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Introduction 44Sc is of great interest as a positron emission tomography (PET) radionuclide due to its suitable nuclear characteristics: Eβ+max = 1.47MeV, branching ratio 94.3% and convenient half-life of 3.97 h. Here, 44Sc was produced via the widely used reaction 44Ca (p,n)44Sc using natural calcium as a target. Methods The irradiation was performed at TRIUMF using the 13 MeV cyclotron. The separation consisted of a combination of DGA branched resin and Dowex 50Wx8 (200–400 mesh). The distribution coefficients of Sc3+ on Dowex 50Wx8 (NH4+ form, 200–400 mesh) with ammonium α-hydroxyisobutyrate (pH = 4.8) medium were determined in this study. Results and conclusion The tested scheme allows both a reliable separation of 44Sc from the target material as well as from the other competitive metals and a final fraction with high specific activity. The achieved radiochemical yield was 95 ± 3%.

Hepatocellular carcinoma (HCC) is a significant cause of morbidity and mortality worldwide with limited therapeutic options for advanced disease. Targeted alpha therapy (TAT) is an emerging class of targeted cancer therapy in which alpha-particle-emitting radionuclides, such as thorium-227, are specifically delivered to cancer tissue. Glypican-3 (GPC3) is a cell surface glycoprotein highly expressed on HCC. In this study, we describe the development and in vivo efficacy of a 227Th-labeled GPC3 targeting antibody conjugate (227Th-octapa-αGPC3) for treatment of HCC in an orthotopic murine model. METHODS: The chelator p-SCN-Bn-H4octapa-NCS (octapa) was conjugated to a GPC3 targeting antibody (αGPC3) for subsequent 227Th radiolabeling (octapa-αGPC3). Conditions were varied to optimize radiolabeling of 227Th. In vitro stability was evaluated by measuring percentage of protein-bound 227Th by gamma-ray spectroscopy. An orthotopic athymic Nu/J murine model using HepG2 cells was developed. Biodistribution and blood clearance of 227Th-octapa-αGPC3 was evaluated in tumor bearing mice. Efficacy of 227Th-octapa-αGPC3 was assessed in tumor bearing animals with serial measurement of serum alpha-fetoprotein at 23 days after radionuclide injection. RESULTS: Octapa-conjugated αGPC3 provided up to 70% 227Th labeling yield in 2 h at room temperature. In the presence of ascorbate, ≥97.8% of 227Th was bound to αGPC3-octapa after 14 d in phosphate buffered saline. In HepG2 tumor-bearing mice, highly specific GPC3 targeting was observed, with significant 227Th-octapa-αGPC3 accumulation in the tumor over time and minimal accumulation in normal tissue. 23 days after treatment, significant reduction in tumor burden was observed in mice receiving 500 kBq/kg 227Th-octapa-αGPC3 by tail vein injection. No acute off-target toxicity was observed and no animals died prior to termination of the study. CONCLUSION:227Th-octapa-αGPC3 was observed to be stable in vitro, maintain high specificity for GPC3 with favorable biodistribution in vivo, and result in significant antitumor activity without significant acute off-target toxicity in an orthotopic murine model of HCC.

Targeted alpha therapy (TAT) is an emerging and powerful tool for treating late-stage cancers for which therapeutic options are limited. At the core of TAT is the development of targeted radiopharmaceuticals, where isotopes are paired with biological targeting vectors that enable tissue- or cell-specific delivery of alpha-emitters. 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and diethylenetriamine pentaacetic acid (DTPA) are commonly used to chelate metallic radionuclides, but have several limitations. Significant efforts are underway to develop effective and stable chelators for alpha-emitters and are at various stages of development and community adoption. Isotopes such as 149Tb, 212/213Bi, 212Pb (for 212Bi), 225Ac, 226/227Th have identified suitable chelators, although further studies, especially in vivo studies, are required; while for others, including 223Ra, 230U, and arguably 211At an ideal chelate remains elusive. In this review, we will summarize the chelation chemistry reported to date for the incorporation of 149Tb, 211At, 212/213Bi, 212Pb (for 212Bi), 223Ra, 225Ac, 226/227Th and 230U into radiopharmaceuticals, with a focus on new discoveries and remaining challenges.

Auger electron therapy exploits the cytotoxicity of low-energy electrons emitted during radioactive decay that travel very short distances (typically1 μm).

The bisoxine hexadentate chelating ligand, H3glyox was investigated for its affinity for Mn2+, Cu2+ and Lu3+ ions; all three metal ions are relevant with applications in nuclear medicine and medicinal inorganic chemistry. The aqueous coordination chemistry and thermodynamic stability of all three metal complexes were thoroughly investigated by detailed DFT structure calculations and stability constant determination, by employing UV in-batch spectrophotometric titrations, giving pM values (pM = −log[Mn+]free when [Mn+] = 1 μM, [L] = 10 μM at pH 7.4 and 25 °C) – pCu (25.2) > pLu (18.1) > pMn (12.0). DFT calculated structures revealed different geometries and coordination preferences of the three metal ions; notable was an inner sphere water molecule in the Mn2+ complex. H3glyox labels [52gMn]Mn2+, [64Cu]Cu2+ and [177Lu]Lu3+ at ambient conditions with apparent molar activities of 40 MBq μmol−1, 500 MBq μmol−1 and 25 GBq μmol−1, respectively. Collectively, these initial investigations provide insight into the effects of metal ion size and charge on the chelation with the hexadentate H3glyox and indicate that further investigations of the Mn2+–H3glyox complex in 52g/55Mn-based bimodal imaging might be worthwhile.

Targeted α-therapy (TAT) is an emerging powerful tool treating late-stage cancers for which therapeutic options are limited. At the core of TAT are targeted radiopharmaceuticals, where isotopes are paired with targeting vectors to enable tissue- or cell-specific delivery of α-emitters. DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) and DTPA (diethylenetriamine pentaacetic acid) are commonly used to chelate metallic radionuclides but have limitations. Significant efforts are underway to develop effective stable chelators for α-emitters and are at various stages of development and community adoption. Isotopes such as (149)Tb, (212/213)Bi, (212)Pb (for (212)Bi), (225)Ac, and (226/227)Th have found suitable chelators, although further studies, especially in vivo studies, are required. For others, including (223)Ra, (230)U, and, arguably (211)At, the ideal chemistry remains elusive. This review summarizes the methods reported to date for the incorporation of (149)Tb, (211)At, (212/213)Bi, (212)Pb (for (212)Bi), (223)Ra, (225)Ac, (226/227)Th, and (230)U into radiopharmaceuticals, with a focus on new discoveries and remaining challenges.

Purpose The purpose of this study was to evaluate the efficacy and toxicity of a novel lanthanum compound, La(XT), in an ovariectomized (OVX) rat model of osteoporosis. Methods Twenty-four ovariectomized female Sprague Dawley rats were divided into 3 groups receiving a research diet with/without treatment compounds (alendronate: 3 mg/kg; La(XT) 100 mg/kg) for three months. At the time of sacrifice, the kidney, liver, brain, lung and spleen were collected for histological examination. The trabecular bone structure of the tibiae was evaluated using micro-CT and a three-point metaphyseal mechanical test was used to evaluate bone failure load and stiffness. Results No significant differences were noted in plasma levels of calcium, phosphorus, creatinine, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) between the La(XT) treatment compared to the non-treated OVX group. Alendronate-treated animals (positive control) showed higher BV/TV, Tb.N and lower Tb.Th and Tb.Sp when compared to the non-treated OVX group. Mechanical analysis indicated that stiffness was higher in the alendronate (32.88%, p = 0.04) when compared to the non-treated OVX group. Failure load did not differ among the groups. Conclusions No kidney or liver toxicities of La(XT) treatments were found during the three-month study. The absence of liver and kidney toxicity with drug treatment for 3 months, as well as the increased trabecular bone stiffness are encouraging for the pursuit of further studies with La(XT) for a longer duration of time.

Here, we present the synthesis and characterization of a new potentially nonadentate chelator H4pypa and its bifunctional analogue tBu4pypa-C7-NHS conjugated to prostate-specific membrane antigen (PSMA)-targeting peptidomimetic (Glu-urea-Lys). H4pypa is very functionally versatile and biologically stable. Compared to the conventional chelators (e.g., DOTA, DTPA), H4pypa has outstanding affinities for both 111In (EC, t1/2 ≈ 2.8 days) and 177Lu (β-,γ, t1/2 ≈ 6.64 days). Its radiolabeled complexes were achieved at >98% radiochemical yield, RT within 10 min, at a ligand concentration as low as 10-6 M, with excellent stability in human serum over at least 5-7 days (

The bisoxine hexadentate chelating ligand, H

One of the main challenges in targeted alpha therapy is assuring delivery of the α-particle dose to the targeted cells. Thus, it is critical to identify ligands for α-emitting radiometals that will form complexes that are very stable, both in vitro and in vivo. In this investigation, thorium-227 (t1/2 = 18.70 days) chelation of ligands containing hydroxypyridinonate (HOPO) or picolinic acid (pa) moieties and the stability of the resultant complexes were studied. Chelation reactions were followed by reversed-phased HPLC and gamma spectroscopy. Studies revealed that high 227 Th chelation yields could be obtained within 2.5 h or less with ligands containing four Me-3,2-HOPO moieties, 1 (83%) and 2 (65%), and also with ligands containing pa moieties, H4 octapa 3 (65%) and H4 py4pa 6 (87%). No reaction occurred with H4 neunpa-p-Bn-NO2 4, and the chelation reaction with another pa ligand H4 pypa 5 gave inconsistent yields with a very broad radio-HPLC peak. The ligands spermine-(Me-3,2-HOPO)4 1, H4 octapa 3, and H4 py4pa 6 had high stability (i.e., 87% of 227 Th still bound to the ligand) in phosphate-buffered saline at room temperature over a 6-day period. Preliminary studies with ligand 6 demonstrated efficient chelation of thorium-226 (t1/2 = 30.57 min) when heated to 80°C for 5 min.

Both scandium-44 and yttrium-86 are popular PET isotopes with appropriate half-lives for immuno-positron emission tomography (immuno-PET) imaging. Herein, a new bifunctional H(4)pypa ligand, H(4)pypa-phenyl-NCS, is synthesized, conjugated to a monoclonal antibody, TRC105, and labeled with both radionuclides to investigate the long-term in vivo stability of each complex. While the (44)Sc-labeled radiotracer exhibited promising pharmacokinetics and stability in 4T1-xenograft mice (n=3) even upon prolonged interactions with blood serum proteins, the progressive bone uptake of the (86)Y-counterpart indicated in vivo demetallation, obviating H(4)pypa as a suitable chelator for Y(3+) ion in vivo. The solution chemistry of [(nat)Y(pypa)](−) was studied in detail and the complex found to be thermodynamically stable in solution with a pM value 22.0, ≥3 units higher than those of the analogous DOTA- and CHX-A”-DTPA-complexes; the (86)Y-result in vivo was therefore most unexpected. To explore further this in vivo lability, Density Functional Theory (DFT) calculation was performed to predict the geometry of [Y(pypa)](−) and the results were compared with those for the analogous Sc- and Lu-complexes; all three adopted the same coordination geometry (i.e. distorted capped square antiprism), but the metal-ligand bonds were much longer in [Y(pypa)](−) than in [Lu(pypa)](−) and [Sc(pypa)](−), which could indicate that the size of the binding cavity is too small for the Y(3+) ion, but suitable for both the Lu(3+) and Sc(3+) ions. Considered along with results from [(86)Y][Y(pypa-phenyl-TRC105)], it is noted that when matching chelators with radionuclides, chemical data such as the thermodynamic stability and in vitro inertness, albeit useful and necessary, do not always translate to in vivo inertness, especially with the prolonged blood circulation of the radiotracer bound to a monoclonal antibody. Although H(4)pypa is a nonadentate chelator, which theoretically matches the coordination number of the Y(3+) ion, we show herein that its binding cavity, in fact, favors smaller metal ions such as Sc(3+) and Lu(3+) and further exploitation of the Sc-pypa combination is desired.

(44)Sc is an attractive positron-emitting radionuclide for PET imaging; herein, a new complex of the Sc(3+) ion with nonmacrocyclic chelator H(4)pypa was synthesized and characterized with high-resolution electrospray-ionization mass spectrometry (HR-ESI-MS), as well as different nuclear magnetic resonance (NMR) spectroscopic techniques ((1)H, (13)C, (1)H−(13)C HSQC, (1)H−(13)C HMBC, COSY, and NOESY). In aqueous solution (pH = 7), [Sc(pypa)](−) presented two isomeric forms, the structures of which were predicted using density functional theory (DFT) calculation with a small energy difference of 22.4 kJ/mol, explaining their coexistence. [Sc(pypa)](−) was found to have superior thermodynamic stability (pM = 27.1) compared to [Sc(AAZTA)](−) (24.7) and [Sc(DOTA)](−) (23.9). In radiolabeling, [(44)Sc][Sc(pypa)](−) formed efficiently at RT in 15 min over a range of pH (2−5.5), resulting in a complex that is highly stable (>99%) in mouse serum over at least six half-lives of scandium-44. Similar labeling efficiency was observed with the PSMA (prostate-specific membrane antigen)-targeting H(4)pypa-C7-PSMA617 at pH = 5.5 (RT, 15 min), confirming negligible disturbance from the bifunctionalization on scandium-44 scavenging. Moreover, the kinetic inertness of the radiocomplex was proved in vivo. Surprisingly, the molar activity was found to have profound influence on the pharmacokinetics of the radiotracers where lower molar activity drastically reduced the background accumulations, particularly, kidney, and thus, yielded a much higher tumor-to-background contrast.

The purpose of this study is to develop a thorium-227 (227Th) antibody radioimmunoconjugate targeting glypican-3 (GPC3) and to test its therapeutic efficacy in a hepatocellular carcinoma (HCC) orthotopic xenograft model. GPC3 targeting antibody (αGPC3) was conjugated to bifunctional chelator p-SCN-Bn-H4octapa (octapa), and αGPC3-octapa binding affinity for GPC3 was evaluated by flow cytometry. 227Th radiolabeling of this conjugate was optimized, and in vitro stability of 227Th-αGPC3-octapa was evaluated in PBS with and without free radical scavenging agent over 14 days. For in vivo evaluation, an orthotopic xenograft model was generated by hepatic subcapsular injection of human HCC HepG2 cells. In vivo biodistribution was assessed in blood, tumor and organs at 1, 7 and 21 days after tail vein injection of 227Th-αGPC3-octapa (500 KBq/kg). To test therapeutic efficacy, tumor-bearing animals were injected with 227Th-αGPC3-octapa (250 kBq/kg or 500 kBq/kg) and compared to an irrelevant control antibody, 227Th-αBHV1-octapa (500 kBq/kg), and to a no-treatment control. Tumor burden was assessed with serial serum alpha-fetoprotein (AFP) measurements, a marker of tumor burden validated in this model. Toxicity to 227Th-αGPC3-octapa was measured by serum comprehensive metabolic panel obtained 21 days after injection. GPC3 binding affinity was highest after conjugation of αGPC3 with 10 equivalents of octapa. The protein recovery from the conjugation process was >85%, and mass spectral analysis indicated an average of 3.3 octapa moieties per molecule of αGPC3-octapa. After two weeks, >98% of αGPC3-octapa and αBHV1-octapa had 227Th bound in the presence of scavenging agent. αGPC3-octapa maintained high affinity for GPC3 as measured by flow cytometry, indicating the octapa conjugation reaction did not alter immunoreactivity of αGPC3. In vivo, 227Th-αGPC3-octapa accumulated in the tumor over time and cleared from normal tissues with a %ID/g of In conclusion, we report the development of a GPC3 targeted thorium conjugate and demonstrate its in vivo therapeutic efficacy in a murine orthotopic xenograft model of hepatocellular carcinoma. Citation Format: Kevin P. Labadie, Donald K. Hamlin, Aimee Kenoyer, Sara K. Daniel, Alan F. Utria, Andrew D. Ludwig, Heidi L. Kenerson, Delphine L. Chen, Johnnie Orozco, Raymond S. Yeung, Lily Li, Chris Orvig, Yawen Li, D Scott Wilbur, James O. Park. Glypican-3 targeted thorium-227 alpha therapy reduces tumor burden in an orthotopic xenograft model of hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 928.

Potentially nonadentate (N5O4) bifunctional chelator p-SCN-Bn-H(4)neunpa and its immunoconjugate H(4)neunpa-trastuzumab for In-111 radiolabeling are synthesized. The ability of p-SCN-Bn H(4)neunpa and H(4)neunpa-trastuzumab to quantitatively radiolabel (InCl3)-In-111 at an ambient temperature within 15 or 30 min, respectively, is presented. Thermodynamic stability determination with In3+, Bi3+, and La3+ resulted in high conditional stability constant (pM) values. In vitro human serum stability assays have demonstrated both In-111 complexes to have high stability over 5 days. Mouse biodistribution of [In-111][In(p-NO2 Bn neunpa)](-), compared to that of [In-111][In(p-NH2-Bn-CHX-A"-diethylenetriamine pentaacetic acid (DTPA))](2-), at 1, 4, and 24 h shows fast clearance of both complexes from the mice within 24 h. In a second mouse biodistribution study, the immunoconjugates In-neunpa trastuzumab and In-111-CHX-A"-DTPA-trastuzumab demonstrate a similar distribution profile but with slightly lower tumor uptake of In-111-neunpa-trastuzumab compared to that of In-111-CHX-A"-DTPA-trastuzumab. These results were also confirmed by immuno-single photon emission computed tomography (immuno-SPECT) imaging in vivo. These initial investigations reveal the acyclic bifunctional chelator p-SCN-Bn-H(4)neunpa to be a promising chelator for In-111 (and other radiometals) with high in vitro stability and also show H(4)neunpa trastuzumab to be an excellent In-111 chelator with promising biodistribution in mice.

Background Actinium-225 (225Ac, t1/2 = 9.9 d) is a promising candidate radionuclide for use in targeted alpha therapy (TAT), though the currently limited global supply has hindered the development of a suitable Ac-chelating ligand and 225Ac-radiopharmaceuticals towards the clinic. We at TRIUMF have leveraged our Isotope Separation On-Line (ISOL) facility to produce 225Ac and use the resulting radioactivity to screen a number of potential 225Ac-radiopharmaceutical compounds. Results MBq quantities of 225Ac and parent radium-225 (225Ra, t1/2 = 14.8 d) were produced and separated using solid phase extraction DGA resin, resulting in a radiochemically pure 225Ac product in > 98% yield and in an amenable form for radiolabeling of ligands and bioconjugates. Of the many polydentate picolinic acid (“pa”) containing ligands evaluated (H4octapa [N4O4], H4CHXoctapa [N4O4], p-NO2-Bn-H4neunpa [N5O4], and H6phospa [N4O4]), all out-performed the current gold standard, DOTA for 225Ac radiolabeling ability at ambient temperature. Moreover, a melanocortin 1 receptor-targeting peptide conjugate, DOTA-modified cyclized α-melanocyte-stimulating hormone (DOTA-CycMSH), was radiolabeled with 225Ac and proof-of-principle biodistribution studies using B16F10 tumour-bearing mice were conducted. At 2 h post-injection, tumour-to-blood ratios of 20.4 ± 3.4 and 4.8 ± 2.4 were obtained for the non-blocking (molar activity [M.A.] > 200 kBq/nmol) and blocking (M.A. = 1.6 kBq/nmol) experiment, respectively. Conclusion TRIUMF’s ISOL facility is able to provide 225Ac suitable for preclinical screening of radiopharmaceutical compounds; [225Ac(octapa)]−, [225Ac(CHXoctapa)]−, and [225Ac(DOTA-CycMSH)] may be good candidates for further targeted alpha therapy studies. Electronic supplementary material The online version of this article (10.1186/s41181-019-0072-5) contains supplementary material, which is available to authorized users.

68 Ga is an attractive isotope for incorporation into a positron-emission tomography (PET) imaging agent, and is finding use as an alternative generator-produced isotope to 99mTc particularly in imaging of myocardial perfusion. We have synthesized six new chelating ligands based on our previously reported H2dedpa and H2CHXdedpa scaffolds (CHX = cyclohexyl, H2dedpa = 1,2-[[carboxypyridin-2-yl]methylamino]ethane). These ligands are designed to incorporate several lipophilic appendages at the secondary nitrogens, and upon coordination to 68Ga(III) will form lipophilic, cationic complexes designed to mimic the properties of other clinically relevant myocardial perfusion imaging agents. The non-radioactive Ga(III) complexes were prepared and characterized by NMR spectroscopy; each ligand retained its predicted hexadentate N4O2 binding to Ga(III). The radiolabeling properties of the six ligands were assessed using the longer-lived 68Ga surrogate, 67Ga. The absence of ‘free’ uncomplexed 67Ga in the HPLC radio-chromatograms indicated >99% radiochemical yields (10 minutes at ambient temperature, ligand concentrations of 10−4 M). However, the N,N′-benzyl functionalized derivatives displayed multiple peaks corresponding to the presence of additional 67Ga-complexes which complicated further study. Selected 67Ga-CHXdedpa complexes were tested for in vitro stability against the metal-binding protein apo-transferrin, and were found to be sufficiently stable (>80%) in a 2 h challenge assay, suggesting that alternative N,N′-alkylated derivatives which introduce more lipophilic character will be of interest in future studies.

(68)Ga is an attractive radiometal for use in positron emission tomography (PET) imaging. The success of (68)Ga-based agents is dependent on a chelator that exhibits rapid radiometal incorporation, and strong kinetic inertness to prevent transchelation of (68)Ga in vivo. The linear chelating agents H2dedpa (1,2-[[6-carboxypyridin-2-yl]methylamino]ethane) and H2CHXdedpa (CHX = cyclohexyl/cyclohexane) (N4O2) have recently been developed that bind Ga(3+) quickly and under mild conditions, ideal properties to be incorporated into a (68)Ga PET imaging agent. Herein, nitroimidazole (NI) derivatives of H2dedpa and H2CHXdedpa to investigate specific targeting of hypoxic tumor cells are investigated, given that NI can be reduced and retained exclusively in hypoxic cells. Nine N,N'-bis-alkylated derivatives of H2dedpa and H2CHXdedpa have been synthesized; they have been screened for their ability to bind gallium, and cyclic voltammetry of nonradioactive complexes was performed to probe the redox cycling mechanism of NI. The compounds were radiolabeled with (67)Ga and (68)Ga and show promising radiolabeling efficiencies (99%) when labeled at 10(-5) M for 10 min at room temperature. Moreover, stability studies (via apo-transferrin challenge, 37 °C) show that the (67)Ga complexes exhibit exceptional stability (86-99% intact) after 2 h. In vitro uptake studies under hypoxic (0.5% O2) and normoxic (21% O2) conditions in three cancerous cell lines [HT-29 (colon), LCC6(HER-2) (breast), and CHO (Chinese hamster ovarian)] were performed. Of the four H2dedpa or H2CHXdedpa NI derivatives tested, all showed preferential uptake in hypoxic cells compared to normoxic cells with hypoxic/normoxic ratios as high as 7.9 ± 2.7 after 120 min. The results suggest that these novel bis-alkylated NI-containing H2dedpa and H2CHXdedpa ligands would be ideal candidates for further testing in vivo for PET imaging of hypoxia with (68)Ga.

The chiral acyclic ligands H2CHXdedpa (N4O2), H2CHXdedpa-bb (N4O2), and H4CHXoctapa (N4O4) (CHX = cyclohexyl/cyclohexane, H2dedpa = 1,2-[[6-carboxy-pyridin-2-yl]-methylamino]ethane, bb = N,N'-dibenzylated, H4octapa = N,N'-bis(6-carboxy-2-pyridylmethyl)-ethylenediamine-N,N'-diacetic acid) were synthesized, complexed with Ga(III) and/or In(III), and evaluated for their potential as chelating agents in radiopharmaceutical applications. The ligands were compared to the previously studied hexadentate H2dedpa and octadentate H4octapa ligands to determine the effect adding a chiral 1R,2R-trans-cyclohexane to replace the ethylenediamine backbone would have on metal complex stability and radiolabeling kinetics. It was found that [Ga(CHXdedpa)](+) showed very similar properties to those of [Ga(dedpa)](+), with only one isomer in solution observed by NMR spectroscopy, and minimal structural changes in the solid-state X-ray structure. Like [Ga(dedpa)](+), [Ga(CHXdedpa)](+) exhibited exceptionally high thermodynamic stability constants (log KML = 28.11(8)), and the chelate retained the ability to label (67)Ga quantitatively in 10 min at room temperature at ligand concentrations of 1 × 10(-5) M. In vitro kinetic inertness assays demonstrated the [(67)Ga(CHXdedpa)](+) complex to be more stable than [(67)Ga(dedpa)](+) in a human serum competition, with 90.5% and 77.8% of (67)Ga remaining chelate-bound after 2 h, respectively. Preliminary coordination studies of H4CHXoctapa with In(III) demonstrated [In(CHXoctapa)](-) to have an equivalently high thermodynamically stable constant as [In(octapa)](-), with log KML values of 27.16(9) and 26.76(14), respectively. The [(111)In(CHXoctapa)](-) complex showed exceptionally high in vitro kinetic inertness over 120 h in human serum, comparing well with previously reported [(111)In(octapa)](-) values, and an improved stability compared to the current industry "gold standards" 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and diethylenetriaminepentaacetic acid (DTPA). Initial investigations reveal that the chiral acyclic hexadentate H2CHXdedpa and octadentate H4CHXoctapa ligands are ideal candidates for radiopharmaceutical elaboration of gallium or indium isotopes, respectively.

Bone density diseases such as osteoporosis affect a significant number of people worldwide. Lanthanide ions are functional mimics of calcium ions, able to substitute for Ca2+ in the bone mineral component, hydroxyapatite (HAP). Bone undergoes a continuous remodelling cycle and lanthanides can affect this cycle, exerting a positive influence on bone mineral. We have been engaged in efforts to find new lanthanide containing complexes as active agents for treatment of these diseases and have identified two lead compounds, 3-hydroxy-1,2-dimethylpyridin-4(1H)-one (Hdpp) and a phosphinate-EDTA derivative, bis[[bis(carboxymethyl)amino]-methyl]phosphinate (H5XT). In this paper, we report in vivo data for the first time for the two lead compounds. The pharmacokinetics of La(dpp)3 suggest the complex is rapidly cleared from plasma. We demonstrate that La3+ accumulates in the bone following IV dose of either La(dpp)3 or La(XT) and we have investigated the influence of each chelating ligand on the incorporation of La3+ into HAP using ITC and HAP-binding studies.

A series of novel (C^N) cyclometallated Au(III) complexes of general formula [Au(py(b)-H)L(1)L(2)](n+) (py(b)-H = C^N cyclometallated 2-benzylpyridine, L(1) and L(2) being chlorido, phosphane or glucosethiolato ligands, n = 0 or 1) have been synthesized and fully characterized using different techniques, including NMR, IR and far-IR, mass spectrometry, as well as elemental analysis. The crystal structure of one compound has been solved using X-ray diffraction methods. All compounds were tested in vitro in five human cancer cell lines including the lung, breast, colon and ovarian cancer cells. For comparison purposes, all compounds were also tested in a model of healthy human cells from the embryonic kidney. Notably, all new compounds were more toxic than their cyclometallated precursor bearing two chlorido ligands, and the derivative bearing one phosphane ligand presented the most promising toxicity profile in our in vitro screening, displaying a p53 dependent activity in colorectal cancer HCT116 cells. Finally, for the first time C^N cyclometallated gold(III) complexes were shown to be potent inhibitors of the zinc finger protein PARP-1, involved in the mechanism of cisplatin resistance.

The field of medicinal inorganic chemistry has grown consistently during the past 50 years; however, metal-containing coordination compounds represent only a minor proportion of drugs currently on the market, indicating that research in this area has not yet been thoroughly realized. Although platinum-based drugs as cancer chemotherapeutic agents have been widely studied, exact knowledge of the mechanisms governing their accumulation in cells is still lacking. However, evidence suggests active uptake and efflux mechanisms are involved; this may be involved also in other experimental metal coordination and organometallic compounds with promising antitumor activities in vitro and in vivo, such as ruthenium and gold compounds. Such knowledge would be necessary to elucidate the balance between activity and toxicity profiles of metal compounds. In this review, we present an overview of the information available on the cellular accumulation of Pt compounds from in vitro, in vivo and clinical studies, as well as a summary of reports on the possible accumulation mechanisms for different families of experimental anticancer metal complexes (e.g., Ru Au and Ir). Finally, we discuss the need for rationalization of the investigational approaches available to study metallodrug cellular transport.

The acyclic ligands H4C3octapa and p-SCN-Bn-H4C3octapa were synthesized for the first time, using nosyl protection chemistry. These new ligands were compared to the previously studied ligands H4octapa and p-SCN-Bn-H4octapa to determine the extent to which the addition of a single carbon atom to the backbone of the ligand would affect metal coordination, complex stability, and, ultimately, utility for in vivo radiopharmaceutical applications. Although only a single carbon atom was added to H4C3octapa and the metal donor atoms and denticity were not changed, the solution chemistry and radiochemistry properties were drastically altered, highlighting the importance of careful ligand design and radiometal–ligand matching. It was found that [In(C3octapa)]− and [Lu(C3octapa)]− were substantially different from the analogous H4octapa complexes, exhibiting fluxional isomerization and a higher number of isomers, as observed by 1H NMR, VT-NMR, and 2D COSY/HSQC-NMR experiments. Past evaluation of the DFT structures of [In(octapa)]− and [Lu(octapa)]− revealed very symmetric complexes; in contrast, the [In(C3octapa)]− and [Lu(C3octapa)]− complexes were much less symmetric, suggesting lower symmetry and less rigidity than that of the analogous H4octapa complexes. Potentiometric titrations revealed the formation constants (log KML, pM) were ∼2 units lower for the In3+ and Lu3+ complexes of H4C3octapa when compared to that of the more favorable H4octapa ligand (∼2 orders of magnitude less thermodynamically stable). The bifunctional ligands p-SCN-Bn-H4C3octapa and p-SCN-Bn-H4octapa were conjugated to the antibody trastuzumab and radiolabeled with 111In and 177Lu. Over a 5 day stability challenge experiment in blood serum, 111In-octapa– and 111In-C3octapa–trastuzumab immunoconjugates were determined to be ∼91 and ∼24% stable, respectively, and 177Lu-octapa– and 177Lu-C3octapa–trastuzumab, ∼89% and ∼4% stable, respectively. This work suggests that 5-membered chelate rings are superior to 6-membered chelate rings for large metal ions like In3+ and Lu3+, which is a crucial consideration for the design of bifunctional chelates for bioconjugation to targeting vectors for in vivo work., New ligands H4C3octapa and p-SCN-Bn-H4C3octapa were synthesized and compared to the previously studied ligands H4octapa and p-SCN-Bn-H4octapa to determine the extent to which the addition of a single carbon atom to the backbone of the ligand would affect metal coordination, complex stability, and, ultimately, utility for in vivo radiopharmaceutical applications. It was found that [In(C3octapa)]− and [Lu(C3octapa)]− were substantially different from the analogous H4octapa complexes.

The acyclic chelator H6phospa and the bifunctional derivative p-SCN-Bn-H6phospa have been synthesized using nosyl protection chemistry and evaluated with (89)Zr, (111)In, and (177)Lu. The p-SCN-Bn-H6phospa derivative was successfully conjugated to trastuzumab with isotopic dilution assays indicating 3.3 ± 0.1 chelates per antibody and in vitro cellular binding assays indicating an immunoreactivity value of 97.9 ± 2.6%. Radiolabeling of the H6phospa-trastuzumab immunoconjugate was achieved with (111)In in 70-90% yields at room temperature in 30 minutes, while (177)Lu under the same conditions produced more inconsistent yields of 40-80%. Stability experiments in human serum revealed the (111)In-phospa-trastuzumab complex to be 52.0 ± 5.3% intact after 5 days at 37 °C, while the (177)Lu-phospa-trastuzumab to be only 2.0 ± 0.3% intact. Small animal SPECT/CT imaging using mice bearing subcutaneous SKOV-3 ovarian cancer xenografts was performed, and it was found that (111)In-phospa-trastuzumab successfully identified and delineated small (~2 mm in diameter) tumors from surrounding tissues, despite visible uptake in the kidneys and bone due to moderate chelate instability. As predicted from stability assays in serum, the (177)Lu-phospa-trastuzumab conjugate served as a negative control and displayed no tumor uptake, with high uptake in bones indicating rapid and complete radiometal dissociation and suggesting a potential application of H6phospa in transient lanthanide chelation for bone-delivery. Radiolabeling with (89)Zr was attempted, but even with elevated temperatures of 37 °C, the maximum observed radiometal incorporation over 18 hours was 12%. It can be concluded from this work that H6phospa is not superior to the previously studied H4octapa for use with (111)In and (177)Lu, but improvements in (89)Zr radiolabeling were observed over H4octapa, suggesting H6phospa to be an excellent starting point for elaboration of (89)Zr-based radiopharmaceutical development. To our knowledge, H6phospa is the best desferrioxamine alternative for (89)Zr radiolabeling to be studied to date.

We describe a 1D and 2D electron spin echo envelope modulation investigation of VO2+ adsorbed on hydroxyapatite (HA) at different concentrations and compare with VO2+–triphosphate (TPH) complexes studied previously in detail, in an effort to provide more insight into the structure of VO2+ coordination in bone. Structures of this interaction are important because of the role of bone in the long-term storage of administered vanadium, and the likely role of bone in the steady-state release of vanadium leading to the chronic insulin-enhancing anti-diabetic effects of vanadyl complexes. Three similar sets of cross-peaks from phosphorus nuclei observed in the 31P hyperfine sublevel correlation (HYSCORE) spectra of VO2+–HA, VO2+–TPH and VO2+–bone suggest a common tridentate binding motif for triphosphate moieties to the vanadyl ion. The similarities between the systems present the possibility that in vivo vanadyl coordination in bone is relatively uniform. Experiments with HA samples containing different amounts...

Objectives To compare the radiolabeling performance, stability, and practical efficacy of the chelators CHX-A″-DTPA and H 4 octapa with the therapeutic radiometal 90 Y. Methods The bifunctional chelators p -SCN-Bn-H 4 octapa and p -SCN-Bn-CHX-A″-DTPA were conjugated to the HER2-targeting antibody trastuzumab. The resulting immunoconjugates were radiolabeled with 90 Y to compare radiolabeling efficiency, in vitro and in vivo stability, and in vivo performance in a murine model of ovarian cancer. Results High radiochemical yields (>95%) were obtained with 90 Y-CHX-A″-DTPA-trastuzumab and 90 Y-octapa-trastuzumab after 15min at room temperature. Both 90 Y-CHX-A″-DTPA-trastuzumab and 90 Y-octapa-trastuzumab exhibited excellent in vitro and in vivo stability. Furthermore, the radioimmunoconjugates displayed high tumoral uptake values (42.3±4.0%ID/g for 90 Y-CHX-A″-DTPA-trastuzumab and 30.1±7.4%ID/g for 90 Y-octapa-trastuzumab at 72h post-injection) in mice bearing HER2-expressing SKOV3 ovarian cancer xenografts. Finally, 90 Y radioimmunotherapy studies performed in tumor-bearing mice demonstrated that 90 Y-CHX-A″-DTPA-trastuzumab and 90 Y-octapa-trastuzumab are equally effective therapeutic agents, as treatment with both radioimmunoconjugates yielded substantially decreased tumor growth compared to controls. Conclusions Ultimately, this work demonstrates that the acyclic chelators CHX-A″-DTPA and H 4 octapa have comparable radiolabeling, stability, and in vivo performance, making them both suitable choices for applications requiring 90 Y.

Welcome to this themed issue of Dalton Transactions entitled: ‘Frontiers in Radionuclide Imaging and Therapy; A chemical journey from naturally radioactive elements to targeted theranostic agents’.

Molecules designed to sequester, redistribute and/or remove metal ions are attractive therapeutic agents in neurodegenerative diseases such as Alzheimer's disease. The multifactorial nature of the condition and the generally poor target specificity associated with metal ion-binding therapy has led to the development of multifunctional 3-hydroxy-4-(1H)-pyridinone pro-ligands. The excellent qualities of the basic 3-hydroxy-4-pyridinone framework as a low toxicity metal chelator and an antioxidant, as well as its antibacterial and analgesic properties among other functions, inspired us to functionalize it with a framework derived from thioflavin-T, the well-known traditional dye used as a marker to detect amyloid deposits in tissue sections. Thus 2-methyl-3-hydroxy-1-(4-dimethylaminophenyl)-4(1H)-pyridinone (HL1), 2-methyl-3-hydroxy-1-(4-methylaminophenyl)-4(1H)-pyridinone (HL2), 1-(4-aminophenyl)-3-hydroxy-2-methyl-4(1H)-pyridinone (HL3), 1-(6-benzothiazolyl)-3-hydroxy-2-methyl-4(1H)-pyridinone (HL4), 1-(2-benzothiazolyl)-3-hydroxy-2-methyl-4(1H)-pyridinone (HL5) and 2-methyl-3-hydroxy-1-[4-(4-bromophenyl)-2-thiazolyl]-4(1H)-pyridinone (HL6) were obtained. Glycosylation, as well as incorporation of structures mimicking those of known amyloid imaging agents, may target drug action to the site of interest, the metal-overloaded amyloid plaques in the Alzheimer's brain. The pro-ligands were assessed for their antioxidant activity, cytotoxicity and ability to interfere with metal ion-induced amyloid peptide aggregation to screen promising lead compounds. Finally, in a brain uptake study with a radiolabeled glucoconjugate pyridinone, 3-(β-D-glucopyranosyloxy)-1-[4-(4-[125I]iodophenyl)-2-thiazolyl]-2-methyl-4(1H)-pyridinone ([125I]-GL7) was shown to cross the blood–brain barrier using an in situ rat brain perfusion technique.

Naturally occurring hydroxyapatite, Ca5(PO4)3(OH) (HAP), is the main inorganic component of bone matrix, with synthetic analogues finding applications in bioceramics and catalysis. An interesting and valuable property of both natural and synthetic HAP is the ability to undergo cationic and anionic substitution. The lanthanides are well-suited for substitution for the Ca(2+) sites within HAP, because of their similarities in ionic radii, donor atom requirements, and coordination geometries. We have used isothermal titration calorimetry (ITC) to investigate the thermodynamics of ion exchange in HAP with a representative series of lanthanide ions, La(3+), Sm(3+), Gd(3+), Ho(3+), Yb(3+) and Lu(3+), reporting the association constant (Ka), ion-exchange thermodynamic parameters (ΔH, ΔS, ΔG), and binding stoichiometry (n). We also probe the nature of the La(3+):HAP interaction by solid-state nuclear magnetic resonance ((31)P NMR), X-ray diffraction (XRD), and inductively coupled plasma-optical emission spectroscopy (ICP-OES), in support of the ITC results.

In biological systems metal ions promote responses that range from deficiency to toxicity. Some, such as iron and zinc, have a known optimal intake range for normal, healthy individuals. Metal ions contained within well-designed molecules already constitute a great boon for the medicinal pharmacopoeia. However, whether essential or not, the threshold for toxicity can be very low. One of the challenges of designing metal-based drugs is to balance the potential toxicity of an active formulation with the substantial positive impact of these increasingly common therapeutic and diagnostic aids.

The biological fate of a chelated vanadium source is investigated by/n vivo spectroscopic methods to elucidate the chemical form in which the metal ion is accumulated. A pulsed electron paramagnetic resonance study of vanadyl ions in kidney tissue, taken from rats previously treated with bis(ethylmaltolato)oxovanadium(IV) (BEOV) in drinking water, is presented. A combined approach using stimulated echo (3-pulse) electron spin echo envelope modulation (ESEEM) and the two dimensional 4-pulse hyperfine sublevel correlation (HYSCORE) spectroscopies has shown that at least some of the VO(2+) ions are involved in the coordination with nitrogen-containing ligands. From the experimental spectra, a 4N hyperfine coupling constant of 4.9 MHz and a quadrupole coupling constant of 0.6 + 0.04 MHz were determined, consistent with amine coordination of the vanadyl ions. Study of VO-histidine model complexes allowed for a determination of the percentage of nitrogen-coordinated VO(2+) ions in the tissue sample that is found nitrogen-coordinated. By taking into account the bidentate nature of histidine coordination to VO(2+) ions, a more accurate determination of this value is reported. The biological fate of chelated versus free (i.e. salts) vanadyl ion sources has been deduced by comparison to earlier reports. In contrast to its superior pharmacological efficacy over VOSO4, BEOV shares a remarkably similar biological fate after uptake into kidney tissue.

A new potentially multidentate hexaprotic ligand H(6)[TETA-(PO)(2)] has been prepared by reaction of ethylenediamine-N,N'-diacetic acid (EDDA), paraformaldehyde, and phosphinic acid; its coordination properties with three lanthanide ions (La(3+), Gd(3+), and Lu(3+)) have been explored. The structures of the complexes were studied in aqueous solution by potentiometric pH titrations and by (31)P NMR spectroscopy. Four acidity constants were determined potentiometrically in the range 2.5pH14. The four measured pK(a) values can be divided into two groups, and within each group the initial deprotonation was found to have little effect on the second. Variable temperature (31)P and (31)P[(1)H] EXSY NMR spectra showed that, for [Lu(TETA-(PO)(2))](3-), the two phosphorus atoms exist in different chemical environments and undergo an exchange process which is very fast on the NMR time scale at room temperature. This result is consistent with one of the phosphinate residues coordinating the metal ion and exchanging with a free analogue. In the case of [La(TETA-(PO)(2))](3-), only one temperature invariant signal is observed in (31)P NMR spectra; it corresponds to both phosphinate residues remaining uncoordinated to La(3+). The stability of [Ln(TETA-(PO)(2))](3-) has an order of La(3+)Gd(3+)Lu(3+). The coordination of one phosphinate residue to Lu(3+) brings the metal ion closer to the plane of four nitrogens and farther from the four carboxylate arms, resulting in [Lu(TETA-(PO)(2))](3-) having a lower stability than the corresponding La(3+) and Gd(3+) complexes. A pM-pH distribution diagram showed that introducing two phosphinate groups into TETA renders [Gd(TETA-(PO)(2))](3-) more stable than [Gd(TETA)](-). The selectivity factor of the ligand for Gd(3+) vs Ca(2+), Zn(2+), and Cu(2+) has been calculated, and the hydration number for [Dy(TETA-(PO)(2))](3-) has been measured by (17)O NMR spectroscopy to be zero.

A new potentially multidentate hexaprotic ligand H6[TETA-(PO)2] has been prepared by reaction of ethylenediamine-N,N‘-diacetic acid (EDDA), paraformaldehyde, and phosphinic acid; its coordination properties with three lanthanide ions (La3+, Gd3+, and Lu3+) have been explored. The structures of the complexes were studied in aqueous solution by potentiometric pH titrations and by 31P NMR spectroscopy. Four acidity constants were determined potentiometrically in the range 2.5 < pH < 14. The four measured pKa values can be divided into two groups, and within each group the initial deprotonation was found to have little effect on the second. Variable temperature 31P and 31P{1H} EXSY NMR spectra showed that, for [Lu(TETA-(PO)2)]3-, the two phosphorus atoms exist in different chemical environments and undergo an exchange process which is very fast on the NMR time scale at room temperature. This result is consistent with one of the phosphinate residues coordinating the metal ion and exchanging with a free analogu...

We describe a 1D and 2D ESEEM investigation of VO2+ adsorbed on hydroxyapatite (HA) at different concentrations and compare with VO2+-triphosphate (TPH) complexes studied previously in detail, in an effort to provide more insight into the structure of VO2+coordination in bone. Structures of this interaction are important because of the role of bone in the long-term storage of administered vanadium, and the likely role of bone in the steady-state release of vanadium leading to the chronic insulin-enhancing anti-diabetic effects of vanadyl complexes. Three similar sets of cross-peaks from phosphorus nuclei observed in the 31P HYSCORE spectra of VO2+-HA, VO2+-TPH, and VO2+-bone suggest a common tridentate binding motif for triphosphate moieties to the vanadyl ion. The similarities between the systems present the possibility that in vivo vanadyl coordination in bone is relatively uniform. Experiments with HA samples containing different amounts of adsorbed VO2+ demonstrate additional peculiarities of the ion-adsorbent interaction which can be expected in vivo. HYSCORE spectra of HA samples show varying relative intensities of 31P lines from phosphate ligands and 1H lines, especially lines from protons of coordinated water molecules. This result suggests that the number of equatorial phosphate ligands in HA could be different depending on the water content of the sample and the VO2+ concentration; complexes of different structure probably contribute to the spectra of VO2+-HA. Similar behavior can be also expected in vivo during VO2+ accumulation in bones.

The new potentially multidentate ligand (EDDA-KA)2 has been prepared and its acid-base properties determined. Its coordination properties with three lanthanide ions (La3+, Gd3+, and Lu3+) and Fe3+ have been studied in aqueous solution (I = 0.16 M NaCl, 25°C) by potentiometric pH, spectrophotometric, and 1H NMR titrations. In total, eight pKa values could be determined by these diverse methods. From the 1H NMR titrations, all the deprotonation steps could be determined and assigned (in groups). Strong hydrogen bonding among two nitrogen atoms and one oxygen atom on the pyrone ring was observed, and the corresponding pKa values were estimated to be 13.2 and 14.0. By comparison with similar systems, an equilibrium constant for the formation of the hydrogen bond was estimated, KI = 104.4. Eight stability constants in total were determined for various protonation states of the La3+ and Gd3+ complexes, but for Lu3+ only the last four constants were obtained. The species distribution diagram showed that [M(EDDA-KA)2-4H]2- predominated in the range 5 [Formula: see text] pH [Formula: see text] 9 and [M(EDDA-KA)2-6H]4- predominated in the region 9 [Formula: see text] pH [Formula: see text] 11. In the former complex, two strong hydrogen bonds anchored the macrocycle and Ln3+ was coordinated with the four carboxylate groups; in the latter, the two hydrogen bonding protons were absent and the metal ion might also bind to the nitrogens on the macrocycle. The stability of Gd3+-(EDDA-KA)2 is lower than the analogous Gd3+ complexes of DOTA, DTPA, and DTPA-BMA.Key words: acidity constants, stability constants, La3+, Gd3+, Lu3+, Fe3+, amino carboxylate chelator.

A set of 1,3-propanediamine derivatives connected to carbohydrates (5) has been prepared in four steps from peracetylated sugar and 1,3-dibromo-2-propanol in 60-73% yields. D-Glucose, D-mannose, D-galactose, D-xylose, D-ribose, and maltose are utilized as sugar molecules in this work. The diamine moiety was connected to the C1 carbon of the glycopyranose ring via an O-glycoside bond. All of the anomeric configurations and sugar puckering conformations, except in the D-maltose derivative, were determined by X-ray crystallography of the diazido or dibromo precursors. While glycosidation of peracetylated galactopyranose with 1,3-dibromo-2-propanol in the presence of boron trifluoride afforded both anomers, the neighboring group participation of the 2-acetoxy group yielded a single anomer for the other substrates. This method has been used to synthesize a library of sugar-pendant diamines including an OH-protected derivative (6), and an N,N'-diisopropyl-substituted derivative (7). A similar series of reactions using 2,3-dibromo-1-propanol gave ethylenediamine-type derivatives (11), and bis(bromomethyl)bis(hydroxymethyl)methane (12) gave bisglucose-pendant derivatives (16).

Iron(III) complexation with potentially hexadentate H2bbpen (N,N'-bis(2-hydroxybenzyl)-N,N'-bis(2-methylpyridyl)ethylenediamine) was studied. The resulting monocationic complex, [Fe(bbpen)]+ as its NO3- and PF6- salts, was characterized by infrared spectroscopy, mass spectrometry, elemental analyses, cyclic voltammetry, and X-ray crystallographic analysis. Crystals of [Fe(bbpen)]NO3·CH3OH are monoclinic, space group P21/c, a = 10.2640(13), b = 14.7526(10), c = 18.3172(5) Å, β = 97.904(1)°, and Z = 4. The structure was solved by heavy-atom Patterson methods and refined to an R factor of 0.039 for 3526 reflections with I > 3σ(I). The structure of the [Fe(bbpen)]+ cation showed that the ligand is bound in a hexadentate fashion to the central Fe(III) ion, resulting in a distorted octahedral geometry. Magnetic susceptibility measurements indicated the presence of a high-spin Fe(III) ion, and the UV-vis spectrum of [Fe(bbpen)]NO3 exhibits absorption maxima, λmax, at 575 nm (ε = 5400 M-1 cm-1), 323 (8900), and 275 (13 500). The cyclic voltammogram of [Fe(bbpen)]NO3 showed a quasi-reversible, one-electron process corresponding to [FeIII(bbpen)]+ + e- <_> [FeII(bbpen)] at -0.47 V vs. SCE.Key words: cationic, iron(III), phenolate, pyridyl, hexadentate.

A bifunctional derivative of the versatile acyclic chelator H4octapa, p-SCN-Bn-H4octapa, has been synthesized for the first time. The chelator was conjugated to the HER2/neu-targeting antibody trastuzumab and labeled in high radiochemical purity and specific activity with the radioisotopes (111)In and (177)Lu. The in vivo behavior of the resulting radioimmunoconjugates was investigated in mice bearing ovarian cancer xenografts and compared to analogous radioimmunoconjugates employing the ubiquitous chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). The H4octapa-trastuzumab conjugates displayed faster radiolabeling kinetics with more reproducible yields under milder conditions (15 min, RT, ~94-95%) than those based on DOTA-trastuzumab (60 min, 37 °C, ~50-88%). Further, antibody integrity was better preserved in the (111)In- and (177)Lu-octapa-trastuzumab constructs, with immunoreactive fractions of 0.99 for each compared to 0.93-0.95 for (111)In- and (177)Lu-DOTA-trastuzumab. These results translated to improved in vivo biodistribution profiles and SPECT imaging results for (111)In- and (177)Lu-octapa-trastuzumab compared to (111)In- and (177)Lu-DOTA-trastuzumab, with increased tumor uptake and higher tumor-to-tissue activity ratios.

trans-Tetrachlorobis(triphenylphosphine)rhenium(IV), (1), is isomorphous with the triclinic polymorph of mer-trans-trichlorooxobis(triphenylphosphine)rhenium(V), (2) [Lebuis & Beauchamp (1993). Can. J. Chem. 71, 441–449]. The sample of (1) has been partially oxidized (14–25%) to (2) by aerial oxidation, resulting in the title compound, [ReCl4(C18H15P)2]0.86. [ReCl3O(C18H15P)2]0.14. In the crystal lattice, the oxo ligand is located primarily at one of six possible sites. The molecules have trans-octahedral coordination geometry, with Re—P distances in the range 2.564 (1)–2.580 (1) A, having a mean value of 2.571 (7) A, and Re—Cl distances in the range 2.291 (3)–2.339 (1) A.

Preparation of the hydrochloride salt of a new potentially hexadentate ligand precursor P,P,P′,P′-tetrakis(o-hydroxyphenyl)diphosphinoethane dihydrochloride (abbreviated H4P2O4•2HCl) is described. From H4P2O4•2HCl, neutral [Re2O2Cl2(PPh3)2(μ-P2O4)] and dianionic [Re2O2Br4(μ-P2O4)]2−dinuclear rhenium(V) complexes were synthesized. The complexes have been characterized by elemental analysis, infrared spectroscopy, mass spectrometry, and1H/31P{1H} NMR spectra.31P{1H} NMR revealed that only one isomer, presumably the anti, was present for [Re2O2Cl2(PPh3)2(μ-P2O4)], and that two isomers, both anti and syn isomers, were observed for [Re2O2Br4(μ-P2O4)]2−. The coligands (PPh3for the former, Br−for the latter) of both complexes underwent ligand exchange with pyridine. Key words: rhenium, P,P,P′,P′-tetrakis(o-hydroxyphenyl)diphosphinoethane, dimer, isomers.

The rhenium(V) and technetium(V) complexes: [ReO(apa)], [{ReO(epa)}2O], and [TcOCl(epa)] have been prepared from a potentially pentadentate N3O2 ligand, N,N′-3-azapentane-1,5-diylbis(3-(1-iminoethyl)-6-methyl-2H-pyran-2,4(3H)-dione) (H3apa), or a potentially tetradentate N2O2 ligand, N,N′-ethylene-diylbis(3-(1-iminoethyl)-6-methyl-2H-pyran-2,4(3H)-dione) (H2epa). The N2O2 complexes were synthesized in low yields. There was also evidence indicating that H2ppa, N,N′-propylene-diylbis(3-(1-iminoethyl)-6-methyl-2H-pyran-2,4(3H)-dione), hydrolyzed in the course of coordination, forms a rhenium complex of the bidentate monoprotic (O,O) dehydroacetate (dha−), [Re(dha)Cl2(OPPh3)(PPh3)]•EtOH. The structure of this complex was determined by X-ray crystallography. Crystals of [Re(dha)Cl2(OPPh3)(PPh3)] EtOH (C44H37Cl2O5P2Re•C2H6O) are monoclinic, a = 11.064(2), b = 24.167(2), c = 16.6687(8) Å, β = 98.779(7)°, Z = 4, space group P21/c. The structure was solved by the Patterson method and refined by full-matrix least-squares procedures to R = 0.030 and Rw = 0.025 for 6942 reflections with I ≥ 3σ(F2). Keywords: dehydroacetic acetate based Schiff base ligands, rhenium, technetium, N3O2 Schiff base, N2O2 Schiff base, oxygen transfer.

Preliminary experiments with the novel acyclic triazole-containing bifunctional chelator H2azapa and the radiometals (64)Cu, (67)Ga, (111)In, and (177)Lu have established its significant versatile potential as an alternative to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) for metal-based radiopharmaceuticals. Unlike DOTA, H2azapa radiolabels quantitatively with (64)Cu, (67)Ga, (111)In, and (177)Lu in 10 min at room temperature. In vitro competition experiments with human blood serum show that (64)Cu remained predominantly chelate-bound, with only 2% transchelated to serum proteins after 20 h. Biodistribution experiments with [(64)Cu(azapa)] in mice reveal uptake in various organs, particularly in the liver, lungs, heart, intestines, and kidneys. When compared to [(64)Cu(DOTA)](2-), the lipophilic neutral [(64)Cu(azapa)] was cleared through the gastrointestinal tract and accumulated in the liver, which is common for lipophilic compounds or free (64)Cu. The chelator H2azapa is a model complex for a click-based bifunctional chelating agent, and the lipophilic benzyl "place-holders" will be replaced by hydrophilic peptides to modulate the pharmacokinetics and direct activity away from the liver and gut. The solid-state molecular structure of [In(azapa)(H2O)][ClO4] reveals a very rare eight-coordinate distorted square antiprismatic geometry with one triazole arm bound, and the structure of [(64)Cu(azapa)] shows a distorted octahedral geometry. The present study demonstrates significant potential for bioconjugates of H2azapa as alternatives to DOTA in copper-based radiopharmaceuticals, with the highly modular and "clickable" molecular scaffold of H2azapa easily modified into a variety of bioconjugates. H2azapa is a versatile addition to the "pa" family, joining the previously published H2dedpa ((67/68)Ga and (64)Cu), H4octapa ((111)In, (177)Lu, and (90)Y), and H5decapa ((225)Ac) to cover a wide range of important nuclides.

In model studies designed to study the synthesis of potentially hexadentate chelates based on the linkage of three furan rings to a triamine via amide linkages, new 2- and 4-substituted 3-hydroxy-5-methylfurans have been prepared. Particularly, 3-hydroxy-5-methyl-(N-methylformamido)furan (Hahm) and its Al and Ga complexes (M(ahm)3) have been prepared and thoroughly characterized by a variety of techniques, in the solid state and in solution. Solution equilibrium studies (μ = 0.6 M NaCl, 25 °C) uncovered a complicated set of equilibria in the Al3+/Hahm system; the solution potentiometric data were best explained by the presence of mixed ligand (HL = Hahm, L− = ahm−) hydroxo species [Al3(OH)4L3]2+ and [Al(OH)2L2]−, in addition to the expected [AlLn](3−n)+ (n = 1, 2, 3) species. Further solution studies at HL:M ratios of 3:1 (μ = 0.15 M NaCl, 25 °C) showed that Hahm is a relatively weak complexing agent for both Al and Ga, forming tris-ligand species with overall formation constants of 1019.5 and 1020.6, respectively.