A novel radiolabelling method exploiting 11C-dithiocarbamate ligands has been used to generate 11C-labelled Au(I), Au(III), Pd(II) and Pt(II) complexes in high radiochemical yields (71–99%). Labelled complexes were prepared in a rapid one-pot procedure via the substitution reaction of 11C-dithiocarbamate ligands with appropriate transition metal chloride precursors

Cesarac, S

Edgar, F

Lai, T

Miller, P

Plisson, C

White, A

Dalton Transactions

English

Spiral - Imperial College Digital Repository

DaltonTransactionsCOMMUNICATIONCite this: DOI: 10.1039/d2dt00266cReceived 27th January 2022,Accepted 1st March 2022DOI: 10.1039/d2dt00266crsc.li/daltonSynthesis of carbon-11 radiolabelled transitionmetal complexes using 11C-dithiocarbamates†Sara Cesarec, a Fraser Edgar,a,b Titan Lai,a Christophe Plisson,cAndrew J. P. White a and Philip W. Miller *aA novel radiolabelling method exploiting 11C-dithiocarbamateligands has been used to generate 11C-labelled Au(I), Au(III), Pd(II)and Pt(II) complexes in high radiochemical yields (71–99%).Labelled complexes were prepared in a rapid one-pot procedurevia the substitution reaction of 11C-dithiocarbamate ligands withappropriate transition metal chloride precursors.Positron emission tomography (PET) is a functional imagingtechnique that enables the visualisation and quantification ofradiolabelled position emitting tracer compounds in vivo.1,2PET provides a wealth of information on the biodistribution,kinetic and metabolic profiles of tracers for a range of clinicalapplications in oncology, cardiology and neurology, enablingmore accurate diagnoses and improved interventions.3–5 PETis also used in drug discovery programmes where knowledgeof the pharmacokinetic behaviour of novel radiolabelled drugcandidates can accelerate selection and improve dosingregimens.6Carbon-11, along with fluorine-18, is a key positron emit-ting radionuclide commonly used for the synthesis of smallorganic molecule-based PET tracers.7,8 Its physical character-istics: high positron yield (>99%), 20.4 min half-life, favourablepositron energy (Emax = 0.960 MeV), high yielding cyclotronproduction routes and high theoretical molar activities meanthat carbon-11 is at the forefront of novel PET radiotracerdevelopment.9,10 However, the short half-life of carbon-11 pre-sents significant time challenges and hence limits the numberof chemical reactions that can be completed within a shortreaction window (ca. <60 min). To add to this challenge, [11C]CO2 is the main precursor to almost all carbon-11 labelledcompounds, and is often transformed to more reactive [11C]CH3I via a reduction and free-radical iodination process. [11C]CH3I is then added to a target molecule via a nucleophilic sub-stitution reaction to generate the 11C-methylated tracer. Inrecent years, much effort has been devoted to expanding thescope of 11C chemistry beyond simple N-, S-, andO-methylation reactions and into developing new 11C precur-sors and labelling strategies. For example, notable progresshas been made in the 11C-labelling of carbonyl groups with[11C]CO,11 [11C]CO212 and [11C]COF2,13 cyano groups using[11C]HCN14,15 and trifluoromethyl groups with [11C]HCF3.16The novel 11C precursor [11C]CS217 has been developed byus and used to access 11C-labelled organosulfur compoundsthat would be challenging to prepare with established precur-sors. To date, our group and others have used this method togenerate 11C-labelled organic molecules including: dithiocarba-mates, thioureas, isothioureas, thiocyanates, thiazolones, andthe progesterone agonist Tanaproget.18–21 Dithiocarbamatecompounds in particular have found wide ranging applicationsas precursors to nanomaterials,22 agrochemicals23 and thera-peutics.24 They are readily prepared via the reaction of carbondisulfide and primary or secondary amines in the presence oforganic or inorganic bases. Dithiocarbamates are non-selectiveligands known to form complexes with all the transitionmetals in a range of oxidation states, typically forming thermo-dynamically stable bidentate chelates.25,26 The formation ofdithiocarbamate complexes is normally fast and straight-forward, and often simply involve mixing the dithiocarbamatewith transition metal precursors in solvent at room tempera-ture. The ease of formation of dithiocarbamates and their che-lating abilities, coupled with their technically simple and fastcomplexation reactions have led to their investigation asligands for the development of imaging agents with 99mTc,27–2964Cu,30 and other metal ions (Fig. 1).31 Dithiocarbamate com-plexes have also received recurrent interest as therapeutics fortargeting cancer, in particular Au(I) and Au(III) complexes have†Electronic supplementary information (ESI) available. CCDC 2130302–2130303.For ESI and crystallographic data in CIF or other electronic format see DOI:10.1039/d2dt00266caDepartment of Chemistry, Imperial College London, Molecular Sciences ResearchHub, White City Campus, Wood Lane, London, W12 OBZ, UK.E-mail: philip.miller@imperial.ac.ukbSchool of Biomedical Engineering and Imaging Sciences, King’s College London, 4thFloor Lambeth Wing, St Thomas’ Hospital, London, UKcInvicro, Burlington Danes Building, Hammersmith Hospital, Du Cane Road,London, UKThis journal is © The Royal Society of Chemistry 2022 Dalton Trans.Open Access Article. Published on 10 March 2022. Downloaded on 3/25/2022 10:52:27 AM.  This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.View Article OnlineView Journaldisplayed anti-cancer properties for a range tumour celllines.32–36 Given the extensive coordination chemistry ofdithiocarbamates, we hypothesised that the generation of 11C-labelled dithiocarbamates would facilitate access to a diverserange of 11C-labelled transition metal complexes with genericand straightforward labelling protocols. Such labelled com-plexes could therefore aid in the understanding of the behav-iour of transition metal-based therapeutics and result in thedevelopment new PET imaging agents. Herein, we report aproof-of-principle strategy for labelling a range of late tran-sition metal complexes via coordination with 11C-labelleddithiocarbamates.[11C]Carbon disulfide was produced as previously reportedvia the high temperature gas phase reaction of [11C]CH3I withelemental sulfur.18 Passing the gaseous [11C]CS2 into a aceto-nitrile solution of secondary amine, either diethylamine ordibenzylamine, resulted in the quantitative trapping of [11C]CS2 and formation the carbon-11 labelled ammonium dithio-carbamate salts: [11C]N,N-diethyldithiocarbamate (1) and [11C]N,N-dibenzyldithiocarbamate (2) (Scheme 1). Au(III) and Au(I)complexes were selected for proof-of-concept labelling studiesowing to their abilities to from well-defined and stable biden-tate or monodentate dithiocarbamate complexes, and alsobecause of their potential for developing imaging agents tocomplement therapeutic gold–dithiocarbamate complexes.Addition of aqueous NaOH solution to [11C]N,N-diethyl-dithiocarbamate (1) followed by a solution of the gold precur-sor K[AuCl4] and stirring for 5 min at room temperatureresulted in the rapid and efficient labelling of [AuCl2([11C]Fig. 1 99mTc and 64Cu nuclear imaging agents bearing dithiocarbamatechelators (top). A range of Au(III) dithiocarbamate complexes that haveanti-cancer properties (bottom).Scheme 1 Radiosynthesis of 11C-labelled Au(III) and Au(I) complexes via the reaction of [11C]diethyldithiocarbamate (1a) or [11C]dibenzyldithiocarba-mate (2b) with KAuCl4 or AuCl(PPh3) precursors.Table 1 Summary of results for 11C-labelling of Au(III), Au(I), Pd(II) and Pt(II) complexesEntry Transition metal Precursor 11C-labelling precursor 11C-labelled transition metal complex RCYa1 K[AuCl4] [11C][S2CNEt2]− [AuCl2([11C]S2CNEt2)] (3) 86% (n = 2)2 K[AuCl4] [11C][S2CNBn2]− [AuCl2([11C]S2CNBn2)] (4) 71% (n = 2)3 [AuCl(PPh3)] [11C][S2CNEt2]− [Au([11C]S2CNEt2)(PPh3)] (5) 86% (n = 3)4 [PdCl2(dppe)] [11C][S2CNEt2]− [Pd([11C]S2CNEt2)(dppe)]+ (6) 96% (n = 3)5 [PtCl2(dppe)] [11C][S2CNEt2]− [Pt([11C]S2CNEt2)(dppe)]+ (7) 89% (n = 3)6 [PdCl2(dppp)] [11C][S2CNEt2]− [Pd([11C]S2CNEt2)(dppp)]+ (8) 99% (n = 3)7 [PtCl2(dppp)] [11C][S2CNEt2]− [Pt([11C]S2CNEt2)(dppp)]+ (9) 94% (n = 3)aNon-isolated radiochemical yield (RCY) determined by analytical radio-HPLC of the crude product.Fig. 2 A representative radio-HPLC trace (top) and UV-HPLC trace(bottom) of the crude reaction mixture for the formation of [AuCl2([11C]S2CNEt2)] (3) (4.177 min) with co-injection the unlabelled referencecompound [AuCl2(S2CNEt2)] (4.018 min).Communication Dalton TransactionsDalton Trans. This journal is © The Royal Society of Chemistry 2022Open Access Article. Published on 10 March 2022. Downloaded on 3/25/2022 10:52:27 AM.  This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.View Article OnlineS2CNEt2)] (3) (Scheme 1, Table 1 entry 1 and Fig. 2) in 86%RCY. The reaction conditions for the formation of unlabelledof Au(III)–DTC complexes typically need to be carefully con-trolled owing to possible DTC ligand exchange reactions andformation of undesired [Au(DTC)2][AuCl4] complexes. Weexpect, however, that the formation of such 11C labelled[Au(DTC)2]+ bischelates would be limited owing to the stoichio-metry of 11C labelling reactions making them statistically un-likely to form in any significant amounts. The labelled [11C]N,N-dibenzyldithiocarbamate (2) was also found to react with K[AuCl4] to give the analogous complex [AuCl2([11C]S2CNBn2)](4) (Scheme 1, Table 1 entry 2), however, the average RCY of71% obtained for 4 was reduced compared to complex 3.Based on the higher RCYs for complex 3 using [11C]N,N-di-ethyldithiocarbamate, all remaining labelling studies were per-formed with this ligand. Reaction of 1 with the Au(I) precursor[AuCl(PPh3)] to form [Au([11C]S2CNEt2)(PPh3)] (5) under thesame reaction conditions was also equally efficient giving aRCY of 86%, and demonstrating the method can also be usedto form simple mono-dentate Au(I) complexes.In order to expand the scope of these 11C-labelling reactionswith other transition metals, a range of well-defined Pd(II) andPt(II) diphosphine complexes were also investigated. Pd(II) andPt(II) diphosphine complexes are known to form stable cat-ionic chelating dithiocarbamate complexes,37,38 and thereforepresent as suitable complexes for preliminary labelling reac-tions. We focused on labelling a small library of four Pd(II) andPt(II) complexes containing the diphosphine ligands, 1,2-bis-diphenylphosphinoethane (dppe) and 1,3-bis-diphenylpho-sphinopropane (dppp), (Scheme 2). Unlabelled reference com-plexes were prepared via the reaction of sodium N,N-diethyl-dithiocarbamate with Pd(II) or Pt(II) diphosphine chloridesalts.37,38 Single crystal X-ray crystal structures were obtainedfor the reference complexes [Pd(S2CNEt2)(dppp)]Cl and [Pt(S2CNEt2)(dppp)]Cl (Fig. 3). The square planar molecular struc-tures of the two complexes are isostructural and confirm theexpected chelation of the dithiocarbamate ligand, varying onlyslightly in the bond lengths and angles at their respectivemetal centres (Table 2) and are similar to previously publishedDTC complexes.38,39 Unlike the labelling reactions of the Au pre-cursors that proceeded at room temperature, the reaction of 11C-dithiocarbamate 1 with [PdCl2(dppe)] or [PtCl2(dppe)] requiredheating to 60 °C to give appreciable RCYs within 5–8 min inDMF to facilitate solubility. Under these conditions the labelledcomplexes [Pd([11C]S2CNEt2)(dppe)]Cl (6) and [Pt([11C]S2CNEt2)(dppe)]Cl (7) were obtained in high RCYs of 96% and 89%respectively (Scheme 2, Table 1 entries 4 and 5). Labelling of theFig. 3 Isostructural X-ray crystal structures of the square planar dithiocarbamate complexes: [Pd(S2CNEt2)(dppp)]Cl (one of the two independentcomplex cations present in the crystal of 8, left) and [Pt(S2CNEt2)(dppp)]Cl (9, right), counter ions and solvent molecules have been removed forclarity.Scheme 2 Radiosynthesis of 11C-labelled Pd(II) and Pt(II) complexes viathe reaction of [11C]N,N-diethyldithiocarbamate (1) with [MCl2(dppe)] or[MCl2(dppp)], M = Pd or Pt.Dalton Transactions CommunicationThis journal is © The Royal Society of Chemistry 2022 Dalton Trans.Open Access Article. Published on 10 March 2022. Downloaded on 3/25/2022 10:52:27 AM.  This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.View Article Onlinerelated Pd(II) and Pt(II) dppp complexes was discovered to beslightly more efficient resulting in near quantitative RCYs forboth [Pd([11C]S2CNEt2)(dppp)]Cl (8) and [Pt([11C]S2CNEt2)(dppp)]Cl (9) (Scheme 2, Table 1 entries 6 and 7).ConclusionsIn conclusion, a small range of novel 11C-labelled late tran-sition metal complexes has been prepared via the substitutionreaction of 11C-dialkyldithiocarbamates with metal chlorideprecursors. The method was discovered to be an efficient,rapid and practical one-pot process that was amenable to label-ling Au(I), Au(III), Pd(II) and Pt(II) complexes in high RCYs. Theversatility of such dithiocarbamates for coordination to tran-sition metals opens the possibility for the generation of a widerange of labelled complexes that could find applications asPET imaging agents beyond the scope of conventional radio-labelled small organic molecules or could be used to comp-lement a better understanding of the biology of transitionmetal-based therapeutics. We are currently investigatingother DTC complexes that we anticipate could be translatedto further 11C radiolabelling studies and PET imagingapplications.Author contributionsC. S carried out the synthetic chemistry and 11C-radiochemistry. F. E. and T. L. assisted in the isolation andcrystallisation of complexes. P. W. M. and C. P. supervised 11C-radiolabelling experiments. A. J. P. W. conducted the singlecrystal X-ray structure determinations. P. W. M. supervised theproject. All authors contributed to the writing and proofread-ing of the manuscript.Conflicts of interestThere are no conflicts to declare.AcknowledgementsWe are grateful to Imperial College London for the award of astudentship to C. S. and to the King’s College London &Imperial College London EPSRC Centre for Doctoral Trainingin Medical Imaging (EP/L015226/1) for funding F. E. We arealso grateful to the EPSRC (EP/L025140/1) and the RoyalSociety (RG110449) for funding.Notes and references1 M. E. Phelps, Proc. Natl. Acad. Sci. U. S. A., 2000, 97, 9226–9233.2 M. M. Khalil, Basic science of PET imaging, 2016.3 W. A. Weber, M. Schwaiger and N. Avril, Nucl. Med. Biol.,2000, 27, 683–687.4 T. H. Schindler, H. R. Schelbert, A. Quercioli andV. Dilsizian, JACC Cardiovasc. Imaging, 2010, 3, 623–640.5 K. Heurling, A. Leuzy, M. Jonasson, A. Frick, E. R. Zimmer,A. Nordberg and M. Lubberink, Brain Res., 2017, 1670, 220–234.6 P. M. Matthews, E. A. Rabiner, J. Passchier and R. N. Gunn,Br. J. Clin. 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Aboagye, RSCAdv., 2016, 6, 57569–57579.Table 2 Selected bond lengths (Å) and angles (°) data for complexes incrystals of [Pd(S2CNEt2)(dppp)]Cl (8) and [Pt(S2CNEt2)(dppp)]Cl (9)Selected bond lengths (Å) for[Pd(S2CNEt2)(dppp)]Cl (8)Selected bond lengths (Å)[Pt(S2CNEt2)(dppp)]Cl (9)Pd(1A)–P(15A) 2.2701(11) Pt(1)–P(9) 2.2501(10)Pd(1A)–P(11A) 2.2846(11) Pt(1)–P(13) 2.2526(10)Pd(1A)–S(1A) 2.3487(12) Pt(1)–S(1) 2.3541(10)Pd(1A)–S(3A) 2.3498(11) Pt(1)–S(3) 2.3529(10)Selected bond angles (°) Selected bond angles (°)P(15A)–Pd(1A)–P(11A) 92.10(4) P(9)–Pt(1)–P(13) 92.84(4)S(1A)–Pd(1A)–S(3A) 75.25(4) S(3)–Pt(1)–S(1) 74.99(4)Communication Dalton TransactionsDalton Trans. This journal is © The Royal Society of Chemistry 2022Open Access Article. Published on 10 March 2022. Downloaded on 3/25/2022 10:52:27 AM.  This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.View Article Online21 H. Ishii, T. Yamasaki, J. Yui, Y. Zhang, M. Hanyu,M. Ogawa, N. Nengaki, A. B. Tsuji, Y. 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Synthesis of carbon-11 radiolabelled transition metal complexes using 11C-dithiocarbamates

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Synthesis of carbon-11 radiolabelled transition metal complexes using 11C-dithiocarbamates

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