30 Inorganic pharmaceuticals P. J. Blower Nuclear Medicine Department, Kent and Canterbury Hospital, Ethelbert Road, Canterbury, Kent, UK CT1 3NG 1 Introduction Inorganic pharmaceuticals are taken to include compounds that contain elements other than carbon, hydrogen, nitrogen, oxygen, sulfur, phosphorus and halogens (except astatine), developed or evaluated for clinical or veterinary use to treat or diagnose disease.Radiopharmaceuticals and materials for controlled drug delivery are included, but materials for prosthetic devices are not. In most inorganic pharmaceuticals the ‘‘inorganic’’ component is a metal. Metallic elements provide radioisotopes suitable for radionuclide imaging and therapy1–3 (such as Tc, Re, In, and Cu) or neutron capture therapy (B, Gd).The last two years in particular have witnessed a significant increase in activity in the area of therapeutic radiopharmaceuticals, especially those containing rhenium, copper and yttrium isotopes (discussed below). Metals (Fe, Co, Cu) participate in radical chemistry with oxygen species leading to applications as radiosensitisers or free-radical scavengers. They o§er cytotoxicity (Pt, Au and others including first row transition metal complexes4 and early transition metal polyoxometalates5) for anti-tumour agents,6–8 anti-inflammatory properties (Au) for treatment of rheumatoid disease,6,9–11 and antimicrobial properties. The magnetic properties of metals may be exploited (Gd, Fe, Mn) in contrast agents for magnetic resonance imaging (MRI), in magnetically targeted drug delivery, or in localised magnetisation-induced hyperthermia treatment.The drug-chelating properties of metals (especially Cu) o§er opportunities for control of delivery and biodistribution of organic drugs, and enhancement of their activity.12 Other areas of development include anti-ulcer treatments (Bi),6 photodynamic therapy,13 and anti-viral agents.14 In this report, the foregoing summary serves to list the categories of applications of inorganic pharmaceuticals. Review articles and papers covering several metals are cited above, while in the following sections developments are categorised by the ‘‘inorganic’’ element concerned, in order of atomic number. 2 Boron The main attraction of boron continues to be the high neutron capture cross-section of the 11B nucleus, useful in neutron capture therapy.The chemical background has been Annu. Rep. Prog. Chem., Sect. A, 1999, 95, 631–655 631reviewed15 and an in vitro method of screening boron compounds for radiobiological e§ects has been developed.16 New bioconjugates designed to deliver boron selectively to tumours include conjugates of carboranes with glycosides17 and intercalating agents (phenanthridium18), and liposomes loaded with boronophenylalanine.19 Some boron-containing compounds have also been evaluated for their inherent cytotoxic properties, including complexes of copper and zinc with boron-containing ligands,20 carboranes and polyhedral hydroborate salts.21 Finally, the potential of 11BNMRfor in vivo MRI using tissue-targeted boron compounds is now being evaluated, and di§erences in boron concentration in di§erent tissues could be demonstrated.22 3 Aluminium Aluminium compounds have long been used as antacids and as adjuvants in vaccine formulation.This area has been reviewed23 and the adsorption of aluminium salts (hydroxide, phosphate) on model vaccine proteins (lysozyme, ovalbumin) has been characterised.24 4 Scandium Scandium has found little use in pharmaceutics to date, but recently production and purification of the b-emitting radionuclide 47Sc, and its conjugation to antibodies using bifunctional chelators for radionuclide therapy, has been described.25 5 Titanium Titanocene dichloride is a cytotoxic complex being evaluated as an anti-cancer agent.26 Use of transition metals as enzyme inhibitors is being explored for possible applications in anti-microbials and other areas.Titanyl sulfate was found to be a potent inhibitor of the trypsin class of proteases and to prevent growth of a number of microorganisms.27 6 Vanadium The most important physiological response of vanadium is its insulin mimetic property. Vanadium complexes and their interactions with biomolecules are being studied in order to improve the currently minimal understanding of this action.28–31 A new class of vanadium-based spermicides comprising vanadocene dithiocarbamate complexes, [V(dtc)Cp 2 ]` is reported, and a crystal structure of the archetypal compound (the diethyldithiocarbamate derivative) has been obtained.32 The anticarcinogenic properties of vanadium salts have been investigated for many years.A vanadium(III) cysteine complex exerted a much more potent anti-carcinogenic and anti-tumour e§ect than either vanadyl sulfate or cysteine.33 Annu. Rep. Prog. Chem., Sect. A, 1999, 95, 631–655 6327 Manganese Paramagnetic manganese compounds continue to be developed as contrast enhancing agents for MRI. Manganese complexes are typically unstable in vivo, leading to neurotoxicity as a result of manganese accumulation within specific regions of the brain.34 The need for stable complexes has prompted evaluation of manganese(III) porphyrin complexes, isolated in the form [MnCl(por)] (por\tetraphenylporphyrins with polyhydroxyamide substituents).These dissociate in water to give [Mn(H 2 O) 2 (por)]`, in which exchange of water molecules leads to enhanced proton relaxation rates.Unfortunately the complexes are too toxic for clinical use.35 Manganese( III) [as well as Gd(III), see below] interacts with phosphate-containing ligands including ATP, leading to possible use to enhance spin relaxation in 31P as well as 1H MRI.36 The ability of manganese to catalyse dismutation of the highly toxic superoxide radicals (HOO·) to hydrogen peroxide and dioxygen (superoxide dismutase- or SODlike activity) is of interest to minimise the toxic e§ects of radicals produced by radiation and inflammation/autoimmune disease.The in vivo anti-inflammatory e§ect of a manganese(III) complex with tetrakis(4-benzoic acid)porphyrin has been attributed to SOD-like activity of the complex and possible scavenging of peroxynitrite ions.37 The crystallographically characterised manganese(II) complex [Mn(ntb)(Hsal)]` also shows SOD-like activity in vitro.38 8 Iron Formulations with improved bioavailability and reduced toxicity for the supplementation of dietary iron are being sought.Phospholipid-encapsulated ferrous sulfate is an example.39 Other applications of iron are closely analogous to those of manganese in that they arise from magnetic properties and interactions with reactive oxygen species.Iron is believed to be an essential co-factor in the cytotoxic activity of the anti-cancer drug bleomycin, which catalyses production of reactive oxygen species in close proximity to DNA. The role of individual domains of the bleomycin molecule has been revisited.This has resulted in improved understanding of the modular design, including the nature and role of the iron-binding site,40 the pyrimidine group,41 the threonine side-chain,42 the bithiazole moiety,43 and the valeric acid linker.44 Iron complexes of salicylic acid45 and bis(salicyl)glycine46 participate in the generation of toxic radical species. In the latter case this induces DNA damage and lipid damage in the presence of sulfite, possibly via formation of the sulfuroxyl radical.It is suggested that such processes may contribute to the biological toxicity of iron. Iron-chelating agents such as pyridoxal isonicotinoyl hydrazone47 have been shown in vitro to protect against such damage induced by ‘‘free’’ (i.e. weakly chelated) iron.On the other hand, iron complexes may also protect against radical damage by demonstrating SOD-like activity, exemplified by a series of iron(III) complexes of pentaazamacrocyclic ligands [FeCl 2 L]~ Mwhich probably exist as [Fe(H 2 O) 2 L]` in aqueous solutionN.48 The magnetism of iron compounds can be exploited in drug targeting by combining drugs with magnetic materials such as metallic iron, iron oxides and ferrites, and then Annu.Rep. Prog. Chem., Sect. A, 1999, 95, 631–655 633magnetically guiding the particles to the target site. This area has been reviewed.49 The magnetic properties of iron (synthetic iron oxides or the ferroprotein ferritin50) find application as contrast agents in MRI. Iron oxide particles conjugated to transferrin accumulate selectively in rat mammary carcinomas, leading to a significant (40%) localised decrease in MRI signal, thus allowing in vivo detection of tumours.51 Another developing application of magnetic iron-containing materials is the treatment of tumours, by using an alternating external magnetic field to induce hyperthermia in tissue to which magnetite particles, contained within cationic liposomes, have been delivered.52 Complexes of iron, especially ferrocene derivatives, have previously been shown to exhibit carcinostatic properties, and 4-ferrocenylbutanoic acid has been coupled reversibly (via amide bond formation) to water-soluble polymers bearing pendant amine groups, to give carcinostatic conjugates.53 The discovery of the biological importance ofNOhas led to renewed interest in its metal complexes, both as agents to lower tissue NO concentration in patients with toxic shock and to deliver it selectively to tumours so that, upon release by photolysis, it can sensitise the tissue to radiotherapy.Iron complexes being evaluated for this application include the Roussin salts [Fe 2 S 2 (NO) 4 ]2~ and [Fe 4 S 3 (NO) 7 ]~ and iron nitrosyl porphyrin complexes.54 9 Cobalt In previous years complexes of Co(III) containing mustard-like ligands have been described as part of a programme to design hypoxia-activated prodrugs for cancer treatment.The complexes are designed to release active nitrogen mustard groups upon reduction (selectively in hypoxic tissue) from kinetically inert Co(III) to labile Co(II). This programme has continued with the synthesis of dithiocarbamate complexes [Co(R) 2 L]` [L\N,N-bis(2-chloroethyl)ethylamine diamine or N,N@-bis(2-chloroethyl) ethylenediamine, R\diethyl-, dimethyl-, or pyrrolidine-dithiocarbamate].Although previous complexes have shown hypoxia-selective cytotoxicity, these complexes do not because the re-oxidation of the reduced species by O 2 is too slow to compete with release of the mustard.55 Use of the b`-emitting radionuclide 57Co for positron emission tomography (PET) applications has been reported.It is proposed that cobalt, administered as CoCl 2 , mimics the distribution of calcium, which is deposited at sites of tissue damage resulting from ischaemia. This o§ers the opportunity to image these sites in vivo, and imaging of ischaemic brain damage in stroke patients56,57 has been reported.Use of 57CoCl 2 to radiolabel lymphocytes for imaging inflammatory processes in vivo has also been reported.58 10 Nickel Antifungal activity of nickel complexes has been demonstrated by preliminary studies with crystallographically characterised complexes of glycoside-containing triamine ligands, which inhibit growth of the pathogenic yeast Candida albicans.59 Annu.Rep. Prog. Chem., Sect. A, 1999, 95, 631–655 63411 Copper The ability of copper complexes to interact with reactive oxygen species has led to possible uses in both sensitising tissues to, and protecting them from, radical damage. The Cu(II) complex of nitrilotriacetic acid increased the levels of reactive oxygen species in cancer cell culture suspensions, and induced DNA fragmentation and apoptosis.60 Likewise, DNA damage to human fibroblasts, induced by the combination of gallate and copper(II), was ascribed to reactive oxygen species.61 A copper complex of famotidine caused DNA damage in the presence of sulfite, possibly due to generation of sulfoxyl radicals.46 Protection against radical damage is the impetus for studies of the SOD-like activity of copper complexes of thiosemicarbazones and bis(thiosemicarbazones),62 cyclic peptides [cyclo-(Gly-His) 4 and cyclo-(Gly-His- Gly) 2 ],63 and bis(Schi§ base) ligands,64 and imidazolate-bridged dinuclear complex.65 Copper complexes also demonstrate inherent cytotoxic properties.Thiosemicarbazone ligands feature again here as they have previously, with thiosemicarbazone derivatives of 5-formyluracil66 and 2-formylpyridine67 each forming ternary complexes with Cu(II) which were subjected to in vitro cytotoxicity tests.The cytotoxic series of copper(I) bis(diphosphine) complexes is extended to include [Cu(dppe) 2 ]Cl, which was conspicuously missing from earlier studies.68 Bis(1,10-phenanthroline)copper69 and bis(acetato)bis(1-methyl-4,5-diphenylimidazole)copper(II)70 both induced DNA scission, leading to suggested applications as anti-tumour agents.Copper complexes of the phenothiazine drug trifluoperazine can inhibit the multi-drug resistance phenotype in both bacteria and mammalian lymphoma cells. The e§ect was greater than that seen with trifluoperazine itself and may reflect inhibition of both the induction of the gene expression and of the eßux pump itself.71 Potential applications of copper in drug delivery/release include the use of ternary complex formation to link immunogens, used for vaccination, to water-soluble polymers via a copper ion bridge.Bovine serum albumin, as a model immunogen, was more immunogenic in this form than alone when administered to mice.72 A prolongedrelease implant formulation for basic fibroblast growth factor was developed by ternary complex formation in which copper ions bridge between the amylopectin hydrogel matrix and the protein drug.73 Several copper radionuclides for both PET imaging and therapy, especially 64Cu (t 1@2 \12 h), are becoming more widely available.The radiotherapeutic e¶cacy and toxicity of the small somatostatin-receptor targeting peptide octreotide, labelled with 64Cu via the well-known macrocyclic bifunctional chelator teta, showed promise in tumour-bearing rats.74 67Cu-labelled monoclonal antibody Lym-1 showed a high therapeutic ratio in patients with non-Hodgkin’s lymphoma.75 The di¶culty in obtaining a reliable supply of 67Cu remains the main obstacle to routine adoption of this promising therapeutic approach.The redox properties of copper have been exploited in the development of PET imaging (and potentially therapeutic) agents selective for hypoxic tissue: two series of complexes based on tetradentate bis(thiosemicarbazone) and Schi§-base ligands show hypoxia selectivity in mammalian cells in vitro,76 and structure–activity relationships have been identified that link hypoxia selectivity, Cu(II)–Cu(I) redox potential and alkyl substitution pattern.77 Another approach suggested for targeted radionuclide therapy for hypoxic tumours combines the hypoxiaselective drug tirapazamine with copper radionuclides, although this report does not Annu.Rep. Prog. Chem., Sect. A, 1999, 95, 631–655 635appear to contain any experimental data.78 Two new monocationic radiocopper complexes79,80 have been synthesised and evaluated in animals as myocardial imaging agents but are insu¶ciently lipophilic to show the required level of myocardium uptake. A series of macrocyclic chelators for linking copper to biomolecules has been evaluated to find those with the most appropriate e§ects on conjugate biodistribution. Among the series examined, those which were anionic by virtue of carboxyl group substitutents (teta) would prove most suitable because these were more e¶ciently cleared than cationic complexes.81 Understanding of the in vivo processing of copper ions is important to the design of copper radiopharmaceuticals. In mice injected with 64Cu2`, initial accumulation in liver (mostly bound to metallothionein) was followed by transport out of the liver into other tissues including tumours.82 12 Zinc Much of the use of zinc is concerned with supplementing body/tissue concentrations of Zn2` for incorporation into enzymes such as metalloproteinases and transcription factors.These are important in tissue-remodelling and cell division (wound healing, etc.).Recent studies have addressed e¶cacy of topical formulations (zinc ointments for skin disorders,83 zinc lozenges for reducing the duration of common colds,84 and oral zinc supplements85–87). Zinc has also been used in the preparation of controlledrelease forms of protein drugs including hirudin (anti-coagulant) and insulin, by complexing Zn2` with the proteins.88 The earlier discovery that a zinc complex with 3,5-dips, of unknown structure, has anti-convulsant activity has been followed up with a crystal structure determination of the dimethyl sulfoxide adduct [Zn(3,5- dips) 2 (dmso) 2 ].The latter was found to prevent seizures and to reduce radical generation by activated granulocytes.89 13 Gallium The main value of gallium stems from the properties of its radionuclides 67Ga (a c-emitter used for imaging lymphoma and inflammation) and 68Ga (a generatorproduced positron emitter).The similarity of gallium and iron has led in the past to imaging of iron transport processes such as transferrin receptor activity in tumours. Experiments addressing the mechanism of this targeting using gallium citrate (the structure of which has been determined90) broadly confirm the suggestion that transferrin receptors play an important role in the process.91 The iron analogy leads to the use of iron chelators (such as desferrioxamine92) both as bifunctional chelators to label targeting agents with gallium radionuclides, and as an aid to clearance of non-tumour bound gallium to improve tumour imaging.93 The radionuclides (particularly 68Ga) are of interest as labels for non-iron-related imaging agents also.This has led to new developments in bifunctional chelators for gallium (such as 1,4,7-triazacyclononane-1- succinic acid-4,7-diacetic acid94) and in production of the parent radionuclide 68Ge.95 Complexation and structural studies with chelators tris(2-mercaptobenzyl)amine and tris(2-hydroxybenzyl)amine96,97 have been reported.A chelate of 68Ga was used as a hapten in a pre-targeting approach, using a bi-specific antibody with one arm specific Annu. Rep. Prog. Chem., Sect. A, 1999, 95, 631–655 636for a human colon carcinoma antigen and the other specific for one enantiomer of the gallium chelate, leading to improved PET detection of tumours.98 14 Selenium Selenium has long been of interest for possible cancer chemopreventive e§ects, largely assumed to be due to its role in the anti-oxidant enzyme glutathione peroxidase.Recent studies suggest that selenium compounds may increase oxidative stress as well as relieve it.99 Sodium selenite has been found to be an e§ective prophylactic treatment for erysipelas (a Streptococcal infection of the skin) in patients with secondary lymphoedema after cancer surgery.100 15 Rubidium The spin of the 87Rb nucleus (natural abundance 28%, I\3/2) stimulated interest in imaging rubidium distribution in myocardium (in which it is accumulated by mimicking potassium and hence acting as a substrate for the Na/K-ATPase pump) after intravenous administration.Preliminary experiments in isolated hearts suggest that di§erences in Rb` uptake in normal and ischaemic myocardium are su¶cient to detect by MRI, suggesting possible future applications as a diagnostic agent in cardiology. 101,102 16 Strontium The b-emitting radioisotope 89Sr has been in use for many years for the relief of pain associated with bone metastases in cancer patients. It has also been shown that stable strontium administered to rats inhibits carcinogenesis.103 17 Yttrium The b-emitting radionuclide 90Y is one of the leading metallic radionuclides finding applications in targeted radionuclide therapy of cancer, attached via bifunctional chelators to targeting agents such as octreotide104–106 and other peptides which bind to somatostatin receptors and are internalised,104 and monoclonal antibodies.107–112 These conjugates are giving very encouraging results in preliminary clinical and animal evaluations.104,105 Although the widely used dota ligand104–106 forms a chelate with acceptable in vivo kinetic stability, and labelling conditions have been optmised,108 design of new bifunctional chelators has continued.Designs being evaluated include backbone-linked (rather then carboxyl group-linked) derivatives of diethylenetriamine pentaacetic acid,107,112,113 and linker groups that are cleavable in vivo.109,110 A modular delivery system is reported whereby a dota–adenine conjugate labelled with 90Y(or 111In) is injected after pre-adminsitration of a bi-specific antibody that recognises both a tumour antigen and the conjugate.114 Annu.Rep. Prog. Chem., Sect. A, 1999, 95, 631–655 63718 Molybdenum NMR experiments suggest that the anti-tumour activity of molybdocene dichloride [MoCl 2 Cp 2 ] is unlikely to be due to direct interactions with DNA, and other mechanisms must be sought.115 Tetrathiomolybdate [MoS 4 ]2~ reduces the excess copper burden in the livers of LEC rats (a model for Wilson’s disease) o§ering a means of treating Wilson’s disease and copper overload, probably by formation of aMo–S–Cu complex.116 19 Technetium Development of applications of 99.Tc in medical imaging agents continues to be a major part of the inorganic pharmaceuticals field and has been reviewed.117 The developments reported here are categorised into ‘‘technetium-essential’’ tracers (small molecules), ‘‘technetium-tagged’’ tracers (in which the targeting is largely dependent on the carrier molecule), and new technetium cores and chelators.A major area of investigation of Tc-essential tracers is the use of lipophilic cations such as [Tc(mibi) 6 ]` 118–123 and analogues,124,125 [TcO 2M(EtOCH 2 CH 2 ) 2 - PCH 2 CH 2 P(CH 2 CH 2 OEt) 2N2 ]`,120,126 and [Tc(PR 3 ) 2 L]`120,127,128 for imaging myocardium,122,128,120 tumours,119,120,124,126 and assessment of tumour multi-drug resistance.127,125,119 Progress in applications129,130 and tumour targeting mechanisms of the ‘‘pentavalent technetium dmsa complex’’ [TcO(dmsa) 2 ]~131 has been reported, leading to the suggestion that it may be a marker of low tissue pH.132,133 The range of tracers that cross the blood–brain barrier, for cerebral perfusion imaging, has been extended and the mechanisms of brain retention of existing agents [TcO(ecd)] (intracellular ester hydrolysis)134 and [TcO(L)] ML\Me 2 C[CH 2 NHCH(Me)C(Me)–– NOH]N (possible intracellular reaction with thiols)135,136 have been further investigated.New lipophilic complexes based on the TcO3` bis(aminoethane)thiol137 and TcO 2 ` cyclam138 cores have been reported.A long-standing problem with [99.TcO(L)] ML\Me 2 C[CH 2 NHCH(Me)C(Me)–– NOH]N is autoradiolysis, and reports of kit modifications to improve stability continue to appear.139–141 99.Tccomplexes target ischaemic tissue in humans, either because of the oxygen deficiency in these regions M99.Tc–[HON––C(Me)C(Me) 2 NH] 2 (CH 2 ) 4 142N or because of the resulting increased activity of sugar transporters (99.Tc–glucarate complex143).A kit for preparing 99.Tc–ethylenediamine tetrakis(methylenephosphonate) (edtmp) as a new bone imaging agent,144 and optimal conditions for preparation of the uncharged myocardial imaging agent [99.TcN(noet) 2 ], have been reported.145 Synthesis and biodistribution of a 99.Tc complex purportedly containing the disulfide of penicillamine has been reported.146 A number of technetium-tagged targeting agents have been reported, in which 99.Tc is conjugated to cyclic glycoprotein IIb/IIIa receptor antagonist,147 monoclonal antibodies,148–152 oligonucleotides,153,154 dopamine transporter ligands,155–157 peptides,158–165 nicotinamide,166 synthetic polymers,167 endogenous natural surfactant,168 biocytin and biotin.169,170 These have applications or potential applications in imaging tumours,149–154,158,160,161,165,170,171 neurodegenerative disease, 155–157 atherosclerosis,159 inflammation,162 hypoxia,166 blood pool,167 liver Annu.Rep. Prog. Chem., Sect. A, 1999, 95, 631–655 638function169 and the alveolar delivery of aerosolised drugs.148,168 The chemists’ contribution is largely concerned with developing simple and e¶cient methods of linking 99.Tc to the carrier molecule.Progress has been made both in direct binding of 99.Tc to the carrier,148,149,151,158,159,171,172 and in bifunctional linker design. New bifunctional linkers include designs based on diaminodithiols,155–157,161,162 mercaptoacetyltriglycine and analogues,152–154,160,165,169,170 dtpa,167 monodentate thiol,166 cyclopentadienyl,164 hydrazinonicotinamide with various co-ligands,163,147 dithiocarbazate,173 and metallothionein.150 Advances in design of liposomes for delivery of encapsulated 99.Tc have been reported.174,175 Electron microscope studies of the carbon-particle based aerosol Technegas (used for lung ventilation imaging) shows that the 99.Tc label does not a§ect the ultrastructure of the particles.176 The development of novel technetium ‘‘core complex’’ types has continued in a number of directions. The ‘‘3]1’’ approach, developed over the last few years [comprising the 99TcO3` core, a monodentate thiolate ligand and a tridentate ligand E(CH 2 CH 2 SH) 2 where E\S or NR] has for the first time been successful at the carrier-free level with 99.Tc.177 The complexes are remarkably stable in vivo.178 However, they may be subject to intracellular trapping mechanisms by substitution of the monodentate thiolate, suggesting possible applications in brain imaging.179 Another developing theme is the use of chelating and non-chelating organohydrazine, isodiazene and related ligands, demonstrated by the prototype 99Tc complexes [TcCl 3 (N–– NPh 2 )(PPh 3 ) 2 ],180 [TcCl 2 (NO)(g2-HN–– NC 5 H 4 N)(PPh 3 )],181 [TcCl(NO)(g2-N–– NR)(PPh 3 ) 2 ] (R\trifluoromethylpyrimidine),181 [TcCl 3 (g1- N––NC 5 H 4 N)(g2-HN––NC 5 H 4 N)],182 and [Tc(pyS) 2 (g1-N–– NC 5 H 4 N)(g2-HN––NC 5 - H 4 N)],182 which serve as models for the co-ordination of 99.Tc by the hydrazinonicotinamide ligand used to link technetium to peptides. The well-known high kinetic stability of the technetium(I) and rhenium(I) tricarbonyl cores led to progressively milder routes to technetium carbonyl complexes suitable for radiopharmaceutical application, culminating in simple synthesis of the reactive tris(aqua) species [Tc(H 2 O) 3 (CO) 3 ]`.183 This can be easily coordinated to a range of tridentate chelators such as macrocyclic thioethers184 for linkage to carrier molecules.A technetium(I) carbonyl has also been used to synthesise a benzodiazepine complex [Tc(CO) 2 (PPh 3 ) 2 L] (HL\1,4-benzodiazepine-2-one or 1,2-benzodiazepine-2- thione).185 The interaction between TcO3` and cysteine (H 2 cys) has been further elucidated by demonstrating that in [TcO(cys) 2 ]~ the co-ordination sphere comprises the oxo-group, two thiolate sulfurs, two amine groups, and one carboxylate.186 New polydentate N/O ligand complexes of 99.Tc chelated by N,N@-bis(2-aminoethyl)propane- 1,3-diamine hexaacetic acid187 and N,N-bis(benzohydroxamamide) alkane-x,ydiamine (alkane\1,2-ethane or 1,3-propane)188 have been reported though not structurally characterised. 20 Ruthenium Anti-cancer activity of ruthenium complexes has been reviewed.189 Reactions of a Ru(III) complex [RuCl 2 (pdta)], that shows anti-cancer properties, with water and proteins have been investigated to help elucidate possible mechanisms of action.190 Interactions between ruthenium polypyridyl complexes and DNA have been inves- Annu. Rep. Prog. Chem., Sect. A, 1999, 95, 631–655 639tigated.191 The ability of ruthenium porphyrin nitrosyl complexes to releaseNO upon photolysis o§ers the potential for tissue selective delivery of NO.54 Among a series of transition metal (Ru, Rh, Pt, Au, Cu) complexes of ctz, investigated as anti-trypanosome agents, the ruthenium complex [RuCl 2 (ctz) 2 ] proved most active and its mechanism of action has been investigated.192 21 Rhodium A series of Rh(III) chloride adducts with imidazole and NH 3 ligands, including trans- [RhCl 4 (im) 2 ]~ which has been structurally characterised, has been investigated for cytotoxicity following the observation that their ruthenium analogues have anticancer properties.193 The DNA-intercalating ability, and e§ects on helix structure, of a rhodium phenanthrene derivative have been elucidated by molecular dynamics calculations. 194 22 Palladium Binuclear palladium complexes [MPdCl(diamine)N2 L] (where L is a briging bidentate ligand) analogous to cytotoxic platinum complexes (see below) have been synthesised and screened for cytotoxic activity.195 23 Silver The principal pharmaceutical value of silver compounds is based on the long-established antimicrobial properties, exemplified by topical treatments such as silver sulfadiazene for prevention of infection of burns.Combination treatment with this compound together with other antimicrobials including cerium nitrate was found to o§er no improvement in anti-microbial e¶cacy in vitro.196 Antimicrobial co-ordination polymers of silver, [AgL]n and [Ag(PPh 3 ) 2 L]n (L\1,2,3- or 1,2,4-triazole) have been structurally characterised.197 Other new developments in antimicrobial use involve incorporation of silver into polymeric materials198 and surfaces of medical and surgical devices (wound dressings,199 catheters,200 hydroxyapatite and other coatings for prostheses201–204) for prolonged antimicrobial e§ect in vivo.Silver has some radioisotopes with attractive properties (e.g. 111Ag) for radionuclide therapy but the applications have been hampered by the challenge of finding a kinetically inert chelating system for bioconjugates synthesis. A macrocyclic thioether–amine ligand has been reported to complex silver with high stability205 o§ering a potential solution to this problem. The insolubility and high atomic weight of silver halides is exploited in the use of silver iodide particles as a radio-opaque contrast agent for radiography.206 Annu.Rep. Prog. Chem., Sect. A, 1999, 95, 631–655 64024 Indium All reported pharmaceutical uses of indium involve either radionuclide imaging or radionuclide therapy. Indium-111 is routinely used in labelling proteins and other macromolecules for imaging (e.g. 111In-labelled octreotide analogues). New examples (usually labelled with use of the diethylenetriaminepentaacetic acid anhydride bifunctional chelator) include conjugates of biotin for ‘‘pre-targeting’’,207,208 disulfide crosslinked anti-myosin F!" antibody fragment aggregates,209 and folate.210,211 An important area of investigation is the metabolic fate of the radiolabel during the intracellular catabolism of the carrier peptide or protein, since this a§ects the residence time of the radiolabel within the tissue.Several studies in this area indicate that the indium–dtpa chelate remains intact linked to the amino acid (usually lysine) to which it was originally bound, while the remainder of the protein is broken down around it. The chelate then shows prolonged intracellular retention in target tissue212,213 or kidney. 214 Interposing a cleavable group between the chelator and the protein can facilitate or enhance clearance of radioactivity from non-target tissues.215 As well as emitting gamma photons, 111In emits Auger electrons which are highly cytotoxic when emitted close to DNA. 111In-labelled octreotide is therefore being clinically evaluated for treatment as well as imaging of tumours.Also, when 111In is bound to the metal-binding site of bleomycin to irradiate the DNA, cytotoxicity is greater than for the bleomycin alone or ‘‘free’’ 111In.216 25 Tin Tin compounds are an important class of antifungal agents and new compounds under evaluation include [SnR 2 Cl(tscz)]217 and [SnR 3 X] (X\Schi§ base derivative of x-amino acids, linked to Sn via the carboxylate group).218 Related complexes have also been screened for anti-cancer activity.219,220 Tin (stannous salts) is also important as a reducing agent in 99.Tc radiopharmaceutical kits, and methods of protecting it against aerial oxidation,221,222 and analysing it as Sn(II) in the kits,223 have been reported. Tin also has radionuclides that are useful in their own right as therapeutic radiopharmaceuticals: 117.Sn–dtpa complex is being developed as a palliative treatment for painful bone metastases in cancer patients.224,225 26 Samarium Samarium is of interest for its therapeutic radionuclide 153Sm, which as a chelate with ethylenediaminetetrakis(methylenephosphonate) is a lead radiopharmaceutical for palliative treatment of bone metastases.226,227 A number of cyclic and acyclic nitrogen/ oxygen donor chelators have been evaluated for possible application in future therapeutic conjugates of 153Sm.228 27 Gadolinium The Gd3` ion is highly paramagnetic and hence gadolinium compounds have become Annu. Rep.Prog. Chem., Sect. A, 1999, 95, 631–655 641the most important class of paramagnetic contrast enhancing agents for magnetic resonance imaging.229 The prototypical complex is the dtpa chelate [Gd(dtpa)- (H 2 O)]2~ (‘‘gadopentetate’’), which is in routine clinical use230–232 for determination of various physiological parameters by dynamic MRI.New developments include incorporation of the dtpa complex into a variety of vehicles to modify biodistribution, including polymers of varying molecular weight,233,234 red blood cells,235 complexes that bind to albumin236 and lipid nanoparticles.237 E§orts are underway to increase the relaxivity of contrast agents to provide greater sensitivity, by modifying the spin properties [using di- and tri-nuclear complexes such as Fe(III)–Gd(III),238 V(IV)–Gd(III)239 and Gd(III) 3 240 complexes).An alternative approach is to increase the rate of either exchange of co-ordinated water molecules (e.g.by designing chelates with more than one co-ordinated water molecule241,242) or exchange of protons between co-ordinated and outer-sphere water molecules.243,244 Other approaches to contrast agents include porphyrin complexes incorporated into liposomes,245 and dota and dtpa conjugates with fluorescence agents for dual optical/MRI detection.246 Gadolinium is also of interest for its neutron capture cross section, which, like boron, o§ers the potential for neutron capture therapy of cancer if the gadolinium can be deposited within tumours in su¶cient quantity e.g.by means of microcapsules/ microspheres.247,248 28 Other lanthanides Radionuclides of holmium (166Ho), erbium (165Er) and lutetium (177Lu) are finding applications in diagnostic and therapeutic nuclear medicine.A complex of the b- emitter 166Ho with the modified biopolymer chitosan has been synthesised for intraarterial delivery to tumours.249 165Er decays by electron capture with emission of a low energy X-ray rendering it ideal for radioguided surgery, while 177Lu is a b-emitter with therapeutic potential.Both form chelates with edtmp that are taken up in bone metastases and some soft tissue metastases.227,250 Polyaminocarboxylate and polypyridyl ligands have been evaluated as bifunctional chelators for 177Lu for targeted delivery.228 29 Rhenium The use of b-emitting radionuclides 186Re and 188Re for targeted radionuclide therapy provide the main impetus for the pharmaceutical chemistry of rhenium.Much of the chemistry is done in parallel with technetium (see above). Recent developments in rhenium radiopharmaceutical chemistry have been reviewed.128 Interest in therapy with rhenium has heightened recently. This is reflected in improvements in calibration of radionuclide measuring devices for use with rhenium radionuclides.251,252 New applications outside oncology, e.g.use of 188Re (either as a solution of perrhenate253 or as electrodeposited rhenium metal254) in cardiology to prevent re-stenosis after balloon angioplasty, are being investigated. Developments in both ‘‘rhenium-tagged’’ and ‘‘rhenium-essential’’ vehicles have been reported. The rhenium-tagged class includes antibodies and antibody fragments with rhenium Annu.Rep. Prog. Chem., Sect. A, 1999, 95, 631–655 642directly attached, as Re(V) bound via reduced disulfide bonds.255–257 Progress in understanding the co-ordination around rhenium ReO3` in this mode of labelling has been made through structural studies of rhenium complexes with the small peptides Gly-Gly-Cys and Cys-Gly.258 Rhenium-188 has been attached directly to microspheres for intra-tumoral injection259 and radiation synovectomy,260 again by reduction of perrhenate with stannous chloride.For coupling to biomolecules, development of new bifunctional chelating systems continues, including tridentate S-methyl-2- methyldithiocarbazate amino acid conjugates,173 and tetradentate ligands containing thiolate/amide/thioether donors261,262 for chelating ReO3`.The ‘‘3]1’’ approach described above for technetium has also been further developed with rhenium. It provides access to a wide range of uncharged and cationic263 complexes, with targeting moieties bound to rhenium through a monodentate thiol,264 for targeting dopamine transporters265 and steroid hormone receptors.266 Somewhat analogous is the use of tridentate phosphinodithiolate ligands to chelate the ReO3` and Re3` cores.267 A new bis(amido)bis(thiolate)N 2 S 2 chelating system incorporating an (uncoordinated) histidine group268 has been reported.Complexes containing 2-hydrazinopyridine ligands, analogous to those discussed above for technetium, have been characterised.182 A new bifunctional chelator for ReO3` has been developed comprising 1,3,5-triamino-1,3,5-trideoxyinositol with pendant arms, and used for antibody fragment labelling.269 Rhenium analogues of technetium-essential tracers, including [188ReO(dmsa)] 2 ~270–273 and hydroxyethylidine diphosphonate complexes270,271,274,275 are being developed and evaluated for palliative treatment of bone metastases and soft-tissue tumours.Rhenium oxo-complexes with diaminodithiolate ligand sets provided by cysteine,186 D-penicillamine methyl ester,276 and 2,9-dimethyl-4,7-diaza-2,9-decanedithiol277 have been characterised.The use of water-soluble phosphines as ancillary ligands in chelation of rhenium isotopes has been suggested.278 30 Platinum Anti-tumour properties of platinum complexes are the most important themes of inorganic pharmaceuticals when judged by numbers of papers published.The topics currently being developed may be divided into four main areas: in vivo studies of e¶cacy; mechanisms of biological activity; incorporation into various controlled release formulations; and new chemistry. Several clinical and animal studies of e¶cacy and side-e§ects of platinum drugs (cisplatin,26,279,280 carboplatin,281–284 nedaplatin285,286 and oxaliplatin287) in combination with other drugs, have been reported.The major area of activity in the understanding of mechanisms of cytotoxicity is the structural and kinetic study of interactions beween platinum and DNA and the resulting changes in DNA structure.288–298 As well as structural changes caused by direct binding, cisplatin induces superoxide radical formation and this e§ect is enhanced by hyperthermia, providing a possible rationale for the hyperthermic enhancement of cisplatin therapy in vivo.299 Cisplatin can also interfere with repair of DNA double strand breaks induced by radiation, suggesting a way in which radiotherapy and cisplatin treatment can augment each other.300 Toxicity mechanisms that are not necessarily DNA-related have also been inves- Annu.Rep. Prog. Chem., Sect. A, 1999, 95, 631–655 643tigated. The kinetics of ligand substitution (relevant to intracellular delivery and binding to biomolecules) in platinum drugs have been examined,301–304 and the pK!’s of some known in vivo reaction products have been determined.305 The reaction of cisplatin with oxidised glutathione306 and methionine307 are both relevant since these interactions appear to contribute to toxicity.308 The distribution and speciation (protein binding, etc.) of platinum in the body after treatment with platinum drugs has been investigated,309 analytical methods for these studies have been compared310–312 and a tritium-labelled form of oxaliplatin has been reported to support such studies.313 Additional physiological e§ects of platinum drugs include enzyme inhibition properties (erythrocyte acetylcholinesterase314,315), apoptosis induction in certain cell lines,316,317 and enhanced immune system activation.318,319 Since platinum(IV) complexes have become established as a new class of anti-cancer drugs, discussion has arisen over whether they act as prodrugs for platinum(II) species, by intracellular reduction.320–322 The search for orally active platinum drugs has generated studies aimed at optimising gastrointestinal absorption.323 The stability of various platinum drug formulations (infusions of cisplatin324,325 and carboplatin,326,327 either alone or in combination with other drugs) has been determined.With platinum-based drugs firmly established, attention has also turned to development of new dosage forms o§ering improved drug release and delivery properties.Platinum complexes have been incorporated into water-soluble, biodegradable polymeric microsphere carriers for direct injection or implantation into tumours.328,329 Microsphere materials include polyacetamide,53 poly(L-lactic acid),280,330 poly(DLlactic- co-glycolic acid),331,332 albumin,333,334 dextran,335,336 hydroxypropylmethacrylamide337 and hydroxyethylcellulose.338 Implants made of apatite cement mixed with cisplatin have also been evaluated.339 Liposomes340,341 have been used to encapsulate platinum drugs, and the permeation of platinum drugs through various polymer membranes has been measured as a basis for controlled release devices.342 Approaches for targeting specific tissues include attaching the platinum complex to poly(organophosphazene) to which is also attached a b-galactosyl group,343 and incorporating cholylglycinate into the Pt co-ordination sphere.344,345 Both provide selectivity for liver.A novel method of increasing cisplatin uptake, and hence e§ectiveness, into tumour cells was application of electrical pulses (electrochemotherapy) to the tumour at the time of intra-tumoural injection.346 The need for cytotoxic platinum complexes that have reduced side-e§ects (e.g.neuro- and nephro-toxicity) and can circumvent platinum drug resistance has led to synthesis of new types of platinum complexes for cytotoxicity screening, including those that retain the cis-diammine Pt(II) core M[PtCl(NH 3 ) 2 (L)]` (L\procaine)347,348N. Others are based on Pt(II) 1,2- and 1,3-diamine chelates,349 including ester- (for intracellular trapping by hydrolysis350), phenylquinoline- (for DNA intercalation351), or cyclodextrin-functionalised derivatives,352 [PtCl(diamine) L]` (L\thiourea derivative353,354), and [Pt(diamine)(L) 2 ] (L\acyclovir).355 Other Pt(II) complexes reported include sterically hindered complexes [PtCl 2 - (NH 3 )L]356 and [PtCl 2 L 2 ]357 (L\sterically encumbered pyridine or pyrimidine), [PtX 2 (dmso) 2 ] (X\halide or carboxylate358), [Pt(L)(PMe 3 ) 2 ] (L\glycolate; phosphine analogue of nedaplatin359), [PtCl 2 L] (L\thiosemicarbazone derivative360), [PtCl 2 (H 2 C––CH 2 )(R)] (R\pyroxicam),361 and [PtBr 3 (R)]~ (R\benzothiazole).362 Binuclear,363–366 trinuclear367 and tetranuclear368 Pt(II) complexes have also been Annu.Rep. Prog. Chem., Sect. A, 1999, 95, 631–655 644synthesised with the aim of enhancing cytotoxicity by cross-linking DNA strands. Despite the recent recognition of the potential for drugs based on Pt(IV), there are relatively few reports of new Pt(IV) complexes.They include [PtCl 2 (dach) 2 L 2 ] (L\carboxylate)369 and Pt(IV) complexes with carbohydrate ligands.370 31 Gold Gold complexes have been used in arthritis treament for many years and are now being evaluated for anti-cancer purposes as well. Crystallographic studies with antiarthritic drugs have revealed the solid-state structures of gold thiomalate (myochrysin) 371 and an analogue of auranofin, [Au(PR 3 )L] (L\2,3,4,6-tetra-O-acetyl-1- thio-b-glucopyranoside, R\1-ethyl-2-isopropylimidazole).372 The latter was designed to interact with hard metals via the phosphine imidazole groups.Square planar cis-dichlorogold(III) complexes analogous to platinum(II) anti-cancer drugs have shown good cytotoxicity in vitro against cisplatin resistant cell lines.373 Polyamine complexes [Au(en) 2 ]3`, [AuCl(L)]2` (L\1,5-diamino-3-azapentane), and [Au(cyclam)] 3` were also synthesised for evaluation as anti-tumour agents.374 A number of Au(I) phosphine and diphosphine complexes have also been evaluated in an in vitro cytotoxicity screen.375 The b-emitting gold radionuclide 199Au is of interest for targeted radionuclide therapy, and a series of Au(I) complexes with water-soluble monodentate and bidentate phosphines P(CH 2 OH) 3 , (HOCH 2 ) 2 PCH 2 CH 2 P(CH 2 OH) 2 and (HOCH 2 ) 2 P(C 6 H 4 )P(CH 2 OH) 2 has been reported.Only the latter ligand gave a complex [Au(diphos) 2 ]` that showed adequate in vivo stability.376 32 Lead Lead is of interest for its therapeutic radionuclide 212Pb and its imageable c-emitting analogue 203Pb.The former decays by b-emission to 212Bi, which itself then rapidly decays by a-emission. This combination o§ers excellent cell-killing potential if a chelate system capable of retaining the lead during the decay to 212Bi can be designed. The dota ligand provides such a chelator and can be used to conjugate the lead radionuclides to antibodies.377,378 33 Bismuth Anti-ulcer treatments containing bismuth have been used for many years.The complex equilibria and dynamics of these bismuth complexes (e.g. with citrate) in solution have been investigated by NMR using 13C-labelled citrate.379 A formulation containing both bismuth and the antibiotic ciprofloxacin has been described for evaluation as a treatment for the stomach ulcer-causing bacterium Helicobacter pylori.The compound is a salt, [H 2 cip] 2 [Bi 2 Cl 10 ] rather than a co-ordination compound.380 Bismuth has therapeutic a-emitting radionuclides 212Bi (see lead above) and 213Bi, and a Annu. Rep. Prog. Chem., Sect. A, 1999, 95, 631–655 645biotin-conjugated chelate has been synthesised for use in an avidin–biotin pre-targeting approach to tumour radionuclide therapy.381 34 Astatine Astatine has no stable nuclides and its applications are exclusively concerned with potential use in targeted radiotherapy with a-particles (211At).382 Most work on astatine has focused on the formation of At–C bonds by analogy with iodine, leading to species in which the 211At-label is bound to an aromatic ring linked to the targeting moiety.These include a conjugate with biotin (for binding to avidin pre-targeted to tumours)383 and antibody conjugates.384,385 In vitro386 and theoretical387 studies of the radiobiology of a-particles emitted by 211At are now demonstrating their extremely potent cytotoxicity.Thyroid protection strategies are also being evolved to prevent thyroid accumulation of astatide ions released from these conjugates.These include blocking uptake with thiocyanate, perchlorate, or periodate, and attempting to chelate free astatine in vivo using thiol-based chelators cysteine, 2,3-dimercaptopropanesulfonic acid and meso-2,3-dimercaptosuccinic acid.388 35 Actinium Actinium is of interest for its a-emitting radionuclide 225Ac for potential use in targeted radiotherapy, and a practicable generator system has been devised for it.382 This application has not yet been realised even in model systems because of the expected di¶culty in designing chelating agents capable of withstanding the recoil energy of the a-decay.References 1 P. 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