INTRODUCTION:

The incidence of human malignant tumor diseases is still increasing worldwide. Generally, cancer treatment can be performed using one or a combination of the following methods: surgery, chemotherapy and radiation therapy. Their side effects limit the efficiency of chemo- and radiotherapeutic agents, but can be avoided and a much more effective therapy is possible if the drugs used have tumor selectivity. Targeted radionuclide therapy, instead, is a systemic treatment that involves the injection of radioactive substances (radiopharmaceuticals) into the blood circulation¹.

The radiopharmaceuticals suited for this purpose are vehicle molecule radionuclide constructs with high tumor affinity, which can transport toxic doses of radiation to tumors and metastases. The tumor specificity of the vehicle molecule is determined by its affinity to target structures, whereas the ionizing radiation emitted by radionuclides is used to kill cancer cells. An ideal radiopharmaceutical for therapeutic purposes must have high specificity and act exclusively in the malignant tumors cells; must have accurate targeting capacity to reach all the tumor cells wherever they are localized; bring maximum doses of radiation to the tumor leaving healthy tissues and organs unscathed; eliminate malignant tumor cells with great effectiveness. This last point, essentially, depends on the radio physical properties and the ionizing radiation emitted by the radionuclide². While imaging procedures in nuclear medicine require radionuclides that will emit radiation that can penetrate the body, a different class of radionuclides possessing optimal relative biological effectiveness (RBE) is needed for radionuclide therapy. The RBE depends on linear energy transfer (LET), which is defined as the amount of energy transferred to the material penetrated by an ionizing particle per unit distance (measured in keV.μm^-1). In principle, the most suitable radionuclides for tumor therapy are those emitting radiation with short penetration into the tissue, high LET and RBE, such as α emitters or nuclides producing the Auger effect. These will also cause more intense radiation induced side effects on accumulation outside the tumor. Moreover, β emitting radioisotopes with their directly ionizing electron radiation, still offer a higher LET and RBE than γ radiation and represent an acceptable compromise between therapeutic efficacy and levels of adverse side effects.

The element rhenium (Z = 75) was discovered in 1925 by the Noddacks and is one of the rarest elements, occurring naturally as a mixture of two non-radioactive isotopes ¹⁸⁵Re (37.4%) and ¹⁸⁷Re (62.6%). The radioactive isotopes of interest in nuclear medicine are ¹⁸⁸Re and ¹⁸⁶Re with excellent properties that can be used to label many therapeutic molecules, including small molecules, peptides and despite its short half-life, monoclonal antibodies³. Both isotopes are suitable for therapeutic use by means of β-irradiation. Moreover, the secondary γ emission is well suited for imaging purpose. The short half-life of rhenium-188 would seem an unfavourable characteristic for therapeutic applications in view of the fact that a radionuclide with long physical half-life will deliver more decay energy than one with a short half-life having the same initial activity and biokinetics in the target tissue. Conversely, it was reported that higher dose rates delivered over shorter treatment times in biological tissues are more effective than lower dose rates delivered over longer periods⁴. Thus, a radionuclide with a shorter half-life will tend to be more biologically effective than one with similar emission energy but with a longer half-life; both have the same initial activity and biokinetics in the target tissue. One potential advantage of rhenium-188 over other therapeutic radionuclides, is its routine cost effective availability because of the ¹⁸⁸W/¹⁸⁸Re generator. Nevertheless, preclinical and clinical studies have demonstrated favorable pharmacokinetic and dosimetric properties for several ¹⁸⁸Re-based therapeutics⁵.

To develop new radiopharmaceuticals a promising approach is to design coordination complexes that effectively bind the metal ion and in some cases the intrinsic chemistry of the coordination complex can dictate bio-distribution. Further selectivity can be achieved by tethering the coordination complex to targeting vectors such as receptor avid molecules, monoclonal antibodies, fragment antibodies and targeting peptides. This review will focus on selected recent developments in coordination chemistry and ligand design directed toward new rhenium radiopharmaceuticals.

THERAPEUTIC RADIOPHARMACEUTICALS: THE POTENTIAL OF RHENIUM ISOTOPES:

Treatment of secondary tumours with a systematically administered radiopharmaceutical could be a useful supplement to conventional beam radiation treatment, chemotherapy and surgery. The goal is for tumour targeted in situ delivery of radioisotopes to administer a sterilising dose of ionising radiation to cancer sites. This is best achieved with α- and β-emitting (and Auger-electron emitting) isotopes. If the nuclide also emits γ-photons they can be used to simultaneously image the distribution of the therapeutic agent, although such emissions should be of low abundance so they do not increase the dose to non-target tissues⁶. The effects of ionising radiation on cells stem from modification of cellular DNA and the prime target is therefore the cell nucleus. The eventual death of the cell via apoptosis is a result of a series of complex steps that follow the original interactions of radiation with the cellular environment. Chemical reactions initiated by the radiation result in the formation of reactive species such as radicals which can alter certain cell components⁷. Since the principal target is the cell nucleus, very low energy β-emitters and Auger-emitters which have a short path length in tissue must be delivered direct to the nucleus. When higher energy β-emitters are used which have a longer range in tissue, it is not necessary to deliver the radionuclide to the nucleus but the energy of the β-emissions dictates the size of the tumour that can be treated. It is also essential to minimise irradiation of non-target tissue although “cross-fire” can be of use in non-uniform large tumour masses⁸. Ideally, therapeutic radiopharmaceuticals should locate specifically in the target area whilst causing minimum damage to normal tissues. If specific targeting molecules are used, it is essential that the radionuclide is attached in a way that the bioconjugate is sufficiently stable in vivo, the binding ability of the receptor molecule is not compromised, and that the therapeutic agent localises in the target tissue within a time frame that is appropriate for the half-life of the radioisotope. The choice of radionuclide depends on a number of factors including the nature of the emissions, half-life, ease of production, availability, the nature of the decay products, the size of the tumour, and cost. Rhenium has two β-emitting isotopes, ¹⁸⁶Re and ¹⁸⁸Re, that offer potential to be used as therapeutic radionuclides. Rhenium-186 can be produced by neutron irradiation of natural rhenium in a nuclear reactor. Since natural rhenium consists of ¹⁸⁵Re (37.4%) and ¹⁸⁷Re (62.6%) this process leads to a considerable impurity of ¹⁸⁸Re, the shorter half-life means that ¹⁸⁸Re can be removed by allowing it to decay but this also results in considerable loss in activity of the desired isotope. Higher specific activities can be obtained by using isotopically enriched ¹⁸⁵Re. ¹⁸⁶Re can also be generated via ¹⁸⁶W(d,2n)¹⁸⁶Re reaction⁹ or by ¹⁸⁸W(p,n)¹⁸⁸Re reactions^10,11. The ¹⁸⁶Re (t_1/2 90 h, E_max 1.07 MeV β^-, Range(tissue) 5 mm and 137 keV γ (7%)) isotope decays through medium energy β-emissions (max 1.07 MeV) with a range of about 5 mm in tissue that are suitable for treatment of small tumours. The half-life of 90 h makes it particularly useful in the labelling of large biomolecules such as antibodies that are not rapidly cleared from the blood stream^8,12. Rhenium-188 can be obtained as a solution of ¹⁸⁸ReO₄^- in high specific activity from a ¹⁸⁸W/¹⁸⁸Re generator. The generator design involves utilising the ¹⁸⁸Re which forms as a decay product from ¹⁸⁸Wwhich has a half-life of 60 days. The generator has an alumina column to which ¹⁸⁸W-tungstate has been chemisorbed and the decay product of ¹⁸⁸Re is then eluted with a saline solution as Na[¹⁸⁸ReO₄]. A single generator with 0.5 Ci of ¹⁸⁸W can last between 2 and 6 months and in this time it has the potential to provide sufficient radioactive rhenium for the treatment of several hundred patients. ¹⁸⁸Re (t_1/2 16.9 h, E_max 2.1 MeV β^-, Range(tissue) 11 mm and 155 keV γ (15%)) is a high energy β-emitter (max 2.1 MeV) with a range in tissue of about 11 mm. This makes it potentially useful for the treatment of large tumour masses^8,12. Re-188 also emits a gamma photon (Eγ = 0.155 MeV) that can be conveniently used for imaging the distribution of the radiotherapeutic agent soon after its administration to the patient. This possibility can be of great help to determine the response to therapy.

RHENIUM COORDINATION CHEMISTRY:

Rhenium, located in Group 7 of the Periodic Table covers oxidation states from +7 to -1. The chemistry of the high oxidation states (+5, +7) is dominated by strongly π-donating ligands such as oxido, imido and nitride which are able to compensate for the electron deficiency of the metal centre. Stabilisation of the lower oxidation states requires strong π-acceptor ligands like carbonyls, tertiary phosphanes or other π-acid ligands. A fundamental prerequisite for developing a therapeutic agent with some potential clinical utility is to afford a final metallic conjugate showing high chemical inertness and stability under physiological conditions. The design of a robust Re conjugate can be achieved through a careful selection of the most stable rhenium cores. A rhenium atom tightly bound to some characteristic ligand forms these functional groups that usually are strongly resistant to hydrolysis by water molecules. The rhenium(V) nitride, [Re≡N]²⁺ and the rhenium(I) triscarbonyl, [Re(CO)₃]⁺ cores are among the most stable chemical fragments.

The chemistry of rhenium has distinct parallels with technetium, its group 7 congener and many of their complexes are isostructural. The fact that rhenium is a third row element does introduce significant differences in its chemical behaviour, with the decrease in ionisation energy to attain the +7 oxidation state encountered on moving from technetium to rhenium has its origin in the different penetration of 4d as opposed to 5d orbitals. As a consequence [ReO₄]^- is harder to reduce than [TcO₄]^- and this is particularly pertinent considering [ReO₄]^- is the obligate starting material for rhenium radiopharmaceuticals. When these two elements form analogous complexes having exactly the same chemical structure and stability and differ only in the metal center, these species should exhibit the same “in vivo” biological behavior. Despite this, there exists a fundamental difference between the values of the standard reduction potentials of the redox reactions involving technetium and rhenium compounds. On average, 𝐸^∘ of a technetium process is 200 mV higher than that of the corresponding rhenium process. This implies that reduction of [ReO₄]⁻ should be much more difficult than that of [TcO₄]⁻. As a consequence, the methods utilized for the preparation of Re-radiopharmaceuticals cannot simply follow routes employed for obtaining Tc complexes, and usually more drastic conditions are required. This fact always constitutes a fundamental obstacle for the development of new Re-radiopharmaceuticals¹³. A solution to this problem has been proposed by a general phenomenon in coordination chemistry that goes under the name of “expansion of the coordination sphere.” This phenomenon indicates a redox process in which the metal undergoes a concomitant expansion of its coordination arrangement in going from the initial to the final oxidation state. For instance, in all radiopharmaceutical preparations involving [ReO₄]⁻, the starting Re(VII) center should be converted from the tetraoxido anion to the final complex which, usually, has a five- or six-coordination arrangement. The molecular geometry, therefore, should undergo a sudden change from tetrahedral to a more expanded square pyramidal or octahedral geometry. This geometrical process has a great impact on the standard reduction potential of the redox reaction and, generally, its effect determines a decrease of the 𝐸^∘ value. It follows, therefore, that if the reduction process was accomplished without the occurrence of such dramatic, geometrical changes, their detrimental influence on 𝐸^∘ would be completely cancelled. This result could be easily achieved by first transforming the tetrahedral perrhenate anion into some intermediate Re(VII) complex having a more expanded coordination sphere, by simple substitution of the oxido-groups with some suitable ligand, but without changing the starting metal oxidation state. In this way, the reduction process yielding the final product would take place between this intermediate Re(VII) compound, and not from the tetraoxido anion.

Rhenium radiopharmaceuticals:

The rhenium(V) nitride, [Re≡N]²⁺ constitutes a characteristic functional moiety in which the Re⁺⁵ ion is multiply bonded to a nitride nitrogen atom (N^3-). The resulting arrangement of atoms exhibits a very high chemical stability towards both oxidation-reduction reactions involving the rhenium ion and pH variations. This suggests that the synthesis of rhenium(V) nitride radiopharmaceuticals containing the Re≡N multiple bond would allow the facile variation of the other ancillary ligands coordinated to the metal center and hence make possible the fine tuning of the biological properties of the resulting compounds. The oxalate-based approach has been utilized to produce [¹⁸⁸Re≡N]²⁺ core from [¹⁸⁸ReO₄]⁻, at tracer level and under physiological conditions¹⁴ was based on the reaction of [¹⁸⁸ReO₄]⁻ with H₂NN(CH₃)C(=S)SCH₃ (DTCZ) and SnCl₂ in presence of sodium oxalate. In this procedure, the species DTCZ played the role of an efficient donor of nitride nitrogen groups (N³⁻), and SnCl₂ was used as reducing agent. After addition of a suitable dithiocarbamate ligand (L), the intermediate mixture was converted into a single product corresponding to the complex [¹⁸⁸Re(N)(L)₂] in high yields in physiological solutions¹⁵. Synthesis of Bis(dithiocarbamato) nitrido rhenium-188 complex was carried out using a two-step procedure. In the first step, generator eluted [¹⁸⁸ReO₄]^- was reacted in the presence of acetic acid with SnCl₂, oxalate and (DTCZ) to form ¹⁸⁸ReN-intermediate complexes with chemical nature not fully determined which, after the addition of carbonate buffer and the corresponding R₂NCS₂Na (R= alkyl group) ligand, completely converted in the final nitride complex [¹⁸⁸Re(N)(R₂NCS₂)₂]. The highly lipophilic complex bis(diethyldithiocarbamato) nitride rhenium-188, ¹⁸⁸ReN-DEDC, has been successively utilized for labelling lipiodol an iodinated ethyl ester of the poppy-seed fatty oil for the treatment of the Hepatocellular carcinoma. The strategy used for the lipiodol labelling is the dissolution of the strongly lipophilic ¹⁸⁸ReN-DEDC compound into lipiodol, which constitutes a highly hydrophobic material¹⁶.

The ¹⁸⁶Re and ¹⁸⁸Re complexes of the hydroxyethylidenebisphosphonate (HEDP) were developed as therapeutic analogues of the technetium bisphosphonates routinely used for SPECT imaging of bone metastases that arise from malignant tumours. The pain of these bone metastases severely affects the quality of life of suffers and palliative pain relief in patients suffering from metastatic bone pain in prostate and breast cancer with the ¹⁸⁸Re-HEDP and ¹⁸⁶Re-HEDP radiopharmaceuticals with minimal bone marrow toxicity offers a possible alternative to opioid analgesics^17-21. Despite the relative success of Re-HEDP the system is not optimal. A main disadvantage is the uncertain nature of the rhenium complex formed, which is a mixture of anionic polymers and the limited stability of the rhenium complex in the body.

In the last years, the labelling of biologically active molecules has become the most efficient tool to generate affinity of ¹⁸⁸Re complexes for a specific biological target. The most common design of this type of diagnostic and therapeutic agents is based on the so-called “bifunctional approach”²². This strategy consists firstly of the selection of an appropriate biologically active molecule having affinity for a specific biological substrate, and the choice of a convenient chelating system that allows one to stably bind the metal. The connection of these two different molecular blocks, which can be realized though a suitable chemical linker, results in a bifunctional ligand. The corresponding conjugate complex, which is formed by the coordination of the bifunctional ligand to the metal, will incorporate the biologically active molecule within its structure as an appended side chain. Various chelate systems of the type “N₂S₂” or “N₃S” have been investigated for the stable labelling of different biomolecules according to the bifunctional approach²³. Unfortunately, these tetradentate chelating systems rapidly bind the [ReO]³⁺ core to form stable five-coordinate complexes, however the resulting oxido ¹⁸⁸Re complexes frequently degrade much more rapidly limiting further development of rhenium-based therapeutic agents.

In recent years, an alternative approach, called “metal fragment” strategy, to the biologically active labelling, has emerged. The new strategy is based on the preparation of a precursor metal complex, formed by the coordination of specific ligands that stably bind the metal, resulting in a striking inertness towards oxidation-reduction reactions. In addition, this “robust” metal fragment possesses a few substitution-labile coordination positions where transient ligands are easily replaced by a stronger coordination system without reacting with the more stable part of the molecular fragment. If in the chemical structure of the incoming chelating ligand, a bioactive molecule is present, its selective interaction with the metal fragment would result in the formation of a stable final compound incorporating the bioactive substrate. On the basis of this strategy, different rhenium mixed-ligand compounds have been proposed for the development of target specific radiopharmaceuticals, among which the most representative examples are the [Re(CO)₃]⁺¹ system^1,24, the [Re(N)(PNP)]²⁺ (PNP = phosphinoamine ligand) system²⁵, and the so-called “3+1” mixed-ligand system. In particular, based on the “3+1” system, a new class of nitride ¹⁸⁸Re theranostic agents was recently described²⁶. These nitrido rhenium radiopharmaceuticals can be prepared following a specific molecular design grounded on the chemical properties of the [Re≡N]²⁺ functional group. This group exhibits a predictable chemistry characterized by different structural arrangements whose formation is strongly controlled by the chemical nature of the coordinating ligands. In particular, the chemical characterization of rhenium nitrido complexes carried out at macroscopic level showed a highly stable arrangement provided by the combination of the π-donor ligand having the set of [X, Y, Z] as coordinating atoms and a monodentate π-acceptor monophosphane ligand (PR₃) coordinated around the [Re≡N]²⁺ core²⁷. This combination, commonly dubbed as “3+1 complexes” has also been observed in mono oxido complexes^28-30, however, with the metal nitrido core, the chemical requirements are structurally more restrictive because only a selected set of coordinating atoms can give rise to this molecular arrangement. The essential point here is that the tridentate XYZ ligand should be composed by a combination of three donor atoms that have to be selected from the restricted set of S and N donor atoms. On the contrary, the monodentate ligand has to be selected from the category of the π-acceptor ligand, e.g., the monophosphanes. The “3+1” strategy may provide a convenient route to the labelling of bioactive molecules with the [¹⁸⁸ReN]²⁺ core, the SNS-type ligand can be easily prepared by the combinations of two basic amino acids or pseudoamino acids such as cysteine–cysteine, cysteine–isocysteine or cysteine–mercaptoacetic acid to yield potential tridentate chelating systems having [S,N,S] as a set of p-donor atoms²⁶.

Complexes of the Re(I) tricarbonyl core:

Much of the exciting and significant recent progress in the area of targeted rhenium radiopharmaceuticals has focused on use of the rhenium “carbonyl core”^31,32 of the type fac-[Re(CO)₃(H₂O)₃]⁺. The “carbonyl core” approach exploits the stability of the metal tricarbonyl core whilst manipulating the relatively labile water ligands to attach pertinent biomolecules. A variety of mono-, bi- and tri-dentate ligands can react with the tricarbonyl core, displacing the substitutionally labile aqua ligands. The fac-[Re(CO)₃(H₂O)₃]⁺ cation has been referred to as a “semi aquo ion” with three tightly held CO ligands and three labile coordination sites. Carbonyl ligands are known to stabilise low oxidation states via back-bonding mechanism and the trans effect increases the lability of the trans ligands allowing them to be readily substituted. This allows the attachment of a wide variety of ligands to the carbonyl core. The Re(I) complexes have d⁶ low spin octahedral configuration which are known to form stable complexes. The ligand exchange reactions in these systems occur via a dissociative mechanism and for radiopharmaceutical application rapid exchange to form stable complexes is essential. It has been suggested that the best ligands for the fac-[Re(CO)₃]⁺core are aromatic amines as they exhibit fast complexation kinetics to form reasonably stable complexes and that any anchoring of biomolecules to the fac-[Re(CO)₃]⁺ core should be done via a unit that contains at least one aromatic amine. Furthermore, the combination of an aromatic amine with an aliphatic amine or carboxylate group gave complexes that formed quickly whilst having high stability in aqueous solutions³². A wide range of ligands have been investigated for the tricarbonyl core and only a few selected highlights are discussed here.

Tridentate ligands bearing two pyridyl groups derived from amino acids or amino acid analogues react with [Et₄N]₂[ReBr₃(CO)₃] cleanly and in high yield to give complexes of the type [Re(CO)₃L]⁺. The tridentate ligand dipicolylamine is a versatile and useful starting point for bifunctional ligands where the amine nitrogen can be used to tether targeting groups. Addition of an amino acid such as Fmoc-lysine to the amine nitrogen atom allows for further conjugation reactions using standard coupling chemistry or solid phase synthesis³³. This approach has been used to make dipicolylamine ligands conjugated to targeting vectors such as peptides, nucleosides, folate and vitamin B₁₂^34-37. A new molecular agent that adopts the [Re(CO)₃]⁺ approach was intimated earlier in the discussion of rhenium agents that target bone metastases associated with malignant tumours. This system features a [Re^I(CO)₃] core tethered to a bismethylpyridylamine ligand bearing a bisphosphonate functional group. The ligand, dpa-alendronate, is a bifunctional bisphosphonate that forms a single, well-defined Re(I) tricarbonyl complex²¹, [Re(CO)₃(dpa-alendronate)]⁺. This compound has undergone preclinical evaluation in BALB/c female mice revealing that this new compound appears to be superior to the currently clinically approved agent ¹⁸⁶/¹⁸⁸Re-HEDP in targeting and accumulating in areas of high metabolic bone activity whilst having low soft tissue uptake²¹. The tripodal tricarbonyl rhenium complex [Re(CO)₃(trisaminomethylethane)]⁺ has been found to be chemically inert under biologically relevant challenging condition imparting no or little toxicity³⁸. An innovative approach to prepare a wide range of new bifunctional chelates for the [Re(CO)₃]⁺ utilises 1,4-disubstituted 1,2,3-triazole systems prepared by 1,3-dipolar cycloaddition reactions of azides and a glycine derivative with an alkyne functional group. Coordination to the metal ion is provided by a nitrogen atom from the triazole ring, as well as the primary amine and carboxylic acid from the glycine starting material as [Re(CO)₃(NNO)]⁺.

Rhenium complexes in mid to high oxidation states:

The ability of rhenium to form strong metal-nitrogen multiple bonds along with the oxidising ability of the higher oxidation states permits the synthesis of a range of rhenium complexes containing nitride(N^3-), diazenide (NNR) or isodiazene (NNR₂) ligands^8,39-42. This fact has led to attempts to use complexes that contain rhenium-organohydrazine multiple bonds in the development of radiopharmaceuticals.

The chemistry of the bis(diazenido) and bis(isodiazene) complexes is in general complicated by the presence of the two N–N ligands and an advance has seen the synthesis of the monodiazenide complexes [ReCl₂(NNAr)(MeCN)(PPh₃)₂] directly from perrhenate, the hydrazine and triphenylphosphane⁴². The chloride and phosphane ligands can be substituted by a range of polydentate ligands, but this chemistry has yet to be extended to using rhenium radioisotopes^43,44. The coordination chemistry of pyridylhydrazines with both technetium and rhenium has been investigated in this context and carboxyl substituents in hydrazinonicotinic acid (HYNIC) can be used to attach targeting groups. Conjugation to targeting molecules is achieved via the carboxyl group on the pyridyl ring. This procedure has been widely used for the development of specific imaging agents with ^99mTc, but addition of further co-ligands is necessary^45,46. Although extensive use has been made of the HYNIC strategy for ^99mTc, there are few examples of its extension to radioactive rhenium isotopes⁴⁶. Reaction of perrhenate with pyridylhydrazine dihydrochloride gives complexes with two pyridylhydrazines coordinated to the rhenium⁴¹. An investigation of the Re-188-HYNIC labelling of octreotide reported that there were difficulties with the conformation of insoluble ReO₂.

An extension of pyridyl hydrazine methodology is the incorporation of a thioamide tethering group to the terminal hydrazinic nitrogen, creating a very stable, well-defined polydentate ligand system that retains the targeting possibilities well established for the HYNIC system. This system forms well defined and stable complexes with Re^V-oxido, Re^III-diazenide and Re^I(CO)₃cores^47-51. The overall geometry of Re^Voxido complex with the pyridylphenylthiocarbazide derivative is square pyramidal with the oxido group in the apical site. The remaining sites of the coordination sphere are occupied by two pyridylthiocarbazide ligands each coordinating in a bidentate manner coordinating through nitrogen and sulfur atoms of each doubly deprotonated thiocarbazide. Each of the pyridyl nitrogen atoms are protonated to give a complex with an overall charge of +1. This complex can be prepared directly from [¹⁸⁸ReO₄]^- in high yield and radiochemical purity, and has the potential to provide an entry point into well defined discrete rhenium complexes that could in principle be conjugated to targeting molecules using similar strategies as have been developed for HYNIC⁵⁰.

Other ligand systems that have been investigated as co-ligands for the Re^V-oxido core include tetradentate ligands and dimercaptosuccinic acid derivatives. Tetradentate ligands are exemplified by mercaptoacetyltriglycine, MAG3, a ligand that forms complexes with a Re^V-oxido core with the MAG₃ ligand acting as a tetradentate N₃S donor resulting in square pyramidal geometry about the rhenium^52,53. The rhenium(V)-oxido complex of meso- 2,3-dimercaptosuccinc acid (DMSA) has been investigated as a therapeutic analogue of a technetium radiopharmaceutical which is known as “pentavalent technetium-99m-DMSA” which is used as an imaging agent in medullary thyroid carcinoma. The biological properties of [¹⁸⁸Re(O)DMSA] have been investigated in humans with medullary thyroid carcinoma these studies showed selective uptake in tumour tissue and the compound is selectively taken up in bone metastases. In this respect it offers an alternative to ¹⁸⁸Re-HEDP in the palliation of painful bone metastases. A potential advantage of [¹⁸⁸Re(O)DMSA] is that it exhibits a lower uptake in normal bone leading to a lower radiation dose to bone marrow^54,55. The selectivity for bone metastases is thought to arise from interaction of the carboxylate and oxido groups with calcium rich areas of the bone mineral.

Another family of sulfur containing ligands, substituted thiosemicarbzones, form complexes with Re in a variety of oxidation states. Interesting thiosemicarbazone complexes with the [Re(CO)₃]⁺, Re^III and [ReO]³⁺ have been reported but as of yet the chemistry has not been extended to radioactive rhenium isotopes^56-59. A hexadentate thiosemicarbazone ligand forms a complex with Re^V where the ligand loses four protons by deprotonation of both secondary amine nitrogen atoms with the metal ion in a distorted trigonal prismatic coordination environment⁶⁰. This complex represents a rare example of a Re^V complex that does not contain one of the ReO³⁺, ReN²⁺ or Re(NPh)²⁺ cores.

Summary:

Radiometals play an important role in diagnostic and therapeutic radiopharmaceuticals. This field of radiochemistry is multidisciplinary, involving radiometal production, separation of the radiometal from its target, chelate design for complexing the radiometal in a biologically stable environment, specific targeting of the radiometal to its in vivo site, and nuclear imaging and/or radiotherapy applications of the resultant radiopharmaceutical. Synthetic coordination chemistry plays an important role in the development of new radiopharmaceuticals that aim to realise the full potential of ¹⁸⁸Re is dependent on reliable coordination chemistry to form well-defined complexes of ¹⁸⁸Re that can be engineered to accumulate selectively in targeted areas. Translation of chemistry developed for technetium to rhenium is not always straightforward. Perhaps the most exciting recent progress toward this goal has involved the use of new bifunctional ligands, designed to coordinate to the [Re^I(CO)₃]⁺ core³⁷. The progression of radiopharmaceuticals from a research setting to the clinic is a challenging proposition. A number of issues are important, including but not limited to; the availability of isotopes as well as the infrastructure to produce and handle isotopes in a manner that is economically viable. The overall feasibility of new diagnostic or therapeutic agents based on rhenium radioisotopes will depend on a symbiosis between the availability of isotopes and elegant, practical coordination chemistry to produce compounds that construct with the required stability and selectivity. It will remain a challenge for synthetic inorganic chemists to provide novel methods and compounds for the radiopharmaceutical community. Promising contributions are expected from the coordination and organometallic chemistry of the element.

Conflicts of Interest:

The authors declare no conflict of interest.

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Received on 17.05.2017 Modified on 27.05.2017

Asian J. Research Chem. 2017; 10(3):369-376.

DOI: 10.5958/0974-4150.2017.00063.3