Optimised production of technetium-94m for PET imaging by proton-irradiation of phosphomolybdic acid in cyclotron liquid target.

Natural-abundance phosphomolybdic acid (H3(Mo12PO40) ‧12H2O, 0.181-0.552 g Mo/mL) solutions were irradiated with 12.9 MeV protons on a GE PETtrace cyclotron using an adapted standard liquid target. Technetium-94m (94mTc) was produced through the 94Mo(p,n)94mTc nuclear reaction with saturation yields of up to 53 ± 6 MBq/µA. End of bombardment activities of 161 ± 17 MBq and 157 ± 7 MBq were achieved for the 0.552 g Mo/mL solution (10 µA for 30 min) and 0.181 g Mo/mL solution (15 µA for 60 min), respectively. No visible degradation of the niobium target body and foil were seen during the irradiations of up to 15 µA for 60 min. The produced 94mTc was separated from the target phosphomolybdic acid solution with >98% recovery using an aqueous biphasic extraction resin. Compared to previous reported liquid target methods for 94mTc production, the better production yield, in-target solution stability during irradiation and 94mTc separation recovery of phosphomolybdic acid makes it a very promising target material for routine clinical 94mTc production at medical facilities with liquid targets already installed for 18F production.

(125)I-Labelled 2-Iodoestrone-3-sulfate: synthesis, characterization and OATP mediated transport studies in hormone dependent and independent breast cancer cells.

INTRODUCTION: Organic Anion Transporting Polypeptides (OATP) are a family of membrane associated transporters that facilitate estrone-3-sulphate (E3S) uptake by hormone dependent, post-menopausal breast cancers. We have established E3S as a potential ligand for targeting hormone dependent breast cancer cells, and in this study sought to prepare and investigate radioiodinated E3S as a tool to study the OATP system. METHODS: 2- and 4-Iodoestrone-3-sulfates were prepared from estrone via aromatic iodination followed by a rapid and high yielding sulfation procedure. The resulting isomers were separated by preparative HPLC and verified by (1)H NMR and analytical HPLC. Transport studies of 2- and 4-[(125)I]-E3S were conducted in hormone dependent (i.e. MCF-7) and hormone independent (i.e. MDA-MB-231) breast cancer cells in the presence or absence of the specific transport inhibitor, bromosulfophthalein (BSP). Cellular localization of OATP1A2, OATP2B1, OATP3A1 and OATP4A1 were determined by immunofluorescence analysis using anti-Na(+)/K(+) ATPase-α (1:100 dilution) and DAPI as plasma membrane and nuclear markers, respectively. RESULTS: Significantly (p<0.01) higher total accumulation of 2-[(125)I]-E3S was observed in hormone dependent MCF-7 as compared to hormone independent MDA-MB-231 breast cancer cells. In contrast 4-[(125)I]-E3S did not show cellular accumulation in either case. The efficiency of 2-[(125)I]-E3S transport (expressed as a ratio of Vmax/Km) was 2.4 times greater in the MCF-7 as compared to the MDA-MB-231 breast cancer cells. OATP1A2, OATP3A1 and OATP4A1 expression was localized in plasma membranes of MCF-7 and MDA-MB-231 cells confirming the functional role of these transporters in radioiodinated E3S cellular uptake. CONCLUSION: An efficient method for the preparation of 2- and 4-[(125)I]-E3S was developed and where the former demonstrated potential as an in vitro probe for the OATP system. The new E3S probe can be used to study the OATP system and as a platform to create radiopharmaceuticals for imaging breast cancer.

Synthesis and in vitro evaluation of derivatives of the ß1-adrenergic receptor antagonist HX-CH 44.

Isopropyl- and fluoroisopropyl-amino derivatives of the ß(1)-adrenergic receptor antagonist 2-[4-[3-(tert-butyl-amino)-2-hydroxypropoxy]phenyl]-3-methyl-6-methoxy-4(3H)-quinazolinone ((±)HX-CH 44) were synthesized, including a concise and efficient preparation of the core, 2-(4-hydroxyphenyl)-6-methoxy-3-methylquinazolin-4(3H)-one. In vitro binding assays showed that the fluorinated analog was selective towards ß(1)-adrenergic receptors over ß(2)-adrenergic and 5-HT(1A) receptors. An X-ray crystallographic characterization of the fluorinated analog is also reported.

An improved radiosynthesis of the muscarinic M2 radiopharmaceutical, [18F]FP-TZTP.

The radioligand 3-(4-(3-[(18)F]fluoropropylthio)-1,2,5-thiadiazol-3-yl)-1-methyl-1,2,5,6-tetrahydropyridine ([(18)F]FP-TZTP) is an agonist with specificity towards subtype 2 of muscarinic acetylcholine (M2) receptors. It is currently the only radiotracer available for imaging M2 receptors in human subjects with positron emission tomography. The present study reports on an improved method for the synthesis of [(18)F]FP-TZTP, automated using a GE TRACERlab FX(FN) radiosynthesis module. A key facet was the use of a new precursor, 3-(4-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazol-3-ylthio)propyl 4-methylbenzenesulfonate. The precursor was fluorinated via nucleophilic displacement of the tosyloxy group by potassium cryptand [(18)F]fluoride (K[(18)F]/K(222)) in CH(3)CN at 80 degrees C for 5 min, and purified by HPLC. Formulated [(18)F]FP-TZTP was prepared in an uncorrected radiochemical yield of 29+/-4%, with a specific activity of 138+/-41 GBq/micromol (3732+/-1109 mCi/micromol) at the end of synthesis (35 min; n=3). This methodology offers higher yields, faster synthesis times, an optimized precursor, and simpler automation than previously reported.

Synthesis and preliminary evaluation of [(18)F]-fluoro-(2S)-Exaprolol for imaging cerebral beta-adrenergic receptors with PET.

Cerebral beta-adrenergic receptors (beta-ARs) are of interest in several disorders including Parkinson's disease, Alzheimer's disease and in particular major depressive disorder. Development of a positron emission tomography (PET) ligand for imaging beta-ARs would allow the quantification of these receptors in the living human brain so as to better understand both the pathophysiology of depression and how to improve treatment. Currently there are no radioligands suitable for this purpose. In an attempt to achieve this goal, we prepared [(18)F]-labeled (2S)-1-(1-fluoropropan-2-ylamino)-3-(2-cyclohexylphenoxy)propan-2-ol (fluoro-Exaprolol; (2S)-1). Radiolabeling with fluorine-18 was accomplished via preparation of a precursor containing a tosyl leaving group (10), and utilizes the 2-oxazolidinone group to simultaneously protect both the amine and hydroxy groups. The oxazolidinone was readily removed with lithium aluminum hydride following a nucleophilic [(18)F]-fluoride for tosyl displacement to prepare [(18)F]-(2S)-1 in 31% radiochemical yield (uncorrected for decay), with >98% radiochemical purity in <1h. The specific activity of the formulated product was 927 mCi/micromol and the log P (pH 7.4) was 2.97. Preliminary biological evaluations in conscious rats indicated that [(18)F]-(2S)-1 had good brain uptake for imaging (0.8-1.3% injected dose/gram (% ID/g) of wet tissue, 5 min post-injection of the radiotracer) with a slow washout (>0.5% ID/g at 60 min post-injection) in all brain regions. Pharmacological challenges indicate that the binding is largely non-specific, as administration of Propranolol, authentic (2S)-1, or WAY 100635 prior to injection of [(18)F]-(2S)-1 did not block uptake of the radiotracer. These results indicate that [(18)F]-(2S)-1 is not a suitable candidate for PET imaging of cerebral beta-ARs.

Facile radiosynthesis of fluorine-18 labeled beta-blockers. Synthesis, radiolabeling, and ex vivo biodistribution of [18F]-(2S and 2R)-1-(1-fluoropropan-2-ylamino)-3-(m-tolyloxy)propan-2-ol.

An efficient and general method has been developed for fluorine-18 labeling of beta-blockers that possess the propanolamine moiety. A new synthetically versatile intermediate, 3-(1-(benzyloxy)propan-2-yl)-2-oxooxazolidin-5-yl)methyl 4-methylbenzenesulfonate (13), was prepared and can be conjugated to any phenoxy core. To demonstrate the synthetic methodology, fluorinated derivatives of toliprolol were prepared, namely, [(18)F]-(2S and 2R)-1-(1-fluoropropan-2-ylamino)-3-(m-tolyloxy)propan-2-ol ((2S and 2R)-[(18)F]1). The radiosyntheses were accomplished in <1 h, with 20-24% (uncorrected for decay, n = 7) radiochemical yields, >96% radiochemical and >99% enantiomeric purities, with specific activities of 0.9-1.1 Ci/micromol (EOS). Ex vivo biodistribution studies with the radiotracers demonstrated excessively rapid washout that may limit their use for cerebral PET imaging.

Synthesis and screening of a library of Re/Tc-based amyloid probes derived from beta-breaker peptides.

Through the development and application of a unique approach for producing Re-metallopeptides, a new class of peptide-derived probes that are designed to target beta-amyloid plaques was developed. Derivatives of a class of beta-breaker peptides having the core sequence lvffa or affvl (lower case letters represent D-amino acids) and the single amino acid chelate quinoline (SAACQ) ligand which can bind Re and (99m)Tc were prepared on an automated peptide synthesizer. Both monomeric and dimeric peptides were synthesized in modest to good yields where in select examples a biotin-containing amino acid derivative was included to act as a linker point for further conjugation to carrier proteins. The Re complexes for all reported peptides were prepared similarly and screened for their ability to inhibit fibrillogenesis. Two of the reported compounds showed excellent inhibitory properties (8a: 40 +/- 5% amyloid formation versus control; 16: 40 +/- 4%) and warrant further investigation. For one of these leads, the (99m)Tc analogue was synthesized and the product showed high stability toward histidine and cysteine challenges, making it a viable candidate for in vivo biodistribution studies.

Radiosynthesis and initial evaluation of [18F]-FEPPA for PET imaging of peripheral benzodiazepine receptors.

INTRODUCTION: A novel [18F]-radiolabelled phenoxyanilide, [18F]-FEPPA, has been synthesized and evaluated, in vitro and ex vivo, as a potential positron emission tomography imaging agent for the peripheral benzodiazepine receptor (PBR). METHODS: [18F]-FEPPA and two other radiotracers for imaging PBR, namely [11C]-PBR28 and [11C]-PBR28-d3, were synthesised and evaluated in vitro and ex vivo as potential PBR imaging agents. RESULTS: [18F]-FEPPA is efficiently prepared in one step from its tosylate precursor and [18F]-fluoride in high radiochemical yields and at high specific activity. FEPPA displayed a Ki of 0.07 nM for PBR in rat mitochondrial membrane preparations and a suitable lipophilicity for brain penetration (log P of 2.99 at pH 7.4). Upon intravenous injection into rats, [18F]-FEPPA showed moderate brain uptake [standard uptake value (SUV) of 0.6 at 5 min] and a slow washout (SUV of 0.35 after 60 min). Highest uptake of radioactivity was seen in the hypothalamus and olfactory bulb, regions previously reported to be enriched in PBR in rat brain. Analysis of plasma and brain extracts demonstrated that [18F]-FEPPA was rapidly metabolized, but no lipophilic metabolites were observed in either preparation and only 5% radioactive metabolites were present in brain tissue extracts. Blocking studies to determine the extent of specific binding of [18F]-FEPPA in rat brain were problematic due to large perturbations in circulating radiotracer and the lack of a reference region. CONCLUSIONS: Further evaluation of the potential of [18F]-FEPPA will require the employment of rigorous kinetic models and/or appropriate animal models.

Fluoro-pegylated (FPEG) imaging agents targeting Abeta aggregates.

A novel approach of producing positron emission tomography (PET) imaging agents through the formation of bioconjugates based on a pegylation-fluorination strategy resulting in fluoro-pegylated (FPEG) molecules is reported. This approach offers a simple and easy method by which to incorporate 18F in the target molecule without an appreciable increase in the lipophilicity. After 18F labeling, this convenient approach leads to PET imaging probes binding to Abeta aggregates in the brain (an important factor associated with Alzheimer's disease) using the known core structures, such as [2-(4-dimethylaminophenyl)-vinyl]-benzoxazol (3') or 2-phenylbenzothiazole (4). This approach appears to be effective in some core structures, but it cannot be uniformly applied to all structures.

A new strategy for the preparation of peptide-targeted technetium and rhenium radiopharmaceuticals. The automated solid-phase synthesis, characterization, labeling, and screening of a peptide-ligand library targeted at the formyl peptide receptor.

A new solid-phase synthetic methodology was developed that enables libraries of peptide-based Tc(I)/Re(I) radiopharmaceuticals to be prepared using a conventional automated peptide synthesizer. Through the use of a tridentate ligand derived from N-alpha-Fmoc-l-lysine, which we refer to as a single amino acid chelate (SAAC), a series of 12 novel bioconjugates [R-NH(CO)ZLF(SAAC)G, R = ethyl, isopropyl, n-propyl, tert-butyl, n-butyl, benzyl; Z = Met, Nle] that are designed to target the formyl peptide receptor (FPR) were prepared. Construction of the library was carried out in a multiwell format on an Advanced ChemTech 348 peptide synthesizer where multi-milligram quantities of each peptide were isolated in high purity without HPLC purification. After characterization, the library components were screened for their affinity for the FPR receptor using flow cytometry where the K(d) values were found to be in the low micromolar range (0.5-3.0 microM). Compound 5j was subsequently labeled with (99m)Tc(I) and the product isolated in high radiochemical yield using a simple Sep-Pak purification procedure. The retention time of the labeled compound matched that of the fully characterized Re-analogue which was prepared through the use of the same solid-phase synthesis methodology that was used to construct the library. The work reported here is a rare example of a method by which libraries of peptide-ligand conjugates and their rhenium complexes can be prepared.

N,N-bis(2-mercaptoethyl)methylamine: a new coligand for Tc-99m labeling of hydrazinonicotinamide peptides.

Hydrazinonicotinamide (HYNIC) forms stable coordination complexes with Tc-99m when reacted with Tc(V)oxo species such as Tc-mannitol or other Tc-polyhydric complexes. However, radio-HPLC of [Tc-For-MLFK-HYNIC] labeled via Tc-polyhydric ligands demonstrated multiple radiochemical species each with unique biodistribution patterns. This is likely due to the fact that Tc can bind to the hydrazino moiety, as well as polyhydric ligands, in a variety of coordination geometries. Tridentate ligands, such as bis(mercaptoethyl)methylamine (NS2), may constrain the possible coordination geometries and improve overall stability. To investigate this, we synthesized NS2, converted the [Tc-mannitol-For-MLFK-HYNIC] to the corresponding NS2-containing complex [Tc-NS2-For-MLFK-HYNIC], and compared its infection imaging and biodistribution properties with [Tc-mannitol-For-MLFK-HYNIC]. Conversion to the NS2 complex was confirmed by HPLC which showed a single unique hydrophobic species with retention time greater than the [Tc-mannitol-For-MLFK-HYNIC] complex. Imaging experiments with both preparations were performed in rabbits with E. coli infections in the left thigh. Tissue radioactivity measurements demonstrated that compared to Tc-mannitol-peptide, accumulation of Tc-NS2-peptide was lower in blood, heart, and normal muscle and higher in spleen, infected muscle, and pus (p < 0.01). These results indicate that the Tc-NS2-peptide complex is chemically more homogeneous and exhibits improved infection localization and biodistribution properties. In an effort to model the interactions of the metal-HYNIC core with NS2 and related ligand types, the reactions of [ReCl3(NNC5H4NH)(NHNC5H4N)] and [99TcCl3(NNC5H4NH)(NHNC5H4N)], effective structural analogues for the [M(NNC5H4NH(x))2] core, with NS2, C5H3N-2,6-(CH2SH)2, O(CH2CH2SH)2, and S(CH2CH2SH)2 were investigated and the compounds [M[CH3N(CH2CH2S)2](NNC5H4N)(NHNC5H4N] (M = 99Tc (5a), Re (5b)), [Re[C5H3N-2,6-(CH2S)2](NNC5H4N)(NHNC5H4N)].CH2Cl2.0.5MeOH (7), [Re[SCH2CH2)2O] (NNC5H4N)(NHNC5H4N)] (8), and [Re[(SCH2CH2)2S](NNC5H4NH)(NHNC5H4N)]Cl (9) were isolated. Similarly, the reaction of [ReCl3(NNC5H4NH)(NHNC5H4N)] with the bidentate ligands pyridine-2-methanethiol and 3-(trimethlysilyl)pyridine-2-thiol led to the isolation of [ReCl(C5H4N-2-CH2S) (NNC5H4N)(NHNC5H4N)] (10) and [Re(2-SC5H3N-3-SiMe3)2 (NNC5H4N)(NHNC5H4N)] (11), respectively, while reaction with N-methylimidazole-2-thiol yielded the binuclear complex [Re(OH)Cl(SC3H2N2CH3)2(NNC5H4N)2 (NHNC5H4N)2] (12). The analogous metal-(HYNIC-OH) precursor, [ReCl3[NNC5H3NH(CO2R)] [NHNC5H3N(CO2R)]] (R = H, 13a; R = CH3, 13b) has been prepared and coupled to lysine to provide [RCl3[NNC5H3NH(CONHCH2CH2CH2CH2CH(NH2)CO2H)] [NHNC5H3NH(CONHCH2CH2CH2CH2CH(NH2)CO2H)]].2HCl (14.2HCl), while the reaction of the methyl ester 13b with 2-mercaptopyridine yields [Re(2-SC5H4N)2[NNC5H3N(CO2Me)][NHNC5H3N(CO2Me)]] (15). While the chemical studies confirm the robustness of the M-HYNIC core (M = Tc, Re) and its persistence in ligand substitution reactions at adjacent coordination sites of the metal, the isolation of oligomeric structures and the insolubility of the peptide conjugates of 13, 14, and 15 underscore the difficulty of characterizing these materials on the macroscopic scale, an observation relevant to the persistent concerns with reagent purity and identity on the tracer level.

Bridging the gap between in vitro and in vivo imaging: isostructural Re and 99mTc complexes for correlating fluorescence and radioimaging studies.

A bifunctional ligand that is capable of forming Re and 99mTc complexes as complementary fluorescent and radioactive probes was developed. The tridentate bis(quinoline) amine ligand, which is referred to as the SAACQ system, was prepared in a single step from Fmoc protected lysine in high yield. Reaction of the SAACQ ligand with [Re(CO)3Br3]2- resulted in the formation of the SAACQ-(Re(CO)3)+complex which exhibits favorable fluorescence properties including a long lifetime and a large Stoke's shift. Because the SAACQ ligand is derived from an amino acid, it can readily be linked to or incorporated within peptides as a means of targeting the probe to specific receptors. To demonstrate this feature, the SAACQ ligand and the SAACQ-Re complex were incorporated into fMLFG, a peptide that binds to the formyl peptide receptor (FPR). Uptake of the fMLF[(SAACQ-Re(CO)3)+]G conjugate into human leukocytes in vitro was visualized by fluorescence microscopy, and the observed distribution of the peptide was similar to that of a well-established fluorescent FPR probe. The corresponding Tc complex, fMLF[(SAACQ-99mTc(CO)3)+]G, was prepared in excellent yield from [99mTc(CO)3(OH2)3]+, which affords the opportunity to correlate the results of the microscopy experiments with in vivo radioimaging studies because the probes are isostructural.

A new strategy for the preparation of peptide-targeted radiopharmaceuticals based on an fmoc-lysine-derived single amino acid chelate (SAAC). automated solid-phase synthesis, NMR characterization, and in vitro screening of fMLF(SAAC)G and fMLF[(SAAC-Re(CO)3)+]G.

A tridentate single amino acid chelate (SAAC) derived from N-alpha-Fmoc-l-lysine was incorporated within a short peptide sequence using an automated peptide synthesizer. Novel derivatives of the chemotactic peptide fMLF were prepared such that the SAAC and its Re complex were selectively placed between a terminal glycine amino acid and the targeting fMLF sequence. The products, which were synthesized in parallel, were characterized by mass spectrometry and multi-NMR spectroscopy. The latter technique demonstrated that the structures of the targeting portions of the peptides are the same in the SAAC and Re-SAAC derivatives. The affinities of the reported compounds for the formyl peptide receptor were subsequently determined using flow cytometry and were found to be comparable to that of the parent peptide. The results of this work demonstrate the feasibility and numerous benefits of using the SAAC system to prepare peptide-targeted Tc(I) and Re(I) radiopharmaceuticals.

Bifunctional single amino acid chelates for labeling of biomolecules with the [Tc(CO)(3)](+) and [Re(CO)(3)](+) cores. Crystal and molecular structures of [ReBr(CO)(3)(H(2)NCH(2)C(5)H(4)N)], [Re(CO)(3)[(C(5)H(4)NCH(2))(2)NH]]Br, [Re(CO)(3)[(C(5)H(4)NCH(2))(2)NCH(2)CO(2)H]]Br, [Re(CO)(3)[X(Y)NCH(2)CO(2)CH(2)CH(3)]]Br (X = Y = 2-pyridylmethyl; X = 2-pyridylmethyl, Y = 2-(1-methylimidazolyl)methyl; X = Y = 2-(1-methylimidazolyl)methyl), [ReBr(CO)(3)[(C(5)H(4)NCH(2))NH(CH(2)C(4)H(3)S)]], and [Re(CO)(3)[(C(5)H(4)NCH(2))N(CH(2)C(4)H(3)S)(CH(2)CO(2))]].

The reactions of a series of potentially tridentate ligands, derived from single amino acids or amino acid analogues, with [NEt(4)](2)[ReBr(3)(CO)(3)] have been investigated. The model compounds [Re(CO)(3)Br[(2-pyridylmethyl)NH(2)]] (1) and [Re(CO)(3)[(2-pyridylmethyl)(2)NH]]Br (2) were also prepared and structurally characterized. With ligands possessing two pyridyl appendages, (2-pyridylmethyl)(2)NX (X = -CH(2)CO(2)H, -CH(2)CO(2)Et, -CH(2)CH(2)CO(2)H, -CH(2)CH(2)CO(2)Et, -CH(2)CH(2)CH(2)CH(2)CH(NHCO(2)(t)Bu)CO(2)H), complexes of the type [Re(CO)(3)(ligand)]Br (3-6) were isolated. All possess the fac-[Re(CO)(3)N(3)] coordination geometry in the cationic molecular unit. Similarly, the ligands with the imidazolyl arms (2-pyridylmethyl)[2-(1-methylimidazolyl)methyl]NCH(2)CO(2)Et and [2-(1-methylimidazolyl)methyl](2)NCH(2)CO(2)Et, complexes 7 and 8 of the same [Re(CO)(3)(ligand)]Br type, were prepared. Replacement of one pyridyl arm with a thiophene group yielded the complex [Re(CO)(3)[(2-pyridylmethyl)N(CH(2)CO(2))(2-thiophenemethyl)]] (9), while additional substitution of X = -H for -CH(2)CO(2)H yielded [Re(CO)(3)Br[(2-pyridylmethyl)NH(2-thiophenemethyl)]] (10). In both 9 and 10, the thiophene is uncoordinated and pendant, and the derivatives display fac-[Re(CO)(3)N(2)O] and fac-[Re(CO)(3)N(2)Br] coordination geometries, respectively. Crystal data: C(9)H(8)BrN(2)O(3)Re (1), triclinic P1, a = 8.156(1) A, b = 12.077(1) A, c = 12.945(2) A, alpha = 92.183(3) degrees, beta = 107.848(3) degrees, gamma = 100.955(7) degrees, V = 1185.1(3) A, Z = 4; C(15)H(13)BrN(3)O(3)Re (2), tetragonal P4(1), a = 8.6095(3) A, c = 22.228(1) A, V = 1646.9(1) A(3), Z = 4; C(17)H(14)BrN(3)O(5)Re.CH(3)OH (3), monoclinic P2(1)/m, a = 7.4425(3) A, b = 9.7596(4) A, c = 14.0646(6) A, beta = 97.753(1) degrees, V = 1012.26(7) A(3), Z = 2; C(19)H(19)BrN(3)O(5)Re (4), tetragonal P42(1)c, a = 16.895(3) A, c = 15.042(3) A, V = 4293.7(13) A(3), Z = 8; C(18)H(20)BrN(4)O(5)Re.CH(3)OH.H(2)O (7), monoclinic P2(1)/c, a = 10.2816(4) A, b = 30.386(1) A, c = 14.5810(6) A, beta = 99.868(1) degrees, V = 4488.03(3) A(3), Z = 8; C(17)H(21)BrN(5)O(5)Re.0.5CH(2)Cl(2).0.5H(2)O (8), triclinic P1, a = 11.5363(6) A, b = 13.1898(6) A, c = 16.4933(8) A, alpha = 89.356(1) degrees, beta = 74.907(1) degrees, gamma = 76.216(1) degrees, V = 2349.8(2) A(3), Z = 4; C(16)H(13)N(2)O(5)ReS (9), monoclinic P2(1)/c, a = 17.2072(7) A, b = 8.5853(4) A, c = 11.5607(5) A, beta = 101.73(1) degrees, V = 1672.2(1) A(3), Z = 4; and C(14)H(12)N(2)O(3)BrReS (10), triclinic P1, a = 7.5585(3) A, b = 9.7713(4) A, c = 11.7103(4) A, alpha = 109.566(1) degrees, beta = 98.298(1) degrees, gamma = 100.925(1) degrees, V = 779.73(5) A(3), Z = 2.

[Re(III)Cl(3)] core complexes with bifunctional single amino acid chelates.

The reactions of the Re(V) starting material [ReO(PPh(3))(2)Cl(3)] with ligands of the type XN(Y)Z [X = Y = 2-pyridylmethyl, Z = -CH(2)CO(2)Et (L(1)Et), -CH(2)CH(2)CO(2)Et (L(2)Et), -CH(2)CH(2)CH(2)CH(2)CH(NHCO(2)Bu(t))CO(2)H (L(3)H); X = 2-pyridylmethyl, Y = 2-(1-methylimidazolyl)methyl, Z = -CH(2)CO(2)Et (L(4)Et)] yielded the Re(III) trichloride complexes of the type [ReCl(3)(L(n)R)]. The complexes are mononuclear, paramagnetic species with a facial geometry of the chloride ligands. The nitrogen donors of the tridentate L(n)()R ligands complete the distorted octahedral coordination spheres of the complexes. Crystal data: [ReCl(3)(L(1)Et)] (1), monoclinic, C2/m, a = 16.088(3) A, b = 9.980(2) A, c = 12.829(2) A, beta = 91.384(3) degrees, Z = 4, D(calc) = 1.967 g/cm(-)(3); [ReCl(3)(L(4)Et)] (4), monoclinic, C2/c, a = 22.880(1) A, b = 7.4926(4) A, c = 22.560(1) A, beta = 94.186(1) degrees, Z = 8, D(calc) = 2.001 g/cm(-3).

Synthesis of boroxifen, a nido-carborane analogue of tamoxifen.

A nido-carborane analogue of tamoxifen, the widely employed breast cancer therapy agent, was prepared as an archetype of a potential new class of antiestrogen and boron neutron capture therapy agent in which the carborane is incorporated within the framework of the parent compound. The carborane was introduced through the reaction of 6,9-bis(acetonitrile)decaborane with a unique and highly conjugated ene-yne, which was prepared stereoselectively. NMR spectroscopy and a crystal structure of a key intermediate, the carborane analogue of chloro-tamoxifen, demonstrated the structural similarities between the tamoxifen carboranes and their corresponding phenyl analogues.