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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%.

H4pypa is a nonadentate nonmacrocyclic chelator, which previously demonstrated high affinity for scandium-44, lutetium-177, and indium-111. Herein, we report the highly stable binary [Zr(pypa)] complex; the nonradioactive complex was synthesized and characterized in detail using high-resolution electrospray-ionization mass spectroscopy (HR-ESI-MS) and various nuclear magnetic resonance spectroscopies (NMR), which revealed C2v symmetry of the complex. The geometry of [Zr(pypa)] was further detailed via X-ray crystallography and compared with the structure of [Fe(Hpypa)]. Despite a slow complexation rate with an association half-life of 31.4 h at pH 2 and room temperature, the [Zr(pypa)] complex is thermodynamically stable (log KML = 38.92, pZr = 39.4). Radiochemical studies demonstrated quantitative radiolabeling achieved at 10 μM chelator concentration within 2 h at 40 °C and pH = 7, antibody-compatible conditions. Of the utmost importance, [89Zr][Zr(pypa)] is highly kinetically inert upon challenge with excess EDTA and DFO ligands, superior to [89Zr][Zr(DFO)]+, and maintains inertness toward human serum.

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.

A new, high-denticity, bifunctional ligand─H

H4HBEDpa, a new octadentate chelator inspired by the 1960s ligand HBED of Arthur E. Martell, has been investigated for a selection of trivalent metal ions useful in diagnostic and therapeutic applications (Sc3+, Fe3+, Ga3+, In3+, and Lu3+). Complex formation equilibria were thoroughly investigated using combined potentiometric and UV-vis spectrophotometric titrations which revealed effective chelation and high metal-sequestering capacity, in particular for Fe3+, log KFeL = 36.62, [Fe(HBEDpa)]-. X-ray diffraction study of single crystals revealed that the ligand is preorganized and forms hexa-coordinated complexes with Fe3+ and Ga3+ at acidic pH. Density functional theory (DFT) calculations were applied to probe the geometries and energies of all the possible conformers of [M(HBEDpa)]- (M = Sc3+, Fe3+, Ga3+, In3+, and Lu3+). DFT calculations confirmed the experimental findings, indicating that [Fe(HBEDpa)]- is bound tightly in an asymmetric pattern as compared to the symmetrically bound and more open [Ga(HBEDpa)]-, prone to hydrolysis at higher pH. DFT calculations also showed that a large metal ion such as Lu3+ fully coordinates with HBEDpa4-, forming a binary octadentate complex in its lowest-energy form. Smaller metal ions form six or seven coordinate complexes with HBEDpa4-.

A new versatile chelating ligand for intermediate size and softness radiometals [64Cu]Cu2+ and [111In]In3+, H2pyhox, was synthesized by introducing pyridine as a new donor moiety to complement 8-hydroxyquinoline on an ethylenediamine backbone. The combination of pyridine and oxine as donor sets was explored through structural analysis, and crystals of the three metal complexes with Cu2+, La3+, and In3+ demonstrate how the ligand adapts to accommodate metal ions of different sizes and charge. Exhaustive in-batch UV solution studies characterized the protonation constants of the free ligand as well as the formation constants of the metal complexes with Cu2+, In3+, and La3+. Preliminary concentration-dependent radiolabeling studies with [111In]In3+ and [64Cu]Cu2+ show the robustness of H2pyhox to successfully coordinate both radiometals under mild conditions (

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

Background: Hepatocellular carcinoma (HCC) seriously affects human health, especially, it easily develops multi-drug resistance (MDR) which results in treatment failure. There is an urgent need to develop highly effective and low-toxicity therapeutic agents to treat HCC and to overcome its MDR. Targeted drug delivery systems (DDS) for cancer therapy, including nanoparticles, lipids, micelles and liposomes, have been studied for decades. Recently, more attention has been paid to multifunctional DDS containing various ligands such as polymer moieties, targeting moieties, and acid-labile linkages. The polymer moieties such as poly(ethylene glycol) (PEG), chitosan (CTS), hyaluronic acid, pullulan, poly(ethylene oxide) (PEO), poly(propylene oxide) (PPO) protect DDS from degradation. Asialoglycoprotein receptor (ASGPR) and glycyrrhetinic acid receptor (GAR) are most often used as the targeting moieties, which are overexpressed on hepatocytes. Acid-labile linkage, catering for the pH difference between tumor cells and normal tissue, has been utilized to release drugs at tumor tissue. Objectives: This review provides a summary of the recent progress in ASGPR and GAR-mediated and/or pH-responsive HCC-targeted drug delivery. Conclusion: The multifunctional DDS may prolong systemic circulation, continuously release drugs, increase the accumulation of drugs at the targeted site, enhance the anticancer effect, and reduce side effects both in vitro and in vivo. But it is rarely used to investigate MDR of HCC; therefore, it needs to be further studied before going into clinical trials.

A comparative investigation of two structurally related potentially nonadentate chelating ligands, H4neunpa-NH2 and H4noneunpa, has been undertaken to examine the influence of bifunctionalization o...

Advances in nuclear medicine depend on chelating ligands that form highly stable and kinetically inert complexes with relevant radiometal ions for use in diagnosis or therapy. A new potentially decadentate ligand, H5decaox, was synthesised to incorporate two 8-hydroxyquinoline moieties on either end of a diethylenetriamine backbone decorated with three carboxylic acids, one at each N atom of the backbone. Metal complexation was assessed using nuclear magnetic resonance (NMR) spectroscopy and high-resolution mass spectrometry (HR-MS) with In3+, Zr4+ and La3+. Solution thermodynamic studies provided the stepwise protonation constants and metal formation constants, indicating a high affinity for both In3+ and Zr4+ (pIn = 32.3 and pZr = 34.7), and density functional theory (DFT) calculations provided insight into the coordination environments with either metal ion. Concentration dependent radiolabeling experiments with [111In]InCl3 and [89Zr]ZrCl4 showed promise as quantitative radiolabeling (>95%) occurred at micromolar concentrations, under mild, near-physiological conditions of pH 7 and room temperature for 30 minutes. Serum stability of both radiometal complexes was investigated and the [111In]In(decaox) complex remained 91% intact after 24 hours while the [89Zr]Zr(decaox) complex was 86% intact over the same time, comparable to other chelating ligands previously assessed with the same methods. The high radiolabeling yields, limited serum protein transchelation and structural insight of the [89Zr]Zr(decaox) complex suggest a promising fit between the oxinate-containing ligand and the Zr4+ ion, setting the stage for further investigations with a functionalised version of the chelator for its potential in PET imaging.

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.

Amide-based chelators DTPAm, EGTAm and ampam were synthesized to investigate which chelator most ideally coordinates [nat/203Pb]Pb2+ ions for potential radiopharmaceutical applications. 1H NMR spectroscopy was used to study each metal–ligand complex in the solution state. The 1H NMR spectrum of [Pb(DTPAm)]2+ revealed minimal isomerization and fluxional behaviour compared to [Pb(EGTAm)]2+ and [Pb(ampam)]2+, both of which showed fewer spectral changes indicative of less static behaviour. The solid-state coordination properties of each complex were also examined from single crystal structures that were studied by X-ray diffraction (XRD). In the solid-state, octadentate DTPAm coordinated Pb2+ to form an eight-coordinate hemidirected complex; octadentate EGTAm coordinated Pb2+ forming a ten-coordinate holodirected complex with a bidentate NO3− ion also coordinated to the metal centre; decadentate ampam completely encapsulated the Pb2+ ion to form a ten-coordinate holodirected complex with a C2 axis of symmetry. Potentiometric titrations were carried out to assess the thermodynamic stability of each metal–ligand complex. The pM values obtained for [Pb(DTPAm)]2+, [Pb(EGTAm)]2+ and [Pb(ampam)]2+ were 9.7, 7.2 and 10.2, respectively. The affinity of each chelator for Pb2+ ions was tested by [203Pb]Pb2+ radiolabeling studies to evaluate their prospects as chelators for [203/212Pb]Pb2+-based radiopharmaceuticals. DTPAm radiolabeled [203Pb]Pb2+ ions achieving molar activities as high as 3.5 MBq μmol−1 within 15 minutes, at 25 °C, whereas EGTAm and ampam produced lower molar activities of 0.25 MBq μmol−1 within 30 minutes, at 37 °C. EGTAm and ampam were therefore deemed unsuitable for [203/212Pb]Pb2+-based radiopharmaceutical applications, while DTPAm warrants further studies.

A new, bifunctional chelating ligand for immuno-Positron Emission Tomography (PET) was designed, synthesized, and conjugated to Trastuzumab for a proof-of-concept study with

Myeloid cell leukemia 1 (Mcl-1), which belongs to the Bcl-2 family of prosurvival proteins, is a key regulator of cancer cell survival. To date, few drug-like Mcl-1 inhibitors have been reported. Herein, we report the preparation of 10 copper complexes with 9-substituted β-carboline ligands that act as metal-based Mcl-1 inhibitors. Complex 14 was identified as a potent and selective Mcl-1 inhibitor with strong in vitro antitumor activity. Mechanistic studies demonstrated that complex 14 disrupted Mcl-1-Bax/Bak heterodimerization and induced Bax/Bak-dependent apoptosis. In addition, complex 14 significantly (P < 0.001) inhibited tumor growth in vivo, induced tumor necrosis, and extended survival time in an NCI-H460 xenograft model. Furthermore, complex 14 showed no apparent toxicity in mice. Together, these findings indicate that complex 14 is a copper-based Mcl-1 inhibitor with high efficacy and low toxicity that could be developed for the treatment of Mcl-1-related cancers.

A phosphinate-bearing picolinic acid-based chelating ligand (H6dappa) was synthesized and characterized to assess its potential as a bifunctional chelator (BFC) for inorganic radiopharmaceuticals. Nuclear magnetic resonance (NMR) spectroscopy was employed to investigate the chelator coordination chemistry with a variety of nonradioactive trivalent metal ions (In3+, Lu3+, Y3+, Sc3+, La3+, Bi3+). Density functional theory (DFT) calculations explored the coordination environments of aforementioned metal complexes. The thermodynamic stability of H6dappa with four metal ions (In3+, Lu3+, Y3+, Sc3+) was deeply investigated via potentiometric and spectrophotometric (UV-vis) titrations, employing a combination of acidic in-batch, joint potentiometric/spectrophotometric, and ligand-ligand competition titrations; high stability constants and pM values were calculated for all four metal complexes. Radiolabeling conditions for three clinically relevant radiometal ions were optimized ([111In]In3+, [177Lu]Lu3+, [90Y]Y3+), and the serum stability of [111In][In(dappa)]3- was studied. Through concentration-, time-, temperature-, and pH-dependent labeling experiments, it was determined that H6dappa radiolabels most effectively at near-physiological pH for all radiometal ions. Furthermore, very rapid radiolabeling at ambient temperature was observed, as maximal radiolabeling was achieved in less than 1 min. Molar activities of 29.8 GBq/μmol and 28.2 GBq/μmol were achieved for [111In]In3+ and [177Lu]Lu3+, respectively. For H6dappa, high thermodynamic stability did not correlate with kinetic inertness-lability was observed in serum stability studies, suggesting that its metal complexes might not be suitable as a BFC in radiopharmaceuticals.

[44/47Sc]Sc3+, [68Ga]Ga3+, and [111In]In3+ are the three most attractive trivalent smaller radiometalnuclides, offering a wide range of distinct properties (emission energies and types) in the tool...

Herein, we present the syntheses and characterization of a new undecadendate chelator, H4py4pa, and its bifunctional analog H4py4pa-phenyl-NCS, conjugated to the monoclonal antibody, Trastuzumab, which targets the HER2+ cancer. H4py4pa possesses excellent affinity for 225Ac (α, t1/2 = 9.92 d) for targeted alpha therapy (TAT), where quantitative radiolabeling yield was achieved at ambient temperature, pH = 7, in 30 min at 10-6 M chelator concentration, leading to a complex highly stable in mouse serum for at least 9 d. To investigate the chelation of H4py4pa with large metal ions, lanthanum (La3+), which is the largest nonradioactive metal of the lanthanide series, was adopted as a surrogate for 225Ac to enable a series of nonradioactive chemical studies. In line with the 1H NMR spectrum, the DFT (density functional theory)-calculated structure of the [La(py4pa)]- anion possessed a high degree of symmetry, and the La3+ ion was secured by two distinct pairs of picolinate arms. Furthermore, the [La(py4pa)]- complex also demonstrated a superb thermodynamic stability (log K[La(py4pa)]- ∼ 20.33, pLa = 21.0) compared to those of DOTA (log K[La(DOTA)]- ∼ 24.25, pLa = 19.2) or H2macropa (log K[La(macropa)]- = 14.99, pLa ∼ 8.5). Moreover, the functional versatility offered by the bifunctional py4pa precursor permits facile incorporation of various linkers for bioconjugation through direct nucleophilic substitution. In this work, a short phenyl-NCS linker was incorporated to tether H4py4pa to Trastuzumab. Radiolabeling studies, in vitro serum stability, and animal studies were performed in parallel with the DOTA-benzyl-Trastuzumab. Both displayed excellent in vivo stability and tumor specificity.

A rigid chiral acyclic chelator H2CHXhox was synthesized and evaluated for Ga3+-based radiopharmaceutical applications; it was compared to the previously reported hexadentate H2hox to determine the effect of a backbone reinforced from adding a chiral 1S,2S-trans-cyclohexane on metal complex stability, kinetic inertness, and in vivo pharmacokinetics. NMR spectroscopy and theoretical calculation revealed that [Ga(CHXhox)]+ showed a very similar coordination geometry to that of [Ga(hox)]+, and only one isomer in solution was observed by NMR spectroscopy. Solution studies showed that the modification results in a significant improvement in the exceptionally high thermodynamic stability of [Ga(hox)]+ with a 1.56 log unit increase in stability constant (logKML = 35.91(1)). More importantly, H2CHXhox showed very fast Ga3+ complexation at physiological pH 7.4, and acid-assisted Ga3+ complex dissociation kinetic studies (pH 1) in comparison with H2hox revealed a 50-fold increase of the dissociation half-life time from 73 min to 58 h. Fluorescence microscopy imaging study confirmed its cellular uptake and accumulation in endoplasmic reticulum and mitochondria. MTT studies indicated a quite low cytotoxicity of [Ga(CHXhox)]+ over a large concentration range. Dynamic PET imaging studies showed no accumulation in muscle, lungs, bone, and brain, suggesting no release of free Ga3+ ions. [68Ga][Ga(CHXhox)]+ is cleared from the mouse via hepatobiliary and renal pathways. Compared to [68Ga][Ga(hox)]+, the increased lipophilicity of [68Ga][Ga(CHXhox)]+ enhanced heart and liver uptake and decreased kidney clearance. [67Ga][Ga(CHXhox)]+ SPECT/CT imaging and biodistribution study revealed good clearance from liver to gallbladder after 90 min and finally into feces after 5 h. No decomposition or transchelation was observed over the 5 h study. These results confirmed H2CHXhox to be an obvious improvement over H2hox and an excellent candidate in this new "ox" family for the development of radiopharmaceutical compounds.

The peptide is an important class of biological targeting molecule; herein, a new bifunctional octadentate non-macrocyclic H4octapa, tBu4octapa-alkyl-NHS, which is compatible with solid-phase peptide synthesis and thus useful for radiopeptide preparation, has been synthesized. To preserve denticity, the alkyl-N-hydroxylsuccinimide linker was covalently attached to the methylene–carbon on one of the acetate arms, yielding a chiral carbon center. According to density-functional theory (DFT) calculations using [Lu(octapa-alkyl-benzyl-ester)]− as a simulation model, the chirality has minimal effects on the complex geometry; regardless of the S-/R-stereochemistry, DFT calculations revealed two possible geometric isomers, distorted bicapped trigonal antiprism (DBTA) and distorted square antiprism (DSA), due to the asymmetry in the chelator. To evaluate the biological behavior of the new bifunctionalization, two well-studied PSMA (prostate-specific membrane antigen)-targeting peptidomimetics of varying hydrophobicity were chosen as proof-of-principle targeting vector molecules. Radiolabeling both bioconjugates with lutetium-177 was highly efficient at room temperature in 15 min at micromolar chelator concentration pH = 7. Both the in vitro serum challenge and the lanthanum(III) challenge studies revealed complex lability, and notably, progressive bone accumulation was only observed with the more hydrophobic linker (i.e. H4octapa-alkyl-PSMA617). This in vivo result informs potential alterations exerted by the linker on the complex geometry and stability, with an appropriate biological targeting vector adopted for such evaluations.

With the interest in radiometal-containing diagnostic and therapeutic pharmaceuticals burgeoning, appropriate ligands to coordinate completely and stably said radiometals is essential. Reported here are two novel, bis(amido)bis(oxinate)diamine ligands, H2amidohox and H2amidoC3hox, that combine two 8-hydroxyquinoline with two amide donor groups and differ by one carbon in their 1,2-ethylenediaminevs. 1,3-diaminopropane backbones, respectively. Both ligands have been thoroughly studied via metal complexation, solution thermodynamics and radiolabeling with three radiometal ions: [nat/64Cu]Cu2+, [nat/111In]In3+, and [nat/203Pb]Pb2+. X-ray crystallography determined the structures of the hexacoordinated Cu2+-ligand complexes, indicating a better fit of Cu2+ to the H2amidohox binding pocket. Concentration dependent radiolabeling with [64Cu]Cu2+ was quantitative as low as 1 μM with H2amidohox and 10 μM with H2amidoC3hox within 5 minutes at room temperature. However, [64Cu][Cu(amidohox)] maintained higher kinetic inertness against a superoxide dismutase enzyme-challenge assay and ligand challengescompared to the [64Cu][Cu(amidoC3hox)] counterpart. Similarly, H2amidohox had significantly higher radiochemical conversion with both [111In]In3+ (97% at 1 μM) and [203Pb]Pb2+ (97% at 100 μM) under mild conditions compared to H2amidoC3hox (76% with [111In]In3+ at 1 μM and 0% with [203Pb]Pb2+). By studying non-radioactive and radioactive complexation with both ligands, a comprehensive understanding of the coordination differences between two- and three-carbon diamine backbones is discussed. Overall, the ethylenediamine backbone of H2amidohox proves to be superior with rapid radiolabeling and kinetic inertness towards competing ligands and proteins.

8-Hydroxyquinoline (8-HQ, oxine) is a small, monoprotic, bicyclic aromatic compound and its relative donor group orientation imparts impressive bidentate metal chelating abilities that have been exploited in a vast array of applications over decades. 8-HQ and its derivatives have been explored in medicinal applications including anti-neurodegeneration, anticancer properties, and antimicrobial activities. One long established use of 8-HQ in medicinal inorganic chemistry is the coordination of radioactive isotopes of metal ions in nuclear medicine. The metal-oxine complex with the single photon emission computed tomography (SPECT) imaging isotope [111In]In3+ was developed in the 1970s and 1980s to radiolabel leukocytes for inflammation and infection imaging. The [111In][In(oxine)3] complex functions as an ionophore: a moderately stable lipophilic complex to enter cells; however, inside the cell environment [111In]In3+ undergoes exchange and remains localized. As new developments have progressed towards radiopharmaceuticals capable of both imaging and therapy (theranostics), 8-HQ has been re-explored in recent years to investigate its potential to chelate larger radiometal ions with longer half-lives and different indications. Further, metal-oxine complexes have been used to study liposomes and other nanomaterials by tracking these nanomedicines in vivo. Expanding 8-HQ to multidentate ligands for highly thermodynamically stable and kinetically inert complexes has increased the possibilities of this small molecule in nuclear medicine. This article outlines the historic use of metal-oxine complexes in inorganic radiopharmaceutical chemistry, with a focus on recent advances highlighting the possibilities of developing higher denticity, targeted bifunctional chelators with 8-HQ.

H

Amide-based chelators DTPAm, EGTAm and ampam were synthesized to investigate which chelator most ideally coordinates [

A new versatile chelating ligand for intermediate size and softness radiometals [

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.

Zirconium-89 (89Zr) is a suitable radionuclide for positron-emission tomography (PET) of long-circulating targeting vectors such as monoclonal antibodies (mAbs). Due to stability concerns for the most widely used 89Zr-chelating agent desferrioxamine B (DFO) in preclinical studies, alternative 89Zr-chelators are currently being developed. We recently reported on the first tetrakis(3-hydroxy-4-pyridinone) (3,4-HOPO) ligand THPN, which was identified as a promising 89Zr-chelator. In this study, we aimed to further explore this octadentate chelate in vitro and in vivo. The [ZrIV(THPN)] thermodynamic stability was quantified in solution titration studies, which revealed one of the highest formation constants reported for a zirconium chelate (log βML 50.3(1), pM = 42.8). Solution stabilities with iron(III) were also exceptionally high and can compete with some of the strongest FeIII-chelates. A first bifunctional derivative of the octadentate ligand, p-SCN-Bn-THPN, was then produced in a multistep synthesis. To assess and compare the long-term 89Zr complex stability, bifunctional THPN, as well as the literature chelators p-SCN-Phe-DFO and p-SCN-Phe-DFO*, were conjugated to the high-molecular weight (800 kDa) polymeric carrier hyperbranched polyglycerol (HPG). The functionalized HPGs were radiolabeled with 89ZrIV, and the integrity of the radioconjugates was assessed over several days in vitro and in vivo. While all three radioconjugates remained >95% intact over 5 days in human plasma, the in vivo study in healthy mice revealed higher physiologic stability of the DFO and DFO* radiochelates over bifunctional THPN conjugates. This was evidenced by increased bone uptake of osteophilic 89ZrIV for THPN. This finding contrasts with the exceptionally high thermodynamic stability of the chelate and suggests either a kinetic or metabolic lability, or may stem from coordinative changes due to the covalent conjugation of the 89Zr-THPN radiochelate as suggested by density functional theory (DFT) calculations. These important findings inform the design of next generation 3,4-HOPO chelates with the aim of improving the physiologic stability. This study furthermore demonstrates how HPG can be used as a robust carrier tool to assess and compare the long-term in vivo stability of radiochelates.

In this study, we present the synthesis and characterization of the octadentate bispidine ligand, H2bispox2 and its complexes with medicinally useful radiometal nuclides (111In3+ and 177Lu3+), including their X-ray diffraction single crystal structures with the stable isotopes. 111InCl3 radiolabels the ligand quantitatively at ambient conditions ([L] = 10-5 M, room temperature, pH 7 and 15 min) and the in vitro human serum stability assays demonstrated high stability of the [111In(bispox2)]+ complex over 5 days. Moreover, the β - emitter 177Lu radiolabels the ligand at 37 °C in 30 min (pH 8). These initial investigations reveal the potential of the octadentate bispidine ligand H2bispox2 as a useful chelator for 111In and 177Lu-based radiopharmaceuticals.

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 (

A family of phosphonate-bearing chelators was synthesized to study their potential in metal-based (radio)pharmaceuticals. Three ligands (H6phospa, H6dipedpa, H6eppy; structures illustrated in manuscript) were fully characterized, including X-ray crystallographic structures of H6phospa and H6dipedpa. NMR spectroscopy techniques were used to confirm the complexation of each ligand with selected trivalent metal ions. These methods were particularly useful in discerning structural information for Sc3+ and La3+ complexes. Solution studies were conducted to evaluate the complex stability of 15 metal complexes. As a general trend, H6phospa was noted to form the most stable complexes, and H6eppy associated with the least stable complexes. Moreover, In3+ complexes were determined to be the most stable, and complexes with La3+ were the least stable, across all metals. Density functional theory (DFT) was employed to calculate structures of H6phospa and H6dipedpa complexes with La3+ and Sc3+. A comparison of experimental 1H NMR spectra with calculated 1H NMR spectra using DFT-optimized structures was used as a method of structure validation. It was noted that theoretical NMR spectra were very sensitive to a number of variables, such as ligand configuration, protonation state, and the number/orientation of explicit water molecules. In general, the inclusion of an explicit second shell of water molecules qualitatively improved the agreement between theoretical and experimental NMR spectra versus a polarizable continuum solvent model alone. Formation constants were also calculated from DFT results using potential-energy optimized structures. Strong dependence of molecular free energies on explicit water molecule number, water molecule configuration, and protonation state was observed, highlighting the need for dynamic data in accurate first-principles calculations of metal-ligand stability constants.

The bisoxine hexadentate chelating ligand, H

A phosphinate-bearing picolinic acid-based 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.

Myeloid cell leukemia 1 (Mcl-1) is a member of the Bcl-2 family of proteins with anti-apoptotic activity. It plays a key role in the regulation of the intrinsic pathway of apoptosis. Moreover, Mcl-1 is correlated with the progression and drug-resistance of various cancers. The development of inhibitors of Mcl-1 may provide effective cancer therapies. While the inhibitors of other Bcl-2 anti-apoptotic proteins have been well explored, the discovery of Mcl-1inhibitors with high selectivity has been challenging. In this review, we summarize the recent literature on small molecule and peptide inhibitors of Mcl-1, which are divided into different types including peptide inhibitors, gossypol derivatives, marinopyrrole derivatives, S1 derivatives, indole derivatives, quinoline derivatives, S63845, AZD5991, AMG176, etc. Their biological activities are also summarized. Mcl-1 is a valid drug target and inhibition of Mcl-1 with a small molecule inhibitor is a promising strategy for cancer therapy.