Hartmut Spies

Technetium(v) and rhenium(v) complexes for 5-HT2A serotonin receptor binding: Structure-affinity considerations☆

Starting from the lead structure of ketanserin, a prototypic serotonin (5-HT) antagonist, new oxotechnetium(V) and oxorhenium(V) complexes were synthesized that are able to compete with [3H]ketan-serin in receptor-binding assays. To imitate organic 5-HT2 receptor ligands, fragments of ketanserin were combined with chelate moieties. Neutral compounds of the general formula [MOL1L2] (M = Tc, Re; L1 = HS-CH2CH2-S-CH2CH2-SH, N-(2-mercaptophenyl)salicylideneimine, N-(2-mercaptoethyl)-salicylideneimine, 3-(2-([N,N-bis(2-mercapto-S-ethyl)]-amino)ethyl)-2,4-(1H, 3H)-quinazolinedione and L2 = HS-R with R = subst. alkyl) were prepared by common action of a Tc(V) or Re(V) precursor with a mixture of equimolar amounts of a tridentate ligand L1 and a monodentate thiolate L2 bearing fragments of the lead structure. Lipophilic complexes consisting of a small S4 thiolate/thioether chelate unit, protonable nitrogen-containing spacer, and simple benzyl moiety significantly inhibited the specific binding of [3H]ketan-serin with IC50 values between 10 and 50 nM.

SYNTHESIS AND MOLECULAR STRUCTURE OF CHLORO(3-THIAPENTANE-1,5-DITHIOLATO)OXORHENIUM(V)

Abstract Reaction of [BzEt 3 N][ReOCl 4 ] ( 1 ) with 0.9 equiv. of 3-thiapentane-1,5-dithiol (HSSSH) in chloroform delivers [ReO(SSS)Cl] ( 2 ). The chloro ligand can be substituted by mercaptides whth 2 is heated with an excess of a mercaptane, e.g. C 2 H 5 SH, in acetonitrile. Single crystal X-ray analysis of 2 shows square-pyramidal geometry.

Synthesis and reactions of trigonal-bipyramidal rhenium and technetium complexes with a tripodal, tetradentate NS3 ligand

Neutral, trigonal-bipyramidal complexes of technetium and rhenium with the tripodal, tetradentate ligand 2,2′,2″-nitrilotris(ethanethiol), N(CH2CH2SH)3 (H31) have been synthesized and characterized. The technetium complex [99Tc(1) (PPh3)] (2) can be obtained by reduction of K99TcO4 with PPh3 in the presence of H31 or by substitution reaction starting from [99TcCl3(PPh3)2(NCMe)]. The trigonal-bipyramidal complex 2, C24H27NPS3Tc, crystallizes in the monoclinic space group P21/c with a=8.906(2), b=25.804(6), c=11.061(4) A, β=108.42(2)° and Z=4. Rhenium complexes [Re(1) (PR3)] (3) (PR3 = PPh3 (3a, PMe2Ph (3b), PMePH2 (3c), P(n-Bu)3 (3d), P(OEt)3 3e)) have been obtained in analogy to the technetium derivative 2 by reduction of NH4ReO4 with phosphines PR3 in the presence of H31. Complex 3a, C24H27NPReS3, crystallizes in the monoclinic space group P21/n with a=10.855(3), b=16.707(4), c=15.441(5) A, β=92.62(2)° and Z=4. Rhenium complexes containing an isocyanideco-ligand [Re(1) (CNR)] (5) (R=CH2COOMe (5a), t-Bu (5b), Ph (5c), CH2CH2NC4H8O (5d), CH2COOEt (5e)) aan be prepared by substitution of the phosphine ligand in 3 for an isocyanide or by reaction of the isocyanide complexes [ReCl3(PPh3)2(CNR)] (4) (R=CH2COOMe (4a), t-Bu (4b), Ph (4c), CH2CH2NC4H8O (4d)) with H31. The crystal structure of complex 4b has been determined. 4b crystallizes with one molecule of CH2Cl2 per formula unit. Crystals of 4b·CH2Cl2, C42H41Cl5NP2Re, are monoclinic, space group P21/c with a=12.868(3), b=20.454(7), c=16.378(9) A, β=104.71(4)° and Z=4. The substitution reaction starting with complexes of type 3 gives the best yields in the preparation of complexes of type 5. Two complexes of the type [Re(1) (CNR)] were characterized by X-ray crystallography. Crystals of 5a, C10H17N2O2ReS3, are monoclinic, space group P21/c with a=7.827(4), b=13.866(3), c=13.627(6) A, β=93.19(7)° and Z=4. Crystals of 5b, C11H21N2ReS3, are monoclinic, space group P21/c with a=12.084(2), b=11.915(2), c=12.244(3) A, β=114.31(2)° and Z=4. Treatment of 5e with LiOH leads to ester hydrolysis and yields the complex [Re(1) (CNCH2COOH)] (6) while reaction of 5d–5e in the two-phase system toluene/conc. hydrochloric acid gives the carbonyl complex [Re(1) (CO)] (7) which was characterized by X-ray crystallography. Crystals of 7, C7H12NOReS3, are triclinic, space group P1 with a=7.924(2), b=10.467(3), c=13.556(2) A, α=96.61(2), β=90.47(2), γ=101.68(2)° and Z=4 (2 molecules of 7 per asymmetric unit).

Technetium(V) chemistry as relevant to nuclear medicine

This review covers the coordination chemistry of technetium(V) and — to some extent — rhenium(V). In this survey, the complexes are arranged according to donor-atom sets in the coordination sphere.

Lipophilic technetium complexes. VI. Neutral oxotechnetium(V) complexes with monothiole/tridentate dithiole coordination

Abstract Reaction of tridentate dithiole ligands HSCH 2 CH 2 XCH 2 CH 2 SH (HSXSH, X= O, S) and monothioles RSH (thiophenoles, aliphatic thioles, mercaptoacetic acid ethylester) with Tc(V) gluconate (or other starting materials containing the oxotechnetium(V) core such as tetrachlorooxotechnetate) leads to a series of mononuclear, neutral complexes of the general formula TcO(SXS)(SR). In the absence of the monodentate thioles, dinuclear complexes of the general formula (TcO) 2 (SXS) 3 are formed. Infrared, NMR, and UV-Vis data of the resulting compounds are reported. A concept for designing smallsized, neutral Tc complexes, involving the principle of common reaction of both a tridentate and a monodentate ligand with an appropriate Tc precursor, is proposed.

Oxotechnetium(V)bis(dithiolato) complexes

Abstract A series of ten bis(dithiolato)oxotechnetate(V) complexes has been prepared using ligand exchange reaction. Starting from Tc(V) gluconate in aqueous or aqueous/ethanolic solution, complexes with saturated, olefinic and aromatic dithioles have been obtained. Mass, infrared, n.m.r., and UV-visible data of the resulting compounds are reported.

Structural modification of receptor-binding technetium-99m complexes in order to improve brain uptake

Low brain uptake is a generally accepted problem in developing technetium-99m brain receptor imaging agents. For a class of potential 5-HT2A receptorbinding agents we tried to improve the original low brain uptake of 0.4% injected dose (ID) in rats 5 min p.i. by modifying the lipophilic properties of the molecules. Because of the presence of a protonable nitrogen, which according to the pKa value leads to ionization of the molecule at blood pH, the pKa value was considered to be the parameter most suitable for adjustment of lipophilicity. Insertion of ether-oxygen in the molecule of five candidates lowers the apparent pKa value from 10.0 to 8.3 and dramatically increases the brain uptake to 1.3% ID at 5 min. The direct relationship between brain uptake and apparent pKa cannot be simply explained by the increase in the pKa-governed proportion of the neutral species.

No carrier added preparations of ‘3 + 1’ mixed-ligand 99mTc complexes

Abstract The no carrier added (n.c.a.) preparation of potentially receptor-binding ‘3 + 1’ mixed-ligand technetium complexes has not so far been successfully accomplished. This article deals with our results in the preparation of n.c.a. Tc complexes with tridentate S-S-S or S-N-S ligands and a series of bulky monothiolato ligands. It was found that Tc(V) gluconate or Tc(V) ethylene glycolate are suitable precursors for the complex formation. In a two-step procedure consisting of a reaction of the monothiolato ligand with the precursor and subsequent addition of the tridentate ligand, the desired ‘3 + 1’ mixed-ligand complexes are formed with yields of up to 90%. Low ligand concentrations and pH 9–10 promote the formation of the technetium compounds. A comparison of their analytical properties (TLC, HPLC) and biodistribution data of carrier added and no carrier added technetium complexes show the identity of the investigated compounds.

Synthesis and Host−Guest Properties of Multi-Crown Dendrimers towards Sodium Pertechnetate and Mercury(II) Chloride

Multi-crown dendrimers of four different generations have been synthesized by grafting 4, 8, 16, and 32 benzo[15]crown-5 units at the periphery of POPAM dendrimers. The binding of sodium pertechnetate and mercury(II) chloride by the multi-crown dendrimers has been studied by liquid-liquid extraction using the radioactive probes 22Na+, 99TcO4−, and 203Hg2+. The third- and fourth-generation dendrimers 3 and 4, in particular, are capable of extracting mercury(II) with high efficiency (ca. 12 HgII ions per dendrimer molecule, even at low generation). It has been shown that the guest molecules investigated are preferentially encapsulated inside the dendrimers.

Investigations on technetium and rhenium monothio-βdiketonate complexesand x-ray structure of tris(monothiodibenzoylmethanato)technetium(III)

Abstract Six-coordinated tris(monothio-β-diketonates) of Tc(III) and Re(III) have been synthesized by the reaction of M(III) thiourea complexes with the appropriate monothio-β-diketone ligands in methanol. Characterization of the compounds by IR, UV-Vis, 1H NMR and mass spectroscopy indicates that the ligands coordinate as bidentate. The 1H NMR spectra of the paramagnetic substances are well resolved and the chelate ring protons show a large high-field shift of the Tc complcxes and a low-field shift of the corresponding Re analogues. A complete crystal and molecular structure determination, performed on tris(monothiodibenzoylmethanato)technetium(III), is the first structural characterization of a Tc(III) compound with O and S chelate ligands.