Phase-1 clinical trial results of high-specific-activity carrier-free 123I-iobenguane.

UNLABELLED: A first-in-human phase 1 clinical study was performed on 12 healthy adults with a high-specific-activity carrier-free formulation of (123)I-iobenguane. Clinical data are presented on the behavior of this receptor-targeting imaging agent. METHODS: Whole-body and thoracic planar and SPECT imaging were performed over 48 h for calculation of tissue radiation dosimetry and for evaluation of clinical safety and efficacy. RESULTS: A reference clinical imaging database acquired over time for healthy men and women injected with high-specific-activity (123)I-iobenguane showed organ distribution and whole-body retention similar to those of conventional (123)I-iobenguane. The heart-to-mediastinum ratios for the high-specific-activity formulation were statistically higher than for conventional formulations, and the predicted radiation dosimetry estimations for some organs varied significantly from those based on animal distributions. CONCLUSION: Human normal-organ kinetics, radiation dosimetry, clinical safety, and imaging efficacy provide compelling evidence for the use of high-specific-activity (123)I-iobenguane.

Molecular imaging of human ACE-1 expression in transgenic rats.

OBJECTIVES: The aim of this study was to develop a molecular imaging strategy that can monitor myocardial angiotensin-converting enzyme (ACE)-1 upregulation as a function of progressive heart failure. BACKGROUND: High-affinity technetium-99m-labeled lisinopril (Tc-Lis) has been shown to specifically localize in tissues that express ACE in vivo, such as the lungs. Whether Tc-Lis can also detect upregulation of ACE in the heart, by external in vivo imaging, has not been established. METHODS: Twenty-one ACE-1 over-expressing transgenic (Tg) and 18 wild-type control rats were imaged using in vivo micro single-positron emission computed tomography (SPECT)-computed tomography (CT) at 10, 30, 60, and 120 min after Tc-Lis injection. A subgroup of rats received nonradiolabeled (cold) lisinopril before the Tc-Lis injection to evaluate nonspecific binding. After imaging, the rat myocardium was explanted, ex vivo images were acquired, and percent injected dose per gram gamma-well was counted, followed by an assessment of enzyme-linked immunosorbent assay-verified ACE activity and messenger ribonucleic acid expression. RESULTS: On micro SPECT-CT, myocardial ACE-1 uptake was best visualized in Tg rats at 120 min after Tc-Lis injection. The quantitative uptake of Tc-Lis in the myocardium was 5-fold higher in mutant Tg than in control rats at each time point after tracer injection. The percent injected dose per gram uptake was 0.74 ± 0.13 in Tg myocardium at 30 min and was reduced substantially to 0.034 ± 0.003% when pre-treated with cold lisinopril (p = 0.029). Enzyme activity assay showed a >30-fold higher level of ACE-1 activity in the myocardium of Tg rats than in controls. The ACE-1 messenger ribonucleic acid was quantified, and lisinopril was found to have no effect on ACE-1 gene expression. CONCLUSIONS: The Tc-Lis binds specifically to ACE, and the activity can be localized in Tg rat hearts that over-express human ACE-1 with a signal intensity that is sufficiently high to allow external imaging. Such a molecular imaging strategy may help identify susceptibility to heart failure and may allow optimization of pharmacologic intervention.

Comparison of high-specific-activity ultratrace 123/131I-MIBG and carrier-added 123/131I-MIBG on efficacy, pharmacokinetics, and tissue distribution.

Metaiodobenzylguanidine (MIBG) is an enzymatically stable synthetic analog of norepinephrine that when radiolabled with diagnostic ((123)I) or therapeutic ((131)I) isotopes has been shown to concentrate highly in sympathetically innervated tissues such as the heart and neuroendocrine tumors that possesses high levels of norepinephrine transporter (NET). As the transport of MIBG by NET is a saturable event, the specific activity of the preparation may have dramatic effects on both the efficacy and safety of the radiodiagnostic/radiotherapeutic. Using a solid labeling approach (Ultratrace), noncarrier-added radiolabeled MIBG can be efficiently produced. In this study, specific activities of >1200 mCi/micromol for (123)I and >1600 mCi/micromol for (131)I have been achieved. A series of studies were performed to assess the impact of cold carrier MIBG on the tissue distribution of (123/131)I-MIBG in the conscious rat and on cardiovascular parameters in the conscious instrumented dog. The present series of studies demonstrated that the carrier-free Ultratrace MIBG radiolabeled with either (123)I or (131)I exhibited similar tissue distribution to the carrier-added radiolabeled MIBG in all nontarget tissues. In tissues that express NETs, the higher the specific activity of the preparation the greater will be the radiopharmaceutical uptake. This was reflected by greater efficacy in the mouse neuroblastoma SK-N-BE(2c) xenograft model and less appreciable cardiovascular side-effects in dogs when the high-specific-activity radiopharmaceutical was used. The increased uptake and retention of Ultratrace (123/131)I-MIBG may translate into a superior diagnostic and therapeutic potential. Lastly, care must be taken when administering therapeutic doses of the current carrier-added (131)I-MIBG because of its potential to cause adverse cardiovascular side-effects, nausea, and vomiting.

Novel polar single amino acid chelates for technetium-99m tricarbonyl-based radiopharmaceuticals with enhanced renal clearance: application to octreotide.

Single amino acid chelate (SAAC) systems for the incorporation of the M(CO)(3) moiety (M = Tc/Re) have been successfully incorporated into novel synthetic strategies for radiopharmaceuticals and evaluated in a variety of biological applications. However, the lipophilicity of the first generation Tc(CO)(3)-dipyridyl complexes has resulted in substantial hepatobiliary uptake when either examined as lysine derivatives or integrated into biologically active small molecules and peptides. Here we designed, synthesized, and evaluated novel SAAC systems that have been chemically modified to promote overall Tc(CO)(3)L(3) complex hydrophilicity with the intent of enhancing renal clearance. A series of lysine derived SAAC systems containing functionalized polar imidazole rings and/or carboxylic acids were synthesized via reductive alkylation of the epsilon amino group of lysine. The SAAC systems were radiolabeled with (99m)Tc, purified, and evaluated for radiochemical stability, lipophilicity, and tissue distribution in rats. The log P values of the (99m)Tc complexes were determined experimentally and ranged from -0.91 to -2.33. The resulting complexes were stable (>90%) for at least 24 h. Tissue distribution in normal rats of the lead (99m)Tc complexes demonstrated decreased liver (<1 %ID/g) and gastrointestinal clearance (<1.5%ID/g) and increased kidney clearance (>15 %ID/g) at 2 h after injection compared to the dipyridyl lysine complex (DpK). One of the new SAAC ligands, [(99m)Tc]bis-carboxymethylimidazole lysine, was conjugated to the N-terminus of Tyr-3 octreotide and evaluated for localization in nude mice bearing AR42J xenografts to examine tissue distribution, tumor uptake and retention, clearance, and route of excretion for comparison to (111)In-DOTA-Tyr-3-octreotide and (99m)Tc-DpK-Tyr-3-octreotide. (99m)Tc-bis-(carboxymethylimidazole)-lysine-Tyr-3-octreotide exhibited significantly less liver uptake and gastrointestinal clearance compared to (99m)Tc-DpK-Tyr-3-octreotide while maintaining tumor uptake in the same mouse model. These novel chelators demonstrate that lipophilicity can be controlled and organ distribution significantly altered, opening up broad application of these novel SAAC systems for radiopharmaceutical design.

Preclinical evaluation of novel glutamate-urea-lysine analogues that target prostate-specific membrane antigen as molecular imaging pharmaceuticals for prostate cancer.

Prostate-specific membrane antigen (PSMA) is expressed in normal human prostate epithelium and is highly up-regulated in prostate cancer. We previously reported a series of novel small molecule inhibitors targeting PSMA. Two compounds, MIP-1072, (S)-2-(3-((S)-1-carboxy-5-(4-iodobenzylamino)pentyl)ureido)pentanedioic acid, and MIP-1095, (S)-2-(3-((S)-1carboxy-5-(3-(4-iodophenyl)ureido)pentyl)ureido)pentanedioic acid, were selected for further evaluation. MIP-1072 and MIP-1095 potently inhibited the glutamate carboxypeptidase activity of PSMA (K(i) = 4.6 +/- 1.6 nmol/L and 0.24 +/- 0.14 nmol/L, respectively) and, when radiolabeled with (123)I, exhibited high affinity for PSMA on human prostate cancer LNCaP cells (K(d) = 3.8 +/- 1.3 nmol/L and 0.81 +/- 0.39 nmol/L, respectively). The association of [(123)I]MIP-1072 and [(123)I]MIP-1095 with PSMA was specific; there was no binding to human prostate cancer PC3 cells, which lack PSMA, and binding was abolished by coincubation with a structurally unrelated NAALADase inhibitor, 2-(phosphonomethyl)pentanedioic acid (PMPA). [(123)I]MIP-1072 and [(123)I]MIP-1095 internalized into LNCaP cells at 37 degrees C. Tissue distribution studies in mice showed 17.3 +/- 6.3% (at 1 hour) and 34.3 +/- 12.7% (at 4 hours) injected dose per gram of LNCaP xenograft tissue, for [(123)I]MIP-1072 and [(123)I]MIP-1095, respectively. [(123)I]MIP-1095 exhibited greater tumor uptake but slower washout from blood and nontarget tissues compared with [(123)I]MIP-1072. Specific binding to PSMA in vivo was shown by competition with PMPA in LNCaP xenografts, and the absence of uptake in PC3 xenografts. The uptake of [(123)I]MIP-1072 and [(123)I]MIP-1095 in tumor-bearing mice was corroborated by single-photon emission computed tomography/computed tomography (SPECT/CT) imaging. PSMA-specific radiopharmaceuticals should provide a novel molecular targeting option for the detection and staging of prostate cancer.

Comprehensive radiolabeling, stability, and tissue distribution studies of technetium-99m single amino acid chelates (SAAC).

Technetium tricarbonyl chemistry has been a subject of interest in radiopharmaceutical development over the past decade. Despite the extensive work done on developing chelates for Tc(I), a rigorous investigation of the impact of changing donor groups and labeling conditions on radiochemical yields and/or distribution has been lacking. This information is crucially important if these platforms are going to be used to develop molecular imaging probes. Previous studies on the coordination chemistry of the {M(CO)(3)}(+) core have established alkylamine, aromatic nitrogen heterocycles, and carboxylate donors as effective chelating ligands. These observations led to the design of tridentate ligands derived from the amino acid lysine. Such amino acid analogues provide a tridentate donor set for chelation to the metal and an amino acid functionality for conjugation to biomolecules. We recently developed a family of single amino acid chelates (SAAC) that serve this function and can be readily incorporated into peptides via solid-phase synthesis techniques. As part of these continuing studies, we report here on the radiolabeling with technetium-99m ((99m)Tc) and stability of a series of SAAC analogues of lysine. The complexes studied include cationic, neutral, and anionic complexes. The results of tissue distribution studies with these novel complexes in normal rats demonstrate a range of distribution in kidney, liver, and intestines.

Synthesis and evaluation of a series of 99mTc(CO)3+ lisinopril complexes for in vivo imaging of angiotensin-converting enzyme expression.

In animal models of cardiac disease and in human congestive heart failure, expression of angiotensin-converting enzyme (ACE) is upregulated in the failing heart and has been associated with disease progression leading to cardiac failure and fibrosis. To develop probes for imaging ACE expression, a series of di(2-pyridylmethyl)amine (D) chelates capable of binding M(CO)3+ (M = technetium, rhenium) was conjugated to lisinopril by acylation of the epsilon-amine of the lysine residue with a series of di(2-pyridylmethylamino)alkanoic acids where the distance of the chelator from the lisinopril core was investigated by varying the number of methylene spacer groups to produce di(2-pyridylmethyl)amine(Cx)lisinopril analogs: D(C4)lisinopril, D(C5)lisinopril, and D(C8)lisinopril. The inhibitory activity of each rhenium complex was evaluated in vitro against purified rabbit lung ACE and was shown to vary directly with the length of the methylene spacer: Re[D(C8)lisinopril], inhibitory concentration of 50% (IC50) = 3 nM; Re[D(C5)lisinopril], IC50 = 144 nM; and Re[D(C4)lisinopril], IC50 = 1,146 nM, as compared with lisinopril, IC50 = 4 nM. The in vivo specificity for ACE was determined by examining the biodistribution of the 99mTc-[D(C8)lisinopril] analog in rats with and without pretreatment with unlabeled lisinopril. Uptake in the lungs, a tissue that constitutively expresses ACE, was 15.2 percentage injected dose per gram at 10 min after injection and was dramatically reduced by pretreatment with lisinopril, supporting ACE-mediated binding in vivo. Planar anterior imaging analysis of 99mTc-[D(C8)lisinopril] corroborated these data. Thus, high-affinity 99mTc-labeled ACE inhibitor has been designed with potency similar to that of lisinopril and has been demonstrated to specifically localize to tissues that express ACE in vivo. This agent may be useful in monitoring ACE as a function of disease progression in relevant diseases such as heart failure.

Mechanistic investigation of beta-galactosidase-activated MR contrast agents.

We report a mechanistic investigation of an isomeric series of beta-galactosidase-activated magnetic resonance contrast agents. Our strategy focuses on the synthesis of macrocyclic caged-complexes that coordinatively saturate a chelated lanthanide. Enzyme cleavage of the complex results in an open coordination site available for water that creates a detectable MR contrast agent. The complexes consist of a DO3A Gd(III) chelator modified with a galactopyranose at the N-10 position of the macrocycle. We observed significant differences in relaxometric properties and coordination geometry that can be correlated to subtle variations of the linker between the macrocycle and the galactopyranose. After synthesis and purification of the R, S, and racemic mixtures of complexes 1 and 3 and measurement of the hydration number, water residence lifetime, and longitudinal relaxation rates, we propose mechanisms for water exclusion from the lanthanide in the precleavage state. While the stereochemistry of the linker does not influence the agents' properties, the mechanism of water exclusion for each isomer is significantly influenced by the position of modification. Data for one series with a methyl group substituted on the sugar-macrocycle linker at the alpha-position suggests a steric mechanism where the galactopyranose sugar blocks water from the Gd(III) center. In contrast, our observations for a second series with methyl substitution at the beta position of the sugar-macrocycle linker are consistent with a mechanism in which a bidentate anion occupies two available coordination sites of Gd(III) in the precleavage state.

A gadolinium chelate for detection of beta-glucuronidase: a self-immolative approach.

New classes of physiologically responsive magnetic resonance (MR) contrast agents are being developed that are activated by enzymes, secondary messengers, pH, and temperature. To this end, we have prepared a new class of enzyme-activated MR contrast agents using a self-immolative mechanism and investigated the properties of these agents using novel in vitro assays. We have synthesized in nine steps a Gd(III) agent 1 that is activated by the oncologically significant beta-glucuronidase. 1 consists of Gd(III)DO3A (DO3A = 1,4,7-tricarboxymethylene-1,4,7,10-tetraazacyclododecane) bearing a pendant beta-glucuronic acid moiety connected by a self-immolative linker to the macrocycle. LC-MS analysis reveals that 1 is enzymatically processed as predicted by bovine liver beta-glucuronidase, generating 2-aminoethylGdDO3A, 2. Compound 2 was prepared independently in a four-step synthetic procedure. Complex 1 displays a decrease in relaxivity upon titration with bicarbonate anion. The relaxivity increases when 1 is converted to 2 in a buffer mimicking in vivo anion concentrations (Parker, D. In Crown Compounds: Towards Future Applications; Cooper, S. R., Ed.; VCH: New York, 1992; pp 51-67) by 17%, while the relaxivity decreases by 27% for the same experiment in human blood serum. Hydrolytic kinetics catalyzed by bovine liver beta-glucuronidase at interstitial pH = 7.4 fit the Michaelis-Menten model with k cat/Km = 74.9 +/- 10.9 M(-1) s(-1). Monitoring of bulk water proton T1 during incubation with enzyme shows an increase in T1 that mirrors results obtained through the relaxivity measurements of compounds 1 and 2.

Synthesis, characterization and crystal structures of mono-, di- and trinuclear rhenium(I) tricarbonyl complexes with 2,3,5,6-tetra(2-pyridyl)pyrazine.

A series of rhenium(I) tricarbonyl complexes with the ligand 2,3,5,6-tetra(2-pyridyl)pyrazine (tppz) were synthesized and characterized crystallographically. Two different coordination modes were found when tppz functions as a monobidentate ligand. Rhenium(I) may be bound to tppz through pyrazine and pyridyl nitrogens completing a 5-membered coordination ring when the reaction was carried out in toluene. However, the same reaction in methanol produced a yellow complex in which rhenium(I) was bound to tppz through two adjacent pyridyl nitrogens with a 7-membered coordination ring. In the presence of an excess amount of [ReBr(CO)(5)], the dinuclear complex [{ReBr(CO)(3)}(2)(mu-tppz)] (3) was isolated, while the trinuclear complex [{ReCl(CO)(3)}(3)-(mu-tppz)] (4) was obtained in the case of [ReCl(CO)(5)]. Crystal data for 1, C(27)H(16)ClN(6)O(3)Re.MeOH: monoclinic, P2(1)/n, a = 9.2217(7), b = 10.7628(8), c = 26.932(2) A, beta= 94.130(1) degrees , V = 2666.1(3) A(3), Z = 4. 2, C(27)H(16)BrN(6)O(3)Re: monoclinic, P2(1)/n, a = 9.2931(6), b = 10.2387(7), c = 27.993(2) A, beta = 94.615(1) degrees , V = 2654.8(3) A(3),Z = 4. 1', C(27)H(16)ClN(6)O(3)Re.2H(2)O: monoclinic, C(2)/c, a = 18.584(4), b = 21.693(5), c = 15.392(4) A, beta = 122.328(3) degrees , V = 5243(2) A(3), Z = 8. 3, C(30)H(16)Br(2)N(6)O(6)Re(2): triclinic, P1, a = 7.4668(6), b = 11.4902(10), c = 19.3736(16) A, alpha = 73.659(2), beta = 85.183(2), gamma = 77.097(1) degrees , V = 1554.3(2) A(3), Z = 2. 4, C(33)H(16)Cl(3)N(6)O(9)Re(3).1/2C(6)H(6): orthorhombic, Pbca, a = 18.828(1), b = 16.715(1), c = 25.366(2) A, V = 7983.2(10) A(3), Z = 8.

Schiff base chemistry of the rhenium(V)-oxo core with '3+2' ligand donor sets.

Reactions of [ReOCl(3)(PPh(3))(2)] with the bidentate ligands 2-(2-hydroxyphenyl) benzoxazole and (2'-hydroxyphenyl)-2-thiazoline resulted in the isolation of the complexes [ReOCl(2)(OC(6)H(4)-2-C=NC(6)H(4)-2-O)(PPh(3))] (1) and [ReOCl(2)(OC(6)H(4)-2-C=NCH(2)CH(2)S)(PPh(3))] (2). Reactions of 1 with the tridentate Schiff base ligands salicylaldehyde 2-hydroxyanil (H(2)L(1b)), salicylaldehyde 2-mercaptoanil (H(2)L(2b)) afnd S-benzyl-2-[(2-hydroxyphenyl)methylene] dithiocarbazate (H(2)L(3b)) yielded the '3+2' rhenium(V) oxo species [ReO(OC(6)H(4)-2-C=NC(6)H(4)O) (OC(6)H(4)CH=NC(6)H(4)O)] (3), [ReO(OC(6)H(4)-2-C=NC(6)H(4)O)-(OC(6)H(4)CH=NC(6)H(4)S)] (4) and [ReO(OC(6)H(4)-2-C=NC(6)H(4)O){OC(6)H(4)CH=N-N=C(SCH(2)C(6)H(5))S}] (5). Similarly, the reactions of [ReOCl(2)(OC(6)H(4)-2-C=NC(6)H(4)S)(PPh(3))] (2) with H(2)L(2b), H(2)L(3b) and 2-[(2-hydroxyphenyl) methylene]-N-phenyl-hydrazinecarbothioamide (H(2)L(4b)) were exploited to prepare [ReO(OC(6)H(4)-2-C=NC(6)H(4)S)(OC(6)H(4)CH=NC(6)H(4)O)] (6), [ReO(OC(6)H(4)C=NC(6)H(4)S){OC(6)H(4)CH=N-N=C (SCH(2)C(6)H(5))S}] (7) and [ReO(OC(6)H(4)-2-C=NC(6)H(4)S){OC(6)H(4)CH=N-N=C(NHC(6)H(5))}] (8), respectively.

Synthesis and structural characterization of rhenium(I) tricarbonyl complexes with the bidentate ligands o-(diphenylphosphino)benzaldehyde (P∩O) and o-[(diphenylphosphino)benzylidene]analine (P∩N).

A series of rhenium(I) tricarbonyl complexes with bidentate P,O donor ligand o-(diphenylphosphino)benzaldehyde (P∩O) and its Schiff base P,N donor ligand o-[diphenylphosphino)benzylidene]analine (P∩N) have been synthesized and structurally characterized. All the complexes of the type [ReX(CO)(3)(LL)] (where LL = P∩O, P∩N) reveal a distorted octahedral structure with the three carbonyl ligands arranged in the facial fashion. Crystal data for 1, C(22)H(15)ClO(4)PRe·1/2C(6)H(14): triclinic, P1, a=8.7430(4), b=9.5767(4), c=13.9449(6) Å, α=93.651(1), ß=101.265(1), γ=93.048(1); V=1140.20(9) Å(3), Z=2.2, C(22)H(15)BrO(4)Pre: monoclinic, C2/c, a=31.6800(16), b=8.8880(4), c=18.4517(9) Å, ß=124.990(1); V=4256.4(4) Å(3), Z=8. 3, C(28)H(20)ClNO(3)Pre: monoclinic, C2/c, a=22.675(4), b=8.803(2), c=28.218(5) Å, ß=100.192(3); V=5543.5(16) Å(3), Z=8.4, C(28)H(20)BrNO(3)Pre: monoclinic, C2/c, a=23.035(1), b=8.7561(4), c=28.269(1) Å, ß=100.811(1); V=5600.4(5) Å(3), Z=8.

Investigations of the {ReO} core: A '2+2' complex from bidentate and potentially trident ligands: [ReO(η-HOC(6)H(4)-2-CH(2)NC(6)H(4)S)(η-SC(5)H(4)N)(PPh(3))].

The reaction of [ReOCl(3)(PPh(3))(2)] with N-(2-hydroxybenzyl)-2-mercaptoaniline (H(3)hbma) (2) and 2-mercaptopyridine in hot CHCl yields [ReO(η(2)-HOC(6)H(4)-2-CH(2)NC(6)H(4)S)(η(2)-SC(5)H(4)N)(PPh(3))] (3). The structure of 3 consists of distorted octahedral Re(V) monomers. The coordination geometry at the rhenium is defined by a terminal oxo-group, the nitrogen and sulfur donors of the chelating mercaptopyridine, the nitrogen and sulfur donors of a bidentate (Hhbma)(2-) ligand, and the phosphorus of the PPh(3) group. The -C(6)H(4)OH arm of (Hhbma)(2-) is pendant, and the coordinated nitrogen of this ligand is present as a deprotonated amido nitrogen.

Synthesis and characterization of oxorhenium(V)-'3+1' mixed thiolate [SNS]/[S] and [ONS]/[S] complexes. Crystal and molecular structures of [ReO(eta-SCH(2)C(5)H(3)NCH(2)S)(eta-C(6)H(4)Br-4-S)], [ReO(eta-SCH(2)C(5)H(3)NCH(2)O)(eta-C(6)H(4)X-4-S)] (X=Cl, OMe), [ReO(eta-SCH(2)C(5)H(3)NCH(2)O)(eta-C(6)H(4)OCH(3)-4-CH(2)S)] and [ReO(eta-SCH(2)C(5)H(3)NCH(2)S)(eta-C(5)H(4)NH-2-S)][Cl].

The reaction of [ReOCl(3)(PPh(3))(2)] with the tridentate ligands 2,6-dithiomethylpyridine (4) or 6-thiomethyl-2-pyridinemethanol (5) and the appropriate monothiols, such as para-substituted benzenethiols (C(6)H(4)X-4-SH) (where X=F, Cl, Br and OCH(3)) and para-substituted benzylmercaptans (C(6)H(4)X-4-CH(2)SH) (where X=F, Cl and OCH(3)) in the presence of Et(3)N leads to the isolation of a series of integrated '3+1' oxorhenium(V) complexes. Similarly, reaction of [ReOCl(3)(PPh(3))(2)] with 2-mercaptopyridine and 4 afforded a cationic oxorhenium(V) complex, [ReO(eta(3)-SCH(2)C(5)H(3)NCH(2)S)(eta(1)-C(5)H(4)NH-2-S)][Cl] (22). Crystal data for 10, C(13)H(11)BrNOS(3)Re: triclinic, P1, a=7.2909(5), b=14.1978(9), c=15.991(1) A, alpha=77.184(1), beta=86.588(1), gamma=75.507(1) degrees , V=1562.69(18) A(3), Z=4. For 16, C(13)H(11)ClNO(2)S(2)Re: orthorhombic, P2(1)2(1)2(1), a=6.9728(6), b=13.477(1), c=15.761(1) A, V=1481.1(2) A(3), Z=4. For 18, C(14)H(14)NO(3)S(2)Re: monoclinic, P2(1)/c, a=15.6512(14), b=7.6678(7), c=13.732(1) A, beta=112.489(1) degrees , V=1522.7(2) A(3), Z=4. For 21, C(15)H(16)NO(3)S(2)Re: monoclinic, P2(1)/c, a=13.929(1), b=7.741(1), c=15.583(2) A, beta=103.600(2) degrees , V=1633.1(3) A(3), Z=4. For 22, C(12)H(11)ClN(2)OS(3)Re: monoclinic, C2(1)/(c), a=27.827(3), b=8.529(1), c=14.957(2) A, beta=119.314(2) degrees , V=3095.3(6) A(3), Z=8.

Oxorhenium(V) complexes containing tridentate Schiff-base and monothiol coligands.

The reaction of [n-(C(4)H(9))(4)N][ReOBr(4)(OPPh(3))] with the tridentate Schiff-base [HOC(6)H(4)C(H)NC(6)H(4)SH] allows for the isolation of [ReOBr{eta(3)-(OC(6)H(4)C(H)NC(6)H(4)S)}] (1). The reaction of [n-(C(4)H(9))(4)N][ReOBr(4)(OPPh(3))] with [HOC(6)H(4)C(H)NC(6)H(4)SH] and the appropriate benzenethiol (C(6)H(4)X-4-SH) where X=H, Br, Cl, F, and OCH(3) in methanol-acetonitrile treated with triethylamine has led to the isolation of a series of rhenium complexes of the type [ReO{eta(3)-(OC(6)H(4)C(H)NC(6)H(4)S)} (eta(1)-C(6)H(4)X-4-S)] (X=H (2), Br (3), Cl (4), F (5), and OCH(3) (6)). Likewise, under similar reaction conditions, the use of benzylmercaptan ligands of the type (C(6)H(4)X-4-CH(2)SH) where X=H, Cl, F, and OCH(3) has led to the isolation of a series of rhenium complexes of the type [ReO{eta(3)-(OC(6)H(4)C(H)NC(6)H(4)S)} (eta(1)-C(6)H(4)X-4-CH(2)S)] (X=H (7), Cl (8), F (9), and OCH(3) (10)). The incorporation of the appropriate amine functionality into the substituent R of the monodentate ligand allows for the isolation of a cationic oxorhenium(V) species, namely, [ReO{eta(3)-(OC(6)H(4)C(H)NC(6)H(4)S)} (eta(1)-C(5)H(4)NH-2-S)][Br] (11).

The syntheses and structures of '3+2' and '2+2+1' oxorhenium mixed-ligand complexes employing 8-hydroxy-5-nitroquinoline as the bidentate N,O donor ligand.

The syntheses and structural characterizations of a series of novel '3+2' and '2+2+1' mixed-ligand complexes carrying 8-hydroxy-5-nitroquinoline (HL) as the bidentate N,O donor atom system are reported. Thus one-pot reactions of [ReOCl(3)(PPh(3))(2)] with dianionic tridentate ligands H(2)L(n) (where H(2)L(1)=HOC(6)H(4)-2-CH=NC(6)H(4)-2-OH; H(2)L(2)=HOC(6)H(4)-2-CH=N-C(6)H(4)-2-SH; H(2)L(3)=HOC(6)H(4)-2-CH=NN=C(NHC(6)H(5))-SH; H(2)L(4)=2-CH(2)OH-C(5)H(3)N-6-CH(2)SH; and H(2)L(5)=2-CO(2)H-C(5)H(3)N-6-CO(2)H) and HL afforded a series of '3+2' oxorhenium complexes of the type [ReO(H(2)L(n))(L)] 2-6, which exhibit distorted octahedral geometries. Crystals of 1 are monoclinic space group C2/c, a=16.702(1), b=14.275(1), c=22.363(2) A, beta=108.083(1) degrees V=5068.2(7) A(beta) and Z=8; those of 2 are monoclinic space group P2(1)/n, a=8.5093(4) b=38.518(2), c=11.6092(5) A, beta=97.708(1) degrees , V=3770.7(3) A(3) and Z=8; those of 5 are triclinic, space group P1-, a=7.5899(8), b=10.322(1), c=11.905(1) A, alpha=78.636(2) degrees , beta=74.229(2) degrees , gamma=71.391(2) degrees , V=844.3(2) A(3), and Z=2. Upon reaction of 2,6-pyridinedimethanol (H(2)L(6)) with the intermediate complex [ReOCl(2)(L)(PPh(3))] (1), only one of the two methylene hydroxy group was deprotonated and a new '2+2+1' complex [ReO(OCH(3))(HL(6))(L)].CH(3)OH (7) was obtained. Crystal data for 7: monoclinic P2(1)/n, a=12.0579(6), b=11.0993(6), c=14.9262(8) A, beta=107.872(1) degrees , V=1901.2(2) A(3), and Z=8. In the preparation of complex 3, cleavage of the C=N bond of the Schiff base H(2)L(2) was observed and the '2+2+1' complex 8 [ReO(PPh(3))(eta(2)-NHC(6)H(4)-2-S)(L)].CH(2)Cl(2) having 2-aminothiophenol as a dianionic bidentate ligand was isolated. Crystals of 8 are monoclinic space group C2/c, a=25.627(2), b=8.1305(6) c=31.404(2) A beta=96.147(1) degrees , V=6505.7(8) A(3), and Z=8. Reduction of HL to 8-hydroxy-5-aminoquinoline was realized during the formation of complex 6, and a new complex 9 was thus isolated involving the coordination of two sets of N,O donor atoms from L and 8-hydroxy-5-aminoquinoline while a methoxy oxygen atom completes the octahedral coordination geometry. Crystals of 9 are monoclinic space group P2(1)/n, a=7.5330(6), b=15.095(1), c=16.394(1) A, beta=99.690(2) degrees , V=1837.7(3) A(3), and Z=4.

Exploring oxorhenium '3+1' mixed-ligand complexes carrying the S-benzyl-3-[(2-hydroxyphenyl)methylene]dithiocarbazate [ONS]/monothiol [S] donor set: synthesis and characterization.

The reaction of ReOCl(3)(PPh(3))(2) with the potentially tridentate ligand S-benzyl-3-[(2-hydroxyphenyl)methylene]dithiocarbazate ([ONS] donor set) and para-substituted benzenethiols [C(6)H(4)X-4-SH] (where X=H, F, Cl, Br and OCH(3)) in the presence of Et(3)N afforded a series of integrated '3+1' oxorhenium(V) complexes with general formula [ReO{eta(3)-OC(6)H(4)-2-CH=N-N=C(SCH(2)Ph)-S}(eta(1)-C(6)H(4)X-4-S)]. The molecular structure of [ReO{eta(3)-OC(6)H(4)-2-CH=N-N=C(SCH(2)Ph)-S}(eta(1)-C(6)H(4)F-4-S)] (4) was determined by single-crystal X-ray analysis. Complex 4 consists of a central oxorhenium(V) core with phenolic oxygen, azomethine nitrogen and thiol sulfur donor from the thiosemicarbazone Schiff base ligand and one sulfur donor from monothiol ligand completing a distorted square pyramidal environment. Crystal data for 4, C(21)H(16)FN(2)O(2)S(3)Re: orthorhombic, P2(1)2(1)2(1), a=5.6682(3), b=11.6600(6), c=31.697(2) A, V=2094.9(2) A(3), Z=4.

Synthesis and crystal and molecular structure of a tetranuclear cluster based on the rhenium(III)-bisorganohydrazino core: [Re(HNNC(4)H(3)N(2))(NNC(4)H(3)N(2))(OCH(3))(2)](4).

Reaction of NH(4)ReO(4) with excess 2-hydrazinopyrimidine in methanol yields [Re(eta(1)-NNC(4)H(3)N(2)H)(eta(2)-HNNC(4)H(3)N(2))Cl(3)] (1). Attempts to recrystallize 1 by slow diffusion of methanol into DMF after 8 months produced black crystals of [Re(HNNC(4)H(3)N(2))(NNC(4)H(3)N(2))(OCH(3))(2)](4) (2). The structure of 2 consists of isolated tetranuclear clusters, constructed from {Re(eta(2)-HNNC(4)H(3)N(2))(eta(1)-NNC(4)H(3)N(2))(OCH(3))(2)} units linked through the beta-nitrogen of the chelating organodiazene ligand of adjacent units into a box-like aggregate.

Schiff base chemistry of the {ReO} core: structural characterization of the unusual '3 + 2' complex [ReO(eta-OC(6)H(4)-CH=NC(6)H(4)-2-S)(eta-OC(6)H(4))].

The reaction of [ReOCl(3)(PPh(3))(2)] with salicylaldehyde-2-mercaptoanil (1) in methanol yields [ReO(OCH(3))(PPh(3))(eta(3)-OC(6)H(4)CH=NC(6)H(4)S)] (3). Reaction of 3 with 2-(2-hydroxyphenyl)benzothiazole (2) produces [ReO(eta(3)-OC(6)H(4)CH=NC(6)H(4)S)( eta(2)-OC(6)H(4))] (4) in good yield. Compound 4 may also be prepared directly from the reaction of [ReOCl(3)(PPh(3))(2)] with excess 1, after prolonged reaction times in the presence of atmospheric oxygen. The structure of 3 exhibits a distorted octahedral Re(V) center coordinated to a terminal oxo-group, a methoxy ligand, a triphenylphosphine ligand, and the N, O and S donors of the tridentate Schiff base ligand. The octahedral geometry of 4 is defined by the terminal oxo-group, the N, O and S donors of the tridentate Schiff base ligand, and the N and O donors of the bidentate 2-(2-hydroxophenyl)benzothiazole ligand. Oxidation and cyclization of the Schiff base salicylaldehyde-2-mercaptoanil to produce 2-(2-hydroxyphenyl)benzothiazole is precedented and in this instance may be driven by the formation of the robust '3+2' complex 4.

Synthesis and characterization of complexes of the {ReO} core with SNS and S donor ligands.

The reaction of [ReOCl(3)(PPh(3))(2)] with N,N-bis(2-mercaptoethyl)benzylamine and 4-bromobenzenethiol allowed for the isolation of [ReO{eta(3)-(SCH(2)CH(2))(2)N(CH(2)C(6)H(5))}-(eta(1)-C(6)H(4)Br-4-S)] (1). The reaction of [ReOCl(3)(PPh(3))(2)] with [(HSCH(2)CH(2))(2)N(CH(2)C(5)H(4)N)] and the appropriate thiol in chloroform treated with triethylamine has led to the isolation of a series of neutral rhenium complexes of the type [ReO{eta(3)-(SCH(2)CH(2))(2)N(CH(2)C(5)H(4)N)}(eta(1)-C(6)H(4)X-4-S)] (X = Br (2), Cl (3), F (4), and OCH(3) (5)) and [ReO{eta(3)-(SCH(2)CH(2))(2)N(CH(2)C(5)H(4)N)}(eta(1)-C(6)H(4)OCH(3)-4-CH(2)S)] (6). Likewise, under similar reaction conditions, the use of the related tridentate ligand, [(HSCH(2)CH(2))(2)N(CH(2)CH(2)C(5)H(4)N)], has led to the isolation of a series of rhenium complexes of the type [ReO{eta(3)-(SCH(2)CH(2))(2)N(CH(2)CH(2)C(5)H(4)N)}(eta(1)-C(6)H(4)X-4-S)] (X=Br (7), Cl (8), OCH(3) (9)), as well as [ReO{eta(3)-(SCH(2)CH(2))(2)N(CH(2)CH(2)C(5)H(4)N)}(eta(1)-C(6)H(4)Cl-4-CH(2)S)].0.5CH(3)(CH(2))(4)CH(3) (10). These compounds are extensions of the '3+1' approach to the synthesis of materials with the {MO}(3+) core (M=Tc and Re), which have applications in nuclear medicine. The ligands chosen allow systematic exploration of the consequences of para-substitution on the monodentate thiolate ligand [S] and of derivatization of the substituent R on the tridentate aminodithiol ligand [SNS] of the type (HSCH(2)CH(2))(2)NR. Such modifications can influence lipophilicity, charge, size and molecular weight of the complex and consequently the biodistribution.