Oxotechnetium 99mTcO[SN(R)S][S] complexes as potential 5-HT1A receptor imaging agents.

A series of 99mTcO[SN(R)S][S] complexes carrying the 1-(2-methoxyphenyl)piperazine moiety on the tridentate ligand [SN(R)S] was synthesized. For structural characterization and for in vitro binding assays the analogous oxorhenium complexes were prepared. As demonstrated by appropriate competition binding tests in rat hippocampal preparations, all oxorhenium analogues showed affinity for the 5-HT(1A) receptor binding sites with IC(50) values at the nanomolar range (IC(50)= 5.8-103 nM). All 99mTcO[SN(R)S]/[S] complexes showed significant brain uptake in rats at 2 min p.i. (0.24-1.31% ID). However, a clear correlation between distribution of radioactivity in the brain and distribution of 5-HT(1A) receptors could not be established.

Novel mixed ligand technetium complexes as 5-HT1A receptor imaging agents.

The synthesis, characterization and biological evaluation of two novel 3 + 1 mixed ligand 99mTc-complexes, bearing the 1-(2-methoxyphenylpiperazine) moiety, a fragment of the true 5-HT1A antagonist WAY 100635, is reported. Complexes at tracer level 99mTcO[(CH3CH2)2NCH2CH2N(CH2CH2S)2][o-CH3OC6H4N(CH2CH2)2NCH2CH2S], 99mTc-1, and 99mTcO[((CH3)2CH)2NCH2CH2N(CH2CH2S)2][o-CH3OC6H4N (CH2CH2)2NCH2CH2S], 99mTc-2, were prepared using 99mTc-glucoheptonate as precursor. For structural characterization, the analogous oxorhenium complexes, Re-1 and Re-2, were prepared by ligand exchange reaction using ReOCl3(PPh3)2 as precursor, and characterized by elemental analysis and spectroscopic methods. Complex Re-1 was further characterized by crystallographic analysis. Labeling was performed with high yield (>85%) and radiochemical purity (>90%) using very low ligand concentration. The structure of 99mTc complexes was established by comparative HPLC using the well-characterized oxorhenium analogues as references. In vitro binding assays demonstrated the affinity of these complexes for 5-HT1A receptors (IC50 : 67 and 45 nM for Re-1 and Re-2 respectively). Biological studies in mice showed the ability of 99mTc-1 and 99mTc-2 complexes to cross the intact blood-brain barrier (1.4 and 0.9% dose/g, respectively at 1 min post-inj.). The distribution of these complexes in various regions in rat brain is inhomogeneous. The highest ratio between areas reach and poor in 5-HT1A receptors was calculated for complex Tc-1 at 60 min p.i. (hippocampus/cerebellum = 1.7).

Ester-modified 99mTcO[SN(R)S/S] mixed ligand complexes: synthesis and preliminary evaluation.

Two novel 99mTc-(SNS/S) complexes: a mono-ester compound carrying an ethyl ester group on the tridentate ligand, 99mTcO[C(2)H(5)OOCCH(2)N(CH(2)CH(2)S)(2)][SC(6)H(4)CH(3)], 3, and a diester compound, carrying a second ethyl ester group on the monodentate ligand, 99mTcO[C(2)H(5)OOCCH(2)N(CH(2)CH(2)S)(2)][SC(6)H(4)COOC(2)H(5)], 4, were synthesized. The corresponding oxorhenium(V) complexes, 1 and 2 were also synthesized. Enzymatic hydrolysis demonstrated that 3 remains intact after 10 min incubation while 4 is totally converted to an unidentified hydrophilic complex. Tissue distribution data in mice revealed that both complexes, 3 and 4, exhibit significant initial brain uptake (1.42 and 1.01% of injected dose at 5 minutes post injection respectively) and fast blood clearance.

Novel oxorhenium and oxotechnetium complexes from an aminothiol[NS]/thiol[S] mixed-ligand system.

The simultaneous action of a bidentate aminothiol ligand, LnH, (n = 1: (CH3CH2)2NCH2CH2SH and n = 2: C5H10NCH2CH2SH) and a monodentate thiol ligand, LH (LH: p-methoxythiophenol) on a suitable MO (M = Re, 99gTc) precursor results in the formation of complexes of the general formula [MO(Ln)(L)3] (1, 2 for Re and 5. 6 for 99gTc). In solution these complexes gradually transform to [MO(Ln)(L)2] complexes (3, 4 for Re and 7, 8 for 99gTc). The transformation is much faster for oxotechnetium than for oxorhenium complexes. Complexes 1-4, 7, and 8 have been isolated and fully characterized by elemental analysis and spectroscopic methods. Detailed NMR assignments were made for complexes 3, 4, 7, and 8. X-ray studies have demonstrated that the coordination geometry around rhenium in complex 1 is square pyramidal (tau = 0.06), with four sulfur atoms (one from the L1H ligand and three from three molecules of p-methoxythiophenol) in the basal plane and the oxo group in the apical position. The L1H ligand acts as a monodentate ligand with the nitrogen atom being protonated and hydrogen bonded to the oxo group. The four thiols are deprotonated during complexation resulting in a complex with an overall charge of zero. The coordination geometry around rhenium in complex 4 is trigonally distorted square pyramidal (tau = 0.41), while in the oxotechnetium complex 7 it is square pyramidal (tau = 0.16). In both complexes LnH acts as a bidentate ligand. The NS donor atom set of the bidentate ligand and the two sulfur atoms of the two monodentate thiols define the basal plane, while the oxygen atom occupies the apical position. At the technetium tracer level (99mTc), both types of complexes, [99mTcO(Ln)(L)3] and [99mTcO(Ln)(L)2], are formed as indicated by HPLC. At high ligand concentrations the major complex is [99mTcO(Ln)(L)3], while at low concentrations the predominant complex is [99mTcO(Ln)(L)2]. The complexes [99mTcO(Ln)(L)3] transform to the stable complexes [99mTcO(Ln)(L)2]. This transformation is much faster in the absence of ligands. The complexes [99mTcO(Ln)(L)2] are stable, neutral, and also the predominant product of the reaction when low concentrations of ligands are used, a fact that is very important from the radiopharmaceutical point of view.

Synthesis of oxorhenium(V) and oxotechnetium(V) [SN(R)S/S] mixed ligand complexes containing a phenothiazine moiety on the tridentate SN(R)S ligand.

Two oxorhenium and two oxotechnetium [SN(R)S/S] mixed ligand complexes bearing the phenothiazine moiety on the tridentate ligand SN(R)S have been synthesized and characterized. The corresponding complexes at tracer level (99mTc) have also been prepared.

Development of novel mixed-ligand oxotechnetium [SNS/S] complexes as potential 5-HT1A receptor imaging agents.

The "3 + 1" ligand system [SN(R)S/S combination] was applied in order to synthesize neutral mixed-ligand oxotechnetium complexes of the general formula 99mTcO[SN(R)S]/[S] as potential 5-HT1A receptor imaging agents. The complexes are carrying the 1-(2-methoxyphenyl)piperazine moiety, a fragment of the true 5-HT1A antagonist WAY 100635, either on the monodentate ligand [S] or on the tridentate ligand [SN(R)S]. The complexes MO[EtN(CH2CH2S)2] [o-MeOC6H4N(CH2CH2)2NCH2CH2S] (3), MO[o- MeOC6H4N(CH2CH2)2N(CH2)3N(CH2CH2S)2][PhS] (6) and MO[o-MeOC6H4N(CH2CH2)2N(CH2)3N(CH2CH2S)2] [PhCH2CH2S] (9), where M = 99mTc, were prepared at tracer level using 99mTc glucoheptonate as precursor. For structural characterization, the analogous oxorhenium (M = Re, 1, 4 and 7, respectively) and oxotechnetium (M = 99gTc, 2, 5 and 8, respectively) complexes were prepared by ligand exchange reactions. All products were characterized by elemental analysis and spectroscopic methods. Complexes 1, 4 and 7 were further characterized by crystallographic analysis. For 1, the coordination geometry about rhenium can be described as trigonally distorted square pyramidal (tau = 0.36), while for 4 and 7, as distorted trigonal bipyramidal (tau = 0.66 and tau = 0.61, respectively). The coordination sphere about oxorhenium in all complexes is defined by the SNS donor atom set of the tridentate ligand and the sulfur atom of the monodentate coligand. The structure of the 99mTc complexes 3, 6 and 9 was established by comparative HPLC using authentic oxorhenium and oxotechnetium samples. The binding affinity of oxorhenium compounds for the 5-HT1A receptor subtype was determined in rat brain hippocampal preparations (IC50 = 6-31 nM). Preliminary tissue distribution data in healthy mice revealed the ability of all three 99mTc complexes to cross the intact blood-brain barrier (0.49-1.15% ID at 1 min p.i.). In addition, complexes 6 and 9 showed significant brain retention. These promising results have demonstrated that the SNS/S mixed-ligand system can be used in the development of 99mTc complexes as potential 5-HT1A receptor imaging agents.

Novel lipophilic amidate oxorhenium and oxotechnetium complexes as potential brain agents: synthesis, characterization and biological evaluation.

Novel oxorhenium and oxotechnetium complexes based on the tetradentate 1-(2-hydroxybenzamido)-2-(pyridinecarboxamido)benzene, H3L, ligand have been synthesized and characterized herein. Thus, by reacting equimolar quantities of the triply deprotonated ligand L3- with the suitable MO3+ precursor, the following neutral MOL complexes could be easily produced following similar synthetic routes: M = Re (1), M = 99gTc (2), and M = 99mTc (3). Complexes 1 and 2, prepared in macroscopic amounts, were chemically characterized and their structure determined by single-crystal X-ray analysis. They are isostructural metal chelates, adopting a distorted square pyramidal geometry around the metal. The N3O donor atom set of the tetradentate ligand defines the basal plane and the oxygen atom of the M = O core occupies the apex of the pyramid. Complex 3 forms quantitatively at tracer level by mixing the H3L ligand with Na99mTcO4 generator eluate in aqueous alkaline media and using tin chloride as reductant in the presence of citrate. Its structure was established by chromatographic comparison with prototypic complexes 1 and 2 using high-performance liquid chromatographic techniques. When challenged with excess glutathione in vitro, complex 3 is rapidly converted to hydrophilic unidentified metal species. Tissue distribution data after administration of complex 3 in vivo revealed a significant uptake and retention of this compound in brain tissue.

Synthesis, characterization and biological evaluation of a novel "3 + 1" mixed ligand 99mTc complex having an aliphatic thiol as coligand.

A novel "3 + 1" mixed ligand 99mTc complex with N,N-bis(2-mercaptoethyl)-N'N'-diethyl-ethilenediamine as ligand and 1-octanethiol as coligand was prepared and evaluated as potential brain radiopharmaceutical. Preparation at tracer level was accomplished by substitution, using 99mTc-glucoheptonate as precursor and a coligand/ligand ratio of 5. Under these conditions the labeling yield was over 80% and a major product with radiochemical purity >80% was isolated by HPLC methods and used for biological evaluation. Chemical characterization at carrier level was developed using the corresponding rhenium and 99gTc complexes. Results were consistent with the expected "3 + 1" structure and X-ray diffraction study demonstrated that the complex adopted a distorted trigonal bipyramidal geometry. All sulphur atoms underwent ionization leading to the formation of a neutral compound. Biodistribution in mice demonstrated early brain uptake, fast blood clearance and excretion through hepatobiliary system. Although brain/blood ratio increased significantly with time, this novel 99mTc complex did not exhibit ideal properties as brain perfusion radiopharmaceutical since brain uptake was too low.

BRCA1 mutation analysis in breast/ovarian cancer families from Greece.

Germline mutations in BRCA1 gene account for varying proportions of breast/ovarian cancer families, and demonstrate considerable variation in mutational spectra coincident with ethnic and geographical diversity. We have screened for mutations the entire coding sequence of BRCA1 in 30 breast/ovarian cancer women with family history of two or more cases of breast cancer under age 50 and/or ovarian cancer at any age. Genomic DNA from patient was initially analyzed for truncating mutations in exon 11 with PTT followed by DNA sequencing. In the cases where no frameshift mutation was observed in exon 11, all other exons were screened with direct sequencing. Two novel (3099delT, 3277insG) and three already described (3741insA, 1623del5-TTAAA, 5382insC-twice) truncating mutations were identified. In addition, 6 point mutations (L771L, P871L, E1038G, K1183R, S1436S, S1613G) which are already classified as polymorphisms were identified. Three unclassified intronic variants (IVS16-68 G>A, IVS16-92 G>A, IVS18+65G>A) were also detected. These results show that BRCA1 deleterious mutations are present in a fraction (20%) of Greek breast/ovarian cancer families similar to other European countries. Mutations were detected in high- (>/=3 members) as well as in moderate-risk (2 members) families. This is the first report of BRCA1 mutation analysis in Greece.

Permeation studies in vitro and in vivo of potential radiopharmaceuticals with affinity to neuro receptors.

PURPOSE: To check the influence of structural characteristics on their permeation through the blood-brain barrier (BBB), a set of radioactive [99mTc]chelates bearing amine groups was synthesized and tested in vitro as well as in vivo. METHODS: Compounds with different log P and pKa values were obtained by complex forming reactions of [99mTc]pertechnetate with varying substituents. Transport was studied in rats and mice, as well as in an ECV304 cell culture model. RESULTS: In vitro higher permeation was found for compounds with electron attracting substituents in beta-position to the amine group (pKa values 7.4 to 8.3) than for those with more basic amine groups (pKa values > 8.9) even for similar log DH 7.4. In vivo brain uptake between 0.8 and 4.8% of the injected dose (ID) per organ was found for the former, whereas <0.4% ID were present for the latter. CONCLUSIONS: Three structurally diverse classes of [99mTc]chelates showed distinct patterns with regard to brain uptake in vivo and BBB permeability in vitro which could not be predicted by their lipophilicity alone. The close correlation between the data from rats and mice and those obtained with cell cultures render the ECV304 cells an attractive model for the screening of new compounds.

Synthesis and characterization of mixed-ligand oxorhenium complexes with the SNN type of ligand. Isolation of a novel ReO[SN][S][S] complex.

A new series of mixed-ligand oxorhenium complexes 4-9, with ligands 1-3 (L1H2) containing the SNN donor set and monodentate thiols as coligands (L2H), is reported. All complexes were synthesized using ReOCl3(PPh3)2 as precursor. They were isolated as crystalline products and characterized by elemental analysis and IR and NMR spectroscopy. The ligands 1 and 2 (general formula RCH2CH2NHCH2CH2SH, where R = N(C2H5)2 in 1 and pyrrolidin-1-yl in 2) act as tridentate SNN chelates to the ReO3+ core, leaving one open coordination site cis to the oxo group. The fourth coordination site is occupied by a monodentate aromatic thiol which acts as a coligand. Thus, three new "3 + 1" [SNN][S] oxorhenium complexes 4-6 (general formula ReO[RCH2CH2NCH2CH2S][SX], where R = N(C2H5)2 and X = phenyl in 4, R = N(C2H5)2 and X = p-methylphenyl in 5, and R = pyrrolidinlyl and X = p-methylphenyl in 6) were prepared in high yield. Complex 4 adopts an almost perfect square pyramidal geometry (tau = 0.07), while 6 forms a distorted square pyramidal geometry (tau = 0.24). In both complexes 4 and 6, the basal plane is formed by the SNN donor set of the tridentate ligand and the S of the monodentate thiol. On the other hand, the ligand 3, [(CH3)2CH]2NCH2CH2NHCH2CH2SH, acts as a bidentate ligand, probably due to steric hindrance, and it coordinates to the ReO3+ core through the SN atoms, leaving two open coordination sites cis to the oxo group. These two vacant positions are occupied by two molecules of the monodentate thiol coligand, producing a novel type of "2 + 1 + 1" [SN][S][S] oxorhenium mixed-ligand complexes 7-9 (general formula ReO[[(CH3)2CH]2NCH2CH2NHCH2CH2S][SX][SX], where X = phenyl in 7, p-methylphenyl in 8, and benzyl in 9). The coordination sphere about rhenium in 7 and 8 consists of the SN donor set of ligand 3, two sulfurs of the two monodentate thiols, and the doubly bonded oxygen atom in a trigonally distorted square pyramidal geometry (tau = 0.44 and 0.45 for 7 and 8, respectively). Detailed NMR assignments were determined for complexes 5 and 8.

Oxorhenium phosphinophenolato complexes with model peptide fragments: synthesis, characterization, and stability considerations.

The synthesis and characterization of a series of mixed-ligand oxorhenium(V) complexes containing the o-diphenylphosphinophenolato ligand (HL) and model peptide fragments acting as the tridentate coligand are reported. Thus, by reacting equimolar amounts of tiopronin, Gly-Gly, Gly-L-Phe, or glutathione (GSH) peptides on the [(n-C4H9)4N][ReOCl3(L)] precursor in refluxing MeCN/MeOH or aqueous MeCN/MeOH mixtures, the following complexes were obtained: ReO([SC(CH3)CONCH2COO][L])[(n-C4H9)4N], 1, ReO([H2NCH2CONCH2COO][L]), 2, ReO)[H2NCH2CONCH(CH2C6H5)COO][L]), 3, and ReO([SCH2CH(NHCOCH2CH2CHNH2COOH)CONCH2COO][L])Na, 4. The compounds are closed-shell 18-electron oxorhenium species adopting a distorted octahedral geometry, as demonstrated by classical spectroscopical methods including multinuclear NMR. X-ray diffraction analyses for 1 and 2 are also reported. By comparative stability studies of complexes 1-3 against excess GSH it was shown that complex 3 containing the bulky C6H5CH2 substituent adjacent to the coordinated carboxylate group of Phe is the most stable complex.

Synthesis and characterization of six-coordinate "3 + 2" mixed-ligand oxorhenium complexes with the o-diphenylphosphinophenolato ligand and tridentate coligands of different N and S donor atom combinations.

A series of octahedral six-coordinate oxorhenium(V) mixed ligand complexes containing the common [ReO(L)]2+ fragment (L = o-OC6H4P(C6H5)2] have been synthesized and characterized. Hence, it was shown that the [ReO(L)]2+ moiety can accommodate a variety of tridentate ligands containing a central amine group amenable to deprotonation and different combinations of lateral groups, such as ethylamine, substituted ethylamine, ethylthiol, and ethylthioether arms. In particular, by reaction of equimolar amounts of the pertinent HLn ligands with the [(n-C4H9)4N][ReOCl3(L)] precursor in refluxing acetonitrile/methanol or dichloromethane/methanol mixtures, the following series of [ReO(Ln)(L)]+/0 oxorhenium(V) complexes has been generated: ReO[[N(CH2CH2NH2)2][o-OC6H4P(C6H5)2]]Cl (1); ReO[[C2H5)2NCH2CH2NCH2CH2S][o-OC6H4P5)2]] (2); ReO[[(CH2)4NCH2CH2NCH2CH2S][o-OC6H4P(C6H4P(C6H5)2]] (3); and ReO[[C2H5SCH2CH2NCH2CH2S][o-OC6H4P(C6H5)2]] (4). The complexes are closed-shell 18-electron oxorhenium species, which adopt octahedral geometries both in solution and in the solid state, as established by conventional physicochemical techniques including multinuclear NMR and single-crystal X-ray diffraction analyses.

Characterization and preliminary evaluation of ester-modified technetium-99m SNS/S mixed ligand complexes as potential brain perfusion agents.

Two novel [99mTc](SNS/S) mixed ligand complexes carrying a pendant ester function on the monothiolate coligand were synthesized. The corresponding oxorhenium and [99gTc]oxotechnetium complexes prepared at the macroscopic level and chemically characterized were used for structure assignment of [99mTc](SNS/S) complexes prepared at the nanomolar level. Enzymatic hydrolysis of the pendant ester group of [99mTc](SNS/S) mixed ligand complexes by esterase was investigated in vitro and compared with that of the ethyl cysteinate dimer, [99mTc]ECD. Preliminary biodistribution data in mice shows that the complexes are lipophilic and exhibit significant initial uptake in rodent brain.

Glutathione-mediated metabolism of technetium-99m SNS/S mixed ligand complexes: a proposed mechanism of brain retention.

Two series of [99mTc](SNS/S) mixed ligand complexes each carrying the N-diethylaminoethyl or the N-ethyl-substituted bis(2-mercaptoethyl)amine ligand (SNS) are produced at tracer level using tin chloride as reductant and glucoheptonate as transfer ligand. The identity of [99mTc](SNS/S) complexes is established by high-performance liquid chromatographic (HPLC) comparison with authentic rhenium samples. The para substituent R on the phenylthiolate coligand (S) ranges from electron-donating (-NH2) to electron-withdrawing (-NO2) groups, to study complex stability against nucleophiles as a result of N- and R-substitution. The relative resistance of [99mTc](SNS/S) complexes against nucleophilic attack of glutathione (GSH), a native nucleophilic thiol of 2 mM intracerebral concentration, is investigated in vitro by HPLC. The reaction of [99mTc](SNS/S) complexes with GSH is reversible and advances via substitution of the monothiolate ligand by GS- and concomitant formation of the hydrophilic [99mTc](SNS/GS) daughter compound. The N-diethylaminoethyl complexes are found to be more reactive against GSH as compared to the N-ethyl ones. Complex reactivity as a result of R-substitution follows the sequence -NO2 >> -H > -NH2. These in vitro findings correlate well with in vivo distribution data in mice. Thus, brain retention parallels complex susceptibility to GSH attack. Furthermore, isolation of the hydrophilic [99mTc](SNS/GS) metabolite from biological fluids and brain homogenates provides additional evidence that the brain retention mechanism of [99mTc](SNS/S) complexes is GSH-mediated.

Novel 99mTc aminobisthiolato/monothiolato "3 + 1" mixed ligand complexes: structure-activity relationships and preliminary in vivo validation as brain blood flow imaging agents.

A series of neutral, lipophilic 99mTc mixed-ligand complexes of the general formula 99mTcOL1L2, where L1H2 is an N-substituted bis-(2-mercaptoethyl)amine, [X-CH2CH2N(CH2CH2SH)2], [SNS], and L2H is a monodentate thiol (RSH), [S], has been synthesized and evaluated in rodents for potential use in brain blood flow imaging. The complexes were prepared by ligand exchange reaction using 99mTc(V)O-glucoheptonate as precursor and equimolar quantities of the two ligands. In all cases the syn isomer was formed in a high yield, whereas the anti isomer was not always present. The formation of two isomeric complexes-syn and anti-was expected, since the N-substituent (X-CH2CH2N) can assume syn or anti configuration with respect to the 99mTcO3+ core during complexation. One anti and all syn isomers were isolated by HPLC. Their identity was confirmed by comparative HPLC studies with the analogous 99Tc complexes of established structure. In vivo distribution, in particular brain uptake and retention, greatly depended on the type of either tridentate (L1H2) or monodentate (L2H) ligand. All 99mTc complexes showed significant brain uptake in mice (0.78-4.35% injected dose per organ at 5 min postinjection). This initial uptake remained nearly constant for at least 30 min for most of the complexes. Structure-activity relationships of novel 99mTc(V)O SNS/S complexes in mice are reported and discussed. Selected complexes were further studied in rats. High brain uptake, comparable to that of 99mTc-d,l-HMPAO, and sufficient retention 60 min postinjection were provided with complex 18 [X = (C2H5)2N and R = p-CH3OC6H4CH2].

Syn-Anti Isomerism in a Mixed-Ligand Oxorhenium Complex, ReO[SN(R)S][S].

The simultaneous action of the tridentate ligand (C(2)H(5))(2)NCH(2)CH(2)N(CH(2)CH(2)SH)(2) and the monodentate coligand HSC(6)H(4)OCH(3) on a suitable ReO(3+) precursor results in a mixture of syn- and anti-oxorhenium complexes, ReO[(C(2)H(5))(2)NCH(2)CH(2)N(CH(2)CH(2)S)(2)] [SC(6)H(4)OCH(3)], in a ratio of 25/1. The complexes are prepared by a ligand exchange reaction using ReO(eg)(2) (eg = ethylene glycol), ReOCl(3)(PPh(3))(2), or Re(V)-citrate as precursor. Both complexes have been characterized by elemental analysis, FT-IR, UV-vis, X-ray crystallography, and NMR spectroscopy. The syn isomer C(17)H(29)N(2)O(2)S(3)Re crystallizes in the monoclinic space group P2(1)/n, a = 14.109(4) Å, b = 7.518(2) Å, c = 20.900(5) Å, beta = 103.07(1) degrees, V = 2159.4(9) Å(3), Z = 4. The anti isomer C(17)H(29)N(2)O(2)S(3)Re crystallizes in P2(1)/n, a = 9.3850(7) Å, b = 27.979(2) Å, c = 8.3648(6) Å, beta = 99.86(1) degrees, V = 2163.9(3) Å(3), Z = 4. Complete NMR studies show that the orientation of the N substituent chain with respect to the Re=O core greatly influences the observed chemical shifts. Complexes were also prepared at the tracer ((186)Re) level by using (186)Re-citrate as precursor. Corroboration of the structure at tracer level was achieved by comparative HPLC studies.

A New Donor Atom System [(SNN)(S)] for the Synthesis of Neutral Oxotechnetium(V) Mixed-Ligand Complexes.

A new approach to the "3 + 1" mixed ligand oxotechnetium complexes of the general formula TcOL1L2, with ligands (L1H(2)) containing the SNN donor set and various monodentate thiols as coligands (L2H) is reported. The ligands L1H(2) (1-3, general formula R(1)CH(2)CH(2)NHCH(2)C(R(2))(2)SH where R(1) = N(CH(3))(2) and R(2) = H in 1, R(1) = pyrrolidin-1-yl and R(2) = H in 2, and R(1) = piperidin-1-yl and R(2) = CH(3) in 3) act as tridentate SNN chelates to the TcO(3+) core, leaving open one coordination site cis to the oxo group. In the presence of a monodentate thiol (L2H) and using (99)Tc(V)-gluconate as precursor, the vacancy is filled by the thiol which acts as the coligand. With this approach four neutral oxotechnetium complexes (4-7, general formula TcO[R(1)CH(2)CH(2)NCH(2)C(R(2))(2)S][SR] where RSH = p-methoxybenzenethiol, or p-methylbenzenethiol or benzyl mercaptan) were prepared in high yield by reacting L1H(2) and L2H with Tc(V)-gluconate in a ratio 1:1:1. The complexes were characterized by elemental analysis and spectroscopic methods. Complete assignments of (1)H and (13)C NMR resonances were made for all complexes. X-ray crystallographic studies of 5 (R(1) = pyrrolidin-1-yl, R(2) = H, RSH = p-methylbenzenethiol) and 7 (R(1) = piperidin-1-yl, R(2) = CH(3), RSH = benzyl mercaptan) showed that the complexes crystallize in the monoclinic space group P2(1)/n (a = 10.223(1) Å, b = 9.283(1) Å, c = 18.337(2) Å, beta = 97.262(2) degrees, V = 1726.3(4) Å(3), Z = 4; a = 11.876(2) Å, b = 10.470(2) Å, c = 17.098(3) Å, beta = 105.990(4) degrees, V = 2043.8(6) Å(3), Z = 4, for 5 and 7, respectively). Complexes5 and 7 have distorted square pyramidal coordination geometry with the oxo ligand in the axial position. The steric requirements of the oxo group cause the Tc atom to be displaced 0.68 Å out of the mean equatorial plane of the NNSS donor atoms in both complexes.

Synthesis and Characterization of Oxotechnetium(V) Mixed-Ligand Complexes Containing a Tridentate N-Substituted Bis(2-mercaptoethyl)amine and a Monodentate Thiol.

A series of 22 mixed-ligand complexes of the general formula TcOL(1)L(2), where L(1)H(2) are N-substituted bis(2-mercaptoethyl)amine ligands, [SN(R)S], and L(2)H are monodentate thiols as coligand, is reported. The complexes were prepared by the ligand exchange method using Tc-gluconate as precursor and equimolar quantities of the two ligands. In all cases the syn stereoisomer was formed in high yield and isolated as a crystalline product. In four cases HPLC analysis demonstrated the presence of the anti stereoisomer in the reaction mixture. Although the yield was less than 1%, one anti isomer, 4a, was successfully isolated as brown crystals. The isolated complexes were characterized by spectroscopic methods and elemental analysis. The formation of the two diastereomers, syn and anti, was expected due to the configuration of the nitrogen substituent (R) with respect to the central TcO core. The X-ray crystallography showed that the coordination geometry of the syn isomers 9, 11, and 18 is trigonal bipyramidal while for the anti isomer 4a it is distorted square pyramidal. This is the first documentation of syn/anti isomerism in N-substituted TcO[SN(R)S][S] mixed-ligand complexes.

Formulation of a single-component kit for the preparation of technetium-99m labelled ethyl cysteinate dimer: biological and clinical evaluation.

Ethyl cysteinate dimer (ECD) labelled with reduced technetium-99m has recently been proposed as a promising radiopharmaceutical for brain perfusion imaging. In the present study a single-component kit formulation has been developed, thus simplifying the radiolabelling procedure. A method of analysis by electrophoresis has also been developed, permitting identification of radiochemical impurities in the preparation. 99mTc-ECD prepared by the single-component kit was further evaluated in primates and humans. The results demonstrated that the complex is stable in vivo, rapidly extracted and retained in the brain tissue for a sufficient time for single-photon emission tomography studies. Therefore the present single-component kit formulation can be proposed as a reliable instant freeze-dried kit for routine preparation of 99mTc-ECD required for scintigraphic assessment of regional cerebral blood flow.