β-chloromethyl substituent with a Lewis acid proximate to the receptor binding site. Some modeling studies of the dimeric receptor are in agreement with this hypothesis. The lipophilicities of these complexes have been estimated by measuring their partition coefficients between octanol and water, and these P(o/w) coefficients are related to the degree of nonspecific binding to low affinity sites. The potential utility of isotopically labeled steroidal rhenium complexes both as imaging agents and in radiotherapy is discussed.
We describe reactions of [99mTc(H2O)3(CO)3)]+ (1) with Diels–Alder products of cyclopentadiene such as “Thiele’s acid” (HCp-COOH)2 (2) and derivatives thereof in which the corresponding [(Cp-COOH)99mTc(CO)3)] (3) complex did form in water. We propose a metal mediated Diels–Alder reaction mechanism. To show that this reaction was not limited to carboxylate groups, we synthesized conjugates of 2 (HCp-CONHR)2 (4a–c) (4a, R = benzyl amine; 4b, R = Nα-Boc-l-2,3-diaminopropionic acid and 4c, R = glycine). The corresponding 99mTc complexes [(4a)99mTc(CO)3)] 6a, [(4b)99mTc(CO)3)] 6b and [(4c)99mTc(CO)3)] 6c have been prepared along the same route as for Thiele’s acid in aqueous media demonstrating the general applicability of this synthetic strategy. The authenticity of the 99mTc complexes on the no carrier added level have been confirmed by chromatographic comparison with the structurally characterized manganese or rhenium complexes.
Studies of the reaction of 1 with Thiele’s acid bound to a solid phase resin demonstrated the formation of [(Cp-COOH)99mTc(CO)3)] 3 in a heterogeneous reaction. This is the first evidence for the formation of no carrier added 99mTc radiopharmaceuticals containing cyclopentadienyl ligands via solid phase syntheses. Macroscopically, the manganese analogue 5a and the rhenium complexes 5b–c have been prepared and characterized by IR, NMR, ESI-MS and X-ray crystallography for 5a (monoclinic, P21/c, a = 9.8696(2) Å, b = 25.8533(4) Å, c = 11.8414(2) Å, β = 98.7322(17)°) in order to unambiguously assign the authenticity of the corresponding 99mTc complexes.
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.
The first poly(amidoamine) (PAMAM) dendrimers tethered with both (η5-cyclopentadienyl) rhenium tricarbonyl (CpRe(CO)3) units and polyethylene glycol (PEG) chains were prepared and characterized by combining NMR spectroscopy and Fourier-transform IR spectroscopy. Grafting of CpRe(CO)3 units was achieved by reductive amination of formyl-CpRe(CO)3 with the peripheral amines of generation 3 and 4 PAMAMs to yield dendrimers labeled with a variable number of CpRe(CO)3 units, ranging from 8 to 14 for PAMAM-G3 and 17–30 for PAMAM-G4. PEG chains of different lengths were then attached to some of the remaining peripheral amines, and their respective ability to improve the solubility of the metallodendrimers in aqueous buffered media was evaluated. These metallodendrimers represent new infrared probes designed to be coupled to immunological reagents for the amplification of the IR signal in carbonyl metallo immunoassay (CMIA).
(η5-Cyclopentadienyl) tricarbonyl manganese (cymantrenyl) derivatives of the protein bovine serum albumin (BSA) with coupling ratios ranging from 7 to 20 were prepared by reaction of cymantrenyl methyl imidate with some of the lysine residues of BSA. Electrochemical measurements based on the AC voltammetric detection of the reduction of cymantrene bound to BSA protein were successfully set up in aqueous solutions and the detection limit of 2×10−7 M BSA was achieved. This limit is almost two orders of magnitude lower than that measured by IR spectroscopy. Electrochemical detection of cymantrene label will be used for immunoassay analysis of water-soluble analytes in our future work.
Technetium-99m radiopharmaceuticals are increasingly finding application in nuclear medicine for scintigraphic and emission tomographic imaging, morphologic description and functional testing of organs. Over 80% of the radiopharmaceuticals currently clinically used are labeled with the short-lived, metastable nuclide 99mTc, whose nuclear properties are almost optimal with regard to a low radiation exposure of the patient and an effective detection of the emitted γ quanta. 99mTcO can be easily prepared without the use of accelerator systems through generator columns. Most of the 99mTc radiopharmaceuticals are complexes which are synthesized by reduction of 99mTcO in the presence of suitable ligands. To achieve a high organ specificity, some understanding of the relationship between the structure of the diagnostic agent and its organ distribution is necessary. Structure analyses can be carried out on analogous compounds of the long-lived nuclide technetium-99g; these compounds are obtainable in weighable quantities. The development of new 99mTc radiopharmaceuticals is a challenge to coordination chemists. The syntheses, molecular structures, and applications of the most important 99mTc radiopharmaceuticals will be described in this review, and current directions and tendencies of the development will be shown.
SIR97 is the integration of two programs, SIR92 and CAOS, the first devoted to the solution of crystal structures by direct methods, the second to refinement via least-squares-Fourier procedures. Several new features have been introduced in SIR97 with respect to the previous version, SIR92: greater automatization, increased efficiency of the direct methods section, and a powerful graphics interface. The program also provides publication tables and CIF files. © 1999 International Union of Crystallography Printed in Great Britain - all rights reserved.
The reaction of α-bromohippuric acid methyl ester with nickelocene, cyclopentadienylthallium or cyclopentadienyltrimethylsilane afforded N-benzoyl-2-cyclopentadienylglycine methyl ester (1) as two double bond isomers 1a and 1b. Similarly, the cyclopentadienyl(Cp)-containing dipeptide Z-l-Phe-dl-(Cp)Gly-OMe (3) was obtained from Z-l-Phe-dl-Gly(Cl)-OMe and trimethylsilylcyclopentadiene. The amino acids 1a, 1b were susceptible to Diels–Alder cycloaddition and yielded dimer 2 as a mixture of regioisomers. Compound 1 and FeCl2 gave 1,1′-ferrocenylene-bis(glycine) (5), whereas with [(COD)RhCl]2 rhodium η5-cyclopentadienylglycine (6) and η5-cyclopentadienyldipeptide complexes like 7 were obtained from 1 or 3, respectively. Unexpectedly, the η5-cyclopentadienylglycine complexes proved to be very sensitive to light.
An optically-active redox amino acid, L-ferrocenylalanine was synthesized. The amino acid was incorporated into polypeptides in the form of a single L-ferrocenylalanine unit or a L-ferrocenylalanyl-L-ferrocenylalanine unit. Those polypeptides showed reversible redox property on the cyclic voltammetry.
Metal Complexes with Biologically Important Ligands, LXV[1]. — Chiral Half-Sandwich Complexes of Cobalt(III), Rhodium(III), Iridium(III), and Ruthenium(II) with α-Amino Amide, Glycinenitrile, and Peptide Ester Ligands
Cp*Co(CO)I2 (Cp* = η5-C5Me5), [(η6-arene)RuCl2]2 (arene = p-cymene, hexamethylbenzene), and [Cp*MCl2]2 (M = Rh, Ir) react with α-amino amides and various peptide esters to give the N,O-chelate complexes [Cp*(I)Co — NH2C(H)(R1)C(NHR2)-O]+ (1), [(η6-arene)(Cl)Ru — NH2C(H)(R1)C(NHR2)O]+ (2), and [CP*(Cl)M—NH2CH2C(NHR)O]+ (M = Rh, Ir) (5, in solution), respectively. In the solid state the ligands are η1N-bonded in 5. By deprotonation of the peptide bond in 2 and 5 the neutral N, N-chelate complexes (η6-arene)(Cl)Ru — NH2C(H)(R1)C(O)-N̊2 (6) and Cp*(Cl)M — NH2C(H)(R1)C(O)NR2 (M = Rh, Ir) (7) have been obtained. Glycinenitrile is η1-bonded in (η6-p-cymene)(Cl)2Ru(NH2CH2CN) (3) and Cp*(Cl)2Rh(NH2CH2CN) (4). Double deprotonated triglycine methyl ester is a N,N,N-tridentate ligand in (η6-C6Me6)Ru(NH2CH2C(O)NCH2C(O)-NCH2CO2Me) (8). The anions of L-asparagine and of aspartame (L-aspartyl-L-phenylalanine methyl ester) give the complexes 9–12 with tridentate O,N,O- or O,N,N-chelate ligands. The crystal structures of 1d (L = glyglyOEt), 5a (L = glycinamide), 6e (L = glyglyOEt), and 7k (L = glyglyglyOEt) have been determined by X-ray structural analysis.
A range of N-alkoxycarbonyl- and N-carboxamido-oxaziridines has been prepared to test the effects of oxaziridine structure on yields of enolate amination product. Side-products arising from reaction of aldehyde-derived oxaziridines with base were identified, while a ketone-derived oxaziridine afforded moderate yields of amination product with stabilised carbanions.
Enhanced receptor selectivity: Carbonic anhydrase inhibitors are relevant for both cancer diagnosis and therapy. Combining non-radioactive Re compounds with their radioactive (99m) Tc homologs enables the use of identical molecules for therapy and imaging (theragnostic). The syntheses and in vitro evaluation of [(Cp-R)M(CO)(3) ] (Cp=cyclopentadienyl, M=Re, (99m) Tc) with R being a highly potent carbonic-anhydrase-targeting vector is reported.
Seven discrete sugar-pendant diamines were complexed to the {M(CO)(3)}(+) ((99m)Tc/Re) core: 1,3-diamino-2-propyl beta-D-glucopyranoside (L(1)), 1,3-diamino-2-propyl beta-D-xylopyranoside (L(2)), 1,3-diamino-2-propyl alpha-D-mannopyranoside (L(3)), 1,3-diamino-2-propyl alpha-D-galactopyranoside (L(4)), 1,3-diamino-2-propyl beta-D-galactopyranoside (L(5)), 1,3-diamino-2-propyl beta-(alpha-D-glucopyranosyl-(1,4)-D-glucopyranoside) (L(6)), and bis(aminomethyl)bis[(beta-D-glucopyranosyloxy)methyl]methane (L(7)). The Re complexes [Re(L(1)-L(7))(Br)(CO)(3)] were characterized by (1)H and (13)C 1D/2D NMR spectroscopy which confirmed the pendant nature of the carbohydrate moieties in solution. Additional characterization was provided by IR spectroscopy, elemental analysis, and mass spectrometry. Two analogues, [Re(L(2))(CO)(3)Br] and [Re(L(3))(CO)(3)Br], were characterized in the solid state by X-ray crystallography and represent the first reported structures of Re organometallic carbohydrate compounds. Conductivity measurements in H(2)O established that the complexes exist as [Re(L(1)-L(7))(H(2)O)(CO)(3)]Br in aqueous conditions. Radiolabelling of L(1)-L(7) with [(99m)Tc(H(2)O)(3)(CO)(3)](+) afforded in high yield compounds of identical character to the Re analogues. The radiolabelled compounds were determined to exhibit high in vitro stability towards ligand exchange in the presence of an excess of either cysteine or histidine over a 24 h period.
A comparison of two radiometals, technetium and gallium derived radiopharmaceuticals is presented. 99mTc is available from a commercial generator technology where a parent isotope (99Mo) is loaded onto an alumina column and the desired daughter is isolated by passing a saline solution through the system. Technetium is a transition metal that presents a major challenge with respect to designing radiopharmaceuticals that have suitable in vivo properties. While the technetium- and rhenium- organohydrazino cores display the advantages of facile preparation and chemical robustness, the intimate details of the chemistry are complex, dependent upon reaction conditions and the presence of coligands. Gallium-67 is cyclotron produced by the 68Zn (p, 2n)-67Ga reaction in which a thin layer of enriched 68Zn is electrochemically plated on an appropriate metal target. With advanced molecular imaging there is an increasing demand for new agents and a need for innovative radiopharmaceutical discovery and design paradigms.
The biological evaluation of half-sandwich (99m)Tc-complexes that surrogate iodobenzamide with a high affinity for melanin tumor tissue is described. We have synthesized via retro Diels-Alder reaction two models of (99m)Tc complexes which possess the piano stool [Cp(99m)Tc(CO)(3)] motif instead of a phenyl ring as in the original iodobenzamide (123)I-N-(N-benzylpiperidin-4-yl)-2-iodobenzamide (2-IBP) and N-(2-diethylaminoethyl)-4-iodobenzamide (BZA). Diels-Alder products 2a-b (HCp-CONHR)(2) (2a, R=2-diethylaminoethyl; 2b, R=benzylpiperidin-4-yl) were prepared and reacted with fac-[(99m)Tc(H(2)O)(3)(CO)(3))](+) 1 in water to produce the corresponding (99m)Tc complexes [(2a)(99m)Tc(CO)(3))] 4a and [(2b)(99m)Tc(CO)(3))] 4b. The structures of the (99m)Tc complexes on the no-carrier-added level have been confirmed by chromatographic comparison with the corresponding rhenium complexes 3a and 3b, macroscopically characterized by IR, NMR, ESI-MS and X-ray crystallography for 3a [triclinic, P-1, a=7.3518(1) A, b=8.0309(2) A, c=17.5536(3) A, alpha=99.1260(5) degrees, beta=90.4215(14) degree , gamma=117.0187(11) degrees]. The radioconjugate 4b showed good in vitro stability. In murine melanoma B16F1 cells, significant cellular uptake (43.9% of the total applied activity) was attained after 4 h at 37 degrees C with about 50% of the cell-associated radioactivity being internalized in the cells (22% of the applied activity). Furthermore, in melanoma-bearing C57BL6 mice, tumor uptake values of 3.39+/-0.50 %ID g(-1) and 3.21+/-0.26 %ID g(-1) at 1 and 4 h postinjection, respectively, were observed indicating a good retention of 4b in the tumor.
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Theragnostics is a treatment strategy that combines therapeutics with diagnostics. It associates both a diagnostic test that identifies patients most likely to be helped or harmed by a new medication, and targeted drug therapy based on the test results. Bioinformatics, genomics, proteomics, and functional genomics are molecular biology tools essential for the progress of molecular theragnostics. These tools generate the genetic and protein information required for the development of diagnostic assays. Theragnostics includes a wide range of subjects, including personalized medicine, pharmacogenomics, and molecular imaging to develop efficient new targeted therapies with adequate benefit/risk to patients and a better molecular understanding of how to optimize drug selection. Furthermore, theragnostics aims to monitor the response to the treatment, to increase drug efficacy and safety. In addition, theragnostics could eliminate the unnecessary treatment of patients for whom therapy is not appropriate, resulting in significant drug cost savings for the healthcare system. However, the introduction of theragnostic tests into routine health care requires both a demonstration of cost-effectiveness and the availability of appropriate accessible testing systems. This review reports validation studies in oncology and infectious diseases that have demonstrated the benefits of such approach in well-defined subpopulations of patients, moving the field from the drug development process toward clinical practice and routine application. Theragnostics may change the usual business model of pharmaceutical companies from the classic blockbuster model toward targeted therapies.
This feature article covers recent reports of work towards the development of (99m)Tc-carbohydrate based agents for use in SPECT imaging, particularly of cancerous tissue. An outline of some of the key biological functions and coordination chemistry of carbohydrates is given, along with an introduction to bioconjugation and molecular imaging. Technetium coordination chemistry and the subset of this involving bioconjugates are discussed before moving into the focus of the article: glycoconjugates of (99m)Tc(v) and the more recently developed [(99m)Tc(I)(CO)(3)](+). Significant work in the last decade has featured the very attractive [(99m)Tc(CO)(3)](+) core, and the ligand sets designed for this core are discussed in detail.
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Technetium-99m is the most commonly used radionuclide in routine nuclear medicine imaging procedures. Development of 99mTc-labeled receptor-specific imaging agents for studying the central nervous system is potentially useful for evaluation of brain function in normal and disease states. A novel 99mTc-labeled tropane derivative, [99mTc]TRODAT-1, which is useful as a potential CNS dopamine transporter imaging agent, was evaluated and characterized. After i. v. injection into rats, [99mTc]TRODAT-1 displayed specific brain uptake in the rat striatal region (striatum-cerebellum/cerebellum ratio 1.8 at 60 min), where dopamine neurons are concentrated. The specific striatal uptake could be blocked by pretreating rats with a dose of competing dopamine transporter ligand, beta-CIT (or RTI-55, i.v., 1 mg/kg). However, the specific striatal uptake of [99mTc]TRODAT-1 was not affected by co-injection of excess free ligand (TRODAT-1, up to 200 microg per rat) or by pretreating the rats with haloperidol (i.v., 1 mg/kg). The specific uptake in striatal regions of rats that had prior 6-hydroxydopamine lesion in the substantia nigra area showed a dramatic reduction. The radioactive material recovered from the rat striatal homogenates at 60 min after i.v. injection of [99mTc]TRODAT-1 showed primarily the original compound (>95%), a good indication of in vivo stability in brain tissue. Similar and comparable organ distribution patterns and brain regional uptakes of [99mTc]TRODAT-1 were obtained for male and female rats. Ex vivo autoradiography results of rat brain sections further confirmed the high uptake and retention of [99mTc]TRODAT-1 in the striatal region. In vitro binding studies measuring the affinity to dopamine transporters for the free ligand, TRODAT-1, and a nonradioactive rhenium derivative, Re-TRODAT-1, showed Ki values of 9.7 nM and 14.1 nM, respectively. Behavioral studies in rats using the free ligand, TRODAT-1 and Re-TRODAT-1 indicated that, unlike other tropane derivatives, they displayed no effect on locomotor activity, suggesting low toxicity. These results strongly support the conclusions that this novel 99mTc radioligand binds selectively to dopamine transporters in the brain and that is is potentially useful for in vivo assessment of the loss of dopamine neurons in Parkinson's and other neurodegenerative diseases.
Receptor targeting with radiolabeled peptides has become very important in nuclear oncology in the past few years. The most frequently used peptides in the clinic are analogs of somatostatin (SRIF), e.g. OctreoScan, which contain chelators for the radioisotopes 111In, 86Y, 90Y, 67Ga, 68Ga and 64Cu or for 99mTc and 188Re. and were labelled with the halogens 123I and 18F. Radiolabeled analogs of &alpha-melanocyte-stimulating hormone (&alpha-MSH), neurotensin, vasoactive intestinal peptide (VIP), bombesin (BN), substance P (SP) and gastrin/cholecystokinin (CCK) are also being developed, evaluated in vitro and in vivo and tested for clinical application. This review focuses on the expression in tumors and the regulation of receptors for these neuropeptides as well as the development of novel chelator-peptide conjugates suitable for in vivo scintigraphy or internal radiotherapy. The state of the art of radiopeptide pharmaceuticals is illustrated with four SRIF analogs, modified with the macrocyclic chelator 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid (DOTA): [D-Phe1]-octreotide (DOTAOC), [D-Phe1, Tyr3]-octreotide (DOTATOC), vapreotide (DOTAVAP) and lanreotide (DOTALAN). DOTA is almost a universal chelator capable of strongly encapsulating hard metals such as 111In and 67Ga for Single Photon Emission Tomography (SPET), 68Ga, 86Y and 64Cu for Positron Emission Tomography (PET) as well as 90Y for receptor-mediated radionuclide therapy and radiolanthanides which exhibit different interesting decay schemes. From biodistribution studies in experimental animals and from clinical data it is concluded that DOTATOC is currently the most suitable SRIF radiopeptide with the best potential in the clinic.
Synthetic strategies for the bifunctionalization of glucose and 2-deoxyglucose at position C-1 for transition metal coordination are reported. In particular organometallic technetium and rhenium complexes for potential use in diagnostic nuclear medicine were synthesized and investigated. Specifically, a common iminodiacetic acid (IDA) moiety was O-glycosidically connected through an ethylene spacer group to produce the pure alpha- (in case of 2-deoxyglucose) and beta-anomer (in case of glucose). Reaction of the sugar derivatives with the organometallic precursor [M(H2O)3(CO)3]+ (M = 99mTc, Re) produced single products in high yield, which are water-soluble and water-stable. The displacement of the three water molecules of the metal precursor and thus the tridentate coordination of the metal-tricarbonyl core exclusively via the amine and the two carboxylic acid functionalities of the IDA chelate was verified by means of 1D and 2D 1H NMR spectroscopy, mass spectrometry, and IR spectroscopy. The radioactive-labeled products (99mTc) proved their excellent stability in vitro in physiological phosphate buffer (pH = 7.4) and human plasma over a period of 24 h at 37 degrees C.
A straightforward method for the synthesis of enantiomerically pure bis(valine)metallocenes is presented. Derivatives of lithium cyclopentadienylvaline 1a, b were obtained by addition of the (R)- or (S)-Schöllkopf reagents to 6,6-dimethylfulvene as single enantiomers and gave with FeCl2 or [RuCl2(dmso)4] the chiral metallocenes [Fe[C5H4-CMe2-[C4H2N2(OMe)2iPr]]2] (2a, b) and [Ru[C5H4-CMe2-[C4H2N2(OMe)2iPr]]2] (3a, b). Complex 2b was hydrolyzed to the ferrocenylene-bis(valine-methylester) [[Fe[C5H4-CMe2-CH(NH3+)COOMe]2]2+(Cl-)2] (7) without racemization. Complex 7 could be used as ligand and was treated with [[Cp*IrCl2]2] to afford [Fe[C5H4-CMe2-CH(COOMe)(NH2-IrCp*Cl2)]2] (10). The reactions of 1 with CoCl2, [Re(CO)5Br], [[(cod)RhCl2]2] (cod= 1,5-cyclooctadiene) or [Cp*MCl3] (M= Ti, Zr) gave the cyclopentadienyl complexes [[Co[C5H4-CMe2-[C4H2N2(OMe)2iPr]]2]+ I-] (11) and [Re[C5H4-CMe2-[C4H2N2(OMe)2iPr]](CO)3] (13), [(C8H12)Rh[C5H4-CMe2-[C4H2N2(OMe)2(iPr)]]] (14). [[Rh[C5H4-CMe2-[C4H2N2(OMe)2(iPr)]]I]2(mu-I)2] (15), [Cp*Cl2Ti-[C5H4-CMe2-[C4H2N2(OMe)2(iPr)]]] (16), and [Cp*Cl2Zr[C5H4-CMe2-[C4H2N2(OMe)2(iPr)]]] (17), with chiral valine derivatives as substituents on the cyclopentadienyl ring and with excellent diastereoselectivities. Also the Seebach reagent (Boc-BMI) or O'Donnell reagent could be added to 6,6-dimethylfulvene to give the lithium cyclopentadienides Li[C5H4-CMe2-[C3H2(tBu)(N-Boc)(NMe)O]] (18) and Li[C5H4-CMe2-CH(NCPh2)(COOEt)] (21), which formed the ferrocene derivatives [Fe[C5H4-CMe2-[C3H2(tBu)(N-Boc)(NMe)O]]2] (19) and [Fe[C5H4-CMe2-CH(NCPh2)(COOEt)]2] (22). The stable cobaltocinium cation in 11 and the complex 19 could be hydrolyzed to the metallocenes 12 and [Fe(C5H4-CMe2-CH(NH3+)(COO-)]2] (20) with two valines in the 1,1'-position. The structures of 2a, b, 11, 15, and 16 were determined by X-ray diffraction and confirm the diastereomeric purity of the compounds.
Half-sandwich complexes of the type [(RCOCp)M(CO)(3)] with M = Re and (99(m))Tc were synthesized from [M(OH(2))(3)(CO)(3)](+) in water. The R group can be an organic residue or a receptor binding biomolecule with a spacer to cyclopentadienyl (Cp). This provides a general route to Cp complexes of technetium without the need for starting from [TcBr(CO)(5)]. The X-ray structure of [(C(6)H(5)CH(2)COC(5)H(4))Tc(CO)(3)] has been elucidated. The compound crystallizes in the monoclinic space group P2(1)/c with a = 16.1454(9), b = 7.6300(6), and c = 12.3922(7) A and beta = 107.792(6) degrees. We have chosen a serotonergic receptor ligand (WAY) as an example for the derivatization of Cp with a bioactive molecule. WAY is linked to Cp by an aliphatic chain of variable length. The half-sandwich complexes were prepared from water and organic solvents. The structure of [(WAY4-Cp)Re(CO)(3)] could be elucidated. The compound crystallizes in the monoclinic space group P2(1)/c with a = 15.7112(6), b = 6.8775(3), and c = 25.5217(12) A and beta = 103.778(5) degrees. Quantification of inhibition constants gave a clear structure-activity relationship. A single methylene group between the receptor binding site and the half-sandwich complex gave an IC(50) of 217 nM for HT(1A), whereas a butylene linker resulted in retention of the inhibition constant with an IC(50) of 6 nM with respect to underivatized WAY. For use as radiopharmaceuticals, the compounds have also been prepared with (99m)Tc in quantitative yield.
There is a great current interest in developing target-specific radiopharmaceuticals for early detection of diseases and radiotherapy of cancers. This critical review will focus on the role of coordination chemistry in the development of target-specific radiopharmaceuticals. It will also discuss the recent development in technetium, copper, gallium, indium, yttrium and lanthanide chemistry, as well as analytical tools for quality control and characterization of radiolabeled small biomolecules (159 references).
A series of nine organometallic technetium-99m and rhenium complexes of glucose are presented and characterized in vitro regarding their potential as surrogates of [18F]-2-fluoro-desoxy glucose ([18F]-FDG). The glucose derivatives are functionalized at positions C-1, C-2, C-3, and C-6. Different spacer lengths and chelating systems have been introduced at these sites. For the (radio)labeling, the organometallic precursors [99mTc(H2O)3(CO)3]+ and [ReBr3(CO)3](2-) respectively have been used. The resulting complexes have been characterized chemically and radiochemically. The formation of uniform products has been observed on the macroscopic (Re) and no-carrier-added level (99mTc). The Tc-99m complexes revealed good inertness against ligand exchange (Cys and His) and excellent stability in physiological buffered saline as well as in human plasma over a period of 24 h at 37 degrees C. The rhenium complexes have been tested for competitive inhibition of the (yeast) hexokinase. Only for C-2 derivatized glucose complexes with extended spacer functionalities Ki values in the millimolar and sub-millimolar range have been observed. In silico molecular docking experiments supported these experimental findings. However, the competitive inhibitors are not recognized as a pseudosubstrate of hexokinase. The cellular uptake of all 99mTc-complexes into HT-29 colon carcinoma cells via Glut1 was generally low and unspecific independent of the position at the hexose ring, the chelating systems, or the overall charge of the corresponding metal complexes. The current results seem to preclude the use of these compounds as [18F]-FDG surrogates primarily due to the low cellular uptake via Glut1.
Bifunctional chelates offer a general approach for the linking of radioactive metal cations to macromolecules. In the specific case of 99mTc, a variety of technologies have been developed for assembling a metal-chelate-biomolecule complex. An evaluation of these methodologies requires an appreciation of the coordination characteristics and preferences of the technetium core structures and oxidation states, which serve as platforms for the development of the imaging agent. Three technologies, namely, the MAG3-based bifunctional chelates, the N-oxysuccinimidylhydrazino-nicotinamide system and the recently described single amino acid chelates for the {Tc(CO)3}1+ core, are discussed in terms of the fundamental coordination chemistry of the technetium core structures. In assessing the advantages and disadvantages of these technologies, we conclude that the single amino acid analogue chelates (SAAC), which are readily conjugated to small peptides by solid-phase synthesis methods and which form robust complexes with the {Tc(CO)3}1+ core, offer an effective alternative to the previously described methods.
Improvement of scintigraphic tumor imaging is extensively determined by the development of more tumor specific radiopharmaceuticals. Thus, to improve the differential diagnosis, prognosis, planning and monitoring of cancer treatment, several functional pharmaceuticals have been developed. Application of molecular targets for cancer imaging, therapy and prevention using generator-produced isotopes is the major focus of ongoing research projects. Radionuclide imaging modalities (positron emission tomography, PET; single photon emission computed tomography, SPECT) are diagnostic cross-sectional imaging techniques that map the location and concentration of radionuclide-labeled radiotracers. 99mTc- and 68Ga-labeled agents using ethylenedicysteine (EC) as a chelator were synthesized and their potential uses to assess tumor targets were evaluated. 99mTc (t1/2 = 6 hr, 140 keV) is used for SPECT and 68Ga (t1/2 = 68 min, 511 keV) for PET. Molecular targets labeled with Tc-99m and Ga-68 can be utilized for prediction of therapeutic response, monitoring tumor response to treatment and differential diagnosis. Molecular targets for oncological research in (1) cell apoptosis, (2) gene and nucleic acid-based approach, (3) angiogenesis (4) tumor hypoxia, and (5) metabolic imaging are discussed. Numerous imaging ligands in these categories have been developed and evaluated in animals and humans. Molecular targets were imaged and their potential to redirect optimal cancer diagnosis and therapeutics were demonstrated.
To obtain a 99mTc glucose conjugate for imaging, double-ligand transfer (DLT) and related reactions were examined for the preparation of CpM(CO)3 (Cp = cyclopentadienyl; M = Re, Tc) complexes with pendant carbohydrates at Cp. Tricarbonyl{N-(1,3,4,6-tetra-O-acetyl-2-amino-2-deoxy-beta-D-glucopyranose)cyclopentadienyl carboxamide}rhenium(I) (1a) and tricarbonyl{N-(2-amino-2-deoxy-beta-D-glucopyranose)cyclopentadienyl carboxamide}rhenium(I) (2a) were prepared. The compounds were fully characterized by mass spectrometry, elemental analysis, IR, and NMR spectroscopy. Full assignment of the NMR spectra verified the pendant nature of the glucosamine moieties in the solution state and that 2a exists as both anomers. The solid-state structure of 2a was determined by X-ray crystallography, again confirming the pendant nature of the glucosamine, but differing from the solution state in that the beta anomer crystallized preferentially (93%). Compound 2a was determined to be a high-affinity competitive inhibitor (Ki = 330 +/- 70 microM) of the glucose metabolism enzyme hexokinase, demonstrating that it retains certain biological activity. The 99mTc analogues 1b and 2b were prepared in moderate radiochemical yields by means of the single-ligand transfer (SLT) route, which is more pertinent to radiopharmaceutical synthesis.
We have synthesized amino acids conjugated at the alpha-carbon through an alkyl spacer to a small tripod ligand. The tripod coordinates to the fac-[M(CO)3]+ moiety (M = Re, 99mTc). Depending on the lengths of the spacers, these metal complexes with pendent alpha-amino acids are recognized and transported by the l-type amino acid transporter LAT1. The best result was achieved with a butyl spacer. The Ki value of the corresponding complex is comparable to that of the artificial amino acid BCH. Efflux of [3H]-l-phenylalanine shows that the labeled amino acids do not only bind to the transporter but are transported into the cells. These are the first metal-labeled small molecules which are actively internalized to the intracellular space.
In the past 10 years, significant progress has been made in using a technetium-99m dopamine transporter imaging agent, [99mTc]TRODAT, for routine clinical studies. Developing a molecular imaging agent from bench to the bedside is more than a simple scientific venture. Currently, Taiwan is the only place where [99mTc]TRODAT is approved for routine clinical use in the diagnosis of Parkinson's disease. The trials and tribulations of developing [99mTc]TRODAT for routine clinical use in Taiwan provide an interesting case study in how to (critics may say, how not to) develop a molecular imaging agent.
An account is given of the development of the SHELX system of computer programs from SHELX-76 to the present day. In addition to identifying useful innovations that have come into general use through their implementation in SHELX, a critical analysis is presented of the less-successful features, missed opportunities and desirable improvements for future releases of the software. An attempt is made to understand how a program originally designed for photographic intensity data, punched cards and computers over 10000 times slower than an average modern personal computer has managed to survive for so long. SHELXL is the most widely used program for small-molecule refinement and SHELXS and SHELXD are often employed for structure solution despite the availability of objectively superior programs. SHELXL also finds a niche for the refinement of macromolecules against high-resolution or twinned data; SHELXPRO acts as an interface for macromolecular applications. SHELXC, SHELXD and SHELXE are proving useful for the experimental phasing of macromolecules, especially because they are fast and robust and so are often employed in pipelines for high-throughput phasing. This paper could serve as a general literature citation when one or more of the open-source SHELX programs (and the Bruker AXS version SHELXTL) are employed in the course of a crystal-structure determination.
The synthesis of piano-stool type complexes [(Cp-R)Tc-99m(CO)(3)] from water and, if possible, directly from [(TcO4)-Tc-99m](-) is a persisting challenge. Such complexes are vary convenient for labeling biomolecules since they are small in size and "innocent" with respect to noncovalent interactions in biological systems. We found that [(Cp-R)Tc-99m(CO)(3)] can be prepared directly from the dimerized Diels-Alder precursors and from [(TcO4)-Tc-99m](-). Since the concentration of the respective monomers in the reaction solutions was undetectable, the formation of [(Cp-R)Tc-99m(CO)(3)] must be based on a metal-mediated retro Diels-Alder reaction with concerted Cp coordination. The authenticity of the formed Tc-99m complexes was confirmed by comparing their HPLC retention times with those of the structurally characterized rhenium surrogates. Besides the principle access to piano-stool complexes for radiopharmaceutical studies, a metal-mediated retro Diels-Alder reaction under concomitant formation of the corresponding piano-stool complex has, to our knowledge, not been observed before and might apply to other metal cations as well.
- H W P N'dongo
- Y Liu
- D Can
- P Schmutz
- B Spingler
- R J Alberto
N'Dongo, H. W. P.; Liu, Y.; Can, D.; Schmutz, P.; Spingler, B.;
Alberto, R. J. Organomet. Chem. 2009, 694, 981−987.
- D Can
- B Spingler
- P Schmutz
- F Mendes
- P Raposinho
- C Fernandes
- F Carta
- A Innocenti
- I Santos
- C T Supuran
- R Alberto
Can, D.; Spingler, B.; Schmutz, P.; Mendes, F.; Raposinho, P.;
Fernandes, C.; Carta, F.; Innocenti, A.; Santos, I.; Supuran, C. T.;
Alberto, R. Angew. Chem., Int. Ed. 2012, 51, 3354−3357.