Octadentate Oxine-Armed Bispidine Ligand for Radiopharmaceutical

Jun 18, 2019 - pdf. ic9b01016_si_001.pdf (3.12 MB) ... Radiopharmaceutical Chemistry ... Medicinal Inorganic Chemistry Group, Department of Chemistry,...
1 downloads 0 Views 3MB Size
Download PDF
Article Cite This: Inorg. Chem. 2019, 58, 8685−8693

pubs.acs.org/IC

Octadentate Oxine-Armed Bispidine Ligand for Radiopharmaceutical Chemistry Neha Choudhary,†,‡ Alexander Dimmling,†,§ Xiaozhu Wang,† Lily Southcott,†,‡ Valery Radchenko,‡,∥ Brian O. Patrick,∥ Peter Comba,*,§ and Chris Orvig*,†

Downloaded via TRINITY COLG DUBLIN on August 28, 2019 at 07:51:17 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

†

Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada ‡ Life Sciences Division, TRIUMF, 4004 Wesbrook Mall, Vancouver, British Columbia V6T 2A3, Canada § Anorganisch-Chemisches Institut and Interdisciplinary Center for Scientific Computing, Universität Heidelberg, INF 270, D-69120 Heidelberg, Germany ∥ Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada S Supporting Information *

ABSTRACT: 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 177 Lu 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.

■

γ)177Lu) with a half-life of 6.6 days that emits β‑ particles, as well as SPECT imageable γ-rays (113 and 208 keV).8 Recently, 177 Lu-PSMA therapy has gained popularity as a viable therapeutic option in men with metastatic prostate cancer.9 Lutetium is a medium-energy β− emitter (490 keV) with a maximal tissue penetration of 97%). The concentration-dependent radiolabeling was performed at pH 7 and 8 (10 mM NaOAc buffer), respectively and the results are summarized in Table 2. The efficiency of radiolabeling with 111In3+ and 177Lu3+ is very similar to that with the corresponding picolinate ligand H2bispa2 and significantly better than with the “gold standard” DOTA.33 Initial radiolabeling studies with the α-emitter 225Ac (∼4 MBq μmol−1, [L] = 10−4) were attempted with ligand concentrations of 10−4 M but unlike milder labeling kinetics with 111In and 177 Lu, radiolabeling with 225Ac required heating at 85 °C for 1 h. Due to the inability to quantitatively radiolabel 225Ac at room

Table 3. Human Serum Stability Challenge Data Performed at 37 °C (n = 2), with Stability Shown as Percentage of Intact 111 In Complex complex

24 h stability

5 day stability

[111In(bispox2)]+ [111In(octox)]− a [111In(dedpa)]+ a [111In(octapa)]− a [111In(DOTA)]− a [111In(DTPA)]2− a [111In(p-NO2−Bn-neunpa)]− b [111In(bispa2)]+ c

94.6 ± 0.4 91.4 ± 0.6 19.7 ± 1.5 92.3 ± 0.04 89.4 ± 2.2 88.3 ± 2.2 97.8 ± 0.1 87.4 ± 0.6

89.4 ± 0.6 83.6 ± 1.4 NA NA NA 0.5) while [111In(bispox2)]− or [177Lu(bispox2)]− species stay on the baseline (Rf = 0). Developed plates were counted immediately and the radiolabeling yields were calculated by integrating the peaks in the radio-chromatogram, which is consistent with the well-separated radiopeaks of the free metal and the complex on the HPLC radiotraces (tR = 4.8 min for “free” 111In and 12.8 min for [111In(bispox)]+ complex. 111 In Complex Stability Studies in Human Serum. The compound [111In(bispox2)]− was prepared with radiolabeling procedure as described above. To the reaction vial containing the radiometal-chelate complex (500 μL), an equal volume of human serum was added and the competition mixture was incubated at 37 °C. At time points 1 day and 5 days, aliquots were spotted on aluminum-backed silica TLC plates and developed with 10 mM EDTA solution (pH = 7) as mobile phase. Solid State X-ray Analysis. Single colorless rectangular-shaped crystals of H2bispox2 were recrystallized from a methanol/diethyl ether mixture by slow evaporation. A suitable crystal (0.47 × 0.31 × 0.36 mm3) was selected and mounted on a Mylar loop with oil on a Bruker APEX II area detector diffractometer. The crystal was kept at T = 100(2) K during data collection. Using Olex2,50 the structure was solved with the XT51 structure solution program, using the Intrinsic Phasing solution method. The model was refined with version 2017/1 of XL51 using least squares minimization. Single yellow rectangular-shaped crystals of [In(bispox2)](ClO4) were recrystallized from methanol by slow evaporation. A suitable crystal (0.20 × 0.13 × 0.11 mm3) was selected and mounted on a Mylar loop with oil on a Bruker APEX II area detector diffractometer. The crystal was kept at T = 100(2) K during data collection. Using Olex2,50 the structure was solved with the XT51 structure solution program,

using the intrinsic phasing solution method. The model was refined with version 2017/1 of XL51 using least squares minimization. Single orange rectangular-shaped crystals of [Lu(bispox2)(HCO3)] were obtained by recrystallization from methanol solution. A suitable crystal (0.16 × 0.12 × 0.06 mm3) was selected and mounted on a suitable support on an Bruker APEX-II CCD diffractometer. The crystal was kept at a steady T = 98(2) K during data collection. The structure was solved with the SIR200452 structure solution program by using the direct methods solution method and by using Olex250 as the graphical interface. The model was refined with version 2018/1 of ShelXL53 using least squares minimization.

■

ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.inorgchem.9b01016. Detailed information on 1H NMR and 13C NMR spectra of compounds, FT-IR spectra, X-ray crystallography data (including tables of bond lengths and angles), and detailed i-TLC radiochromatographs (PDF) Accession Codes

CCDC 1908810−1908812 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

■

AUTHOR INFORMATION

Corresponding Authors

*(C.O.) E-mail: [email protected]. *(P.C.) E-mail: [email protected]. ORCID

Xiaozhu Wang: 0000-0002-5882-0066 Peter Comba: 0000-0001-7796-3532 Chris Orvig: 0000-0002-2830-5493 Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS We gratefully acknowledge both the Canadian Institutes for Health Research (CIHR) and the Natural Sciences and Engineering Research Council (NSERC) for grant support, NSERC for an IsoSiM CREATE at TRIUMF studentship (N.C.) and for CGS M and PGS D scholarships (L.S.) as well as MITACS for a Globalink Graduate fellowship (N.C.) and UBC for a FYF (L.S.). P.C. acknowledges support by the Deutsche Forschungsgemeinschaft (DFG) and Heidelberg University. TRIUMF receives funding from the National Research Council of Canada. We also thank Mr. Thomas Kostelnik for thoughtful editing.

■

REFERENCES

(1) Blumgart, H. L.; Yens, O. C. Studies on the Velocity Of Blood Flow I. The Method Utilized. J. Clin. Invest. 1927, 4, 1−13. (2) Blumgart, H. L.; Yens, O. C. Studies on the Velocity Of Blood Flow. Ann. Int. Med. 1976, 84, 747. (3) Hoehr, C.; Bénard, F.; Buckley, K.; Crawford, J.; Gottberg, A.; Hanemaayer, V.; Kunz, P.; Ladouceur, K.; Radchenko, V.; Ramogida, C.; Robertson, A.; Ruth, T.; Zacchia, N.; Zeisler, S.; Schaffer, P. Medical isotope production at TRIUMF- from imaging to treatment. Phys. Procedia 2017, 90, 200−208.

8691

DOI: 10.1021/acs.inorgchem.9b01016 Inorg. Chem. 2019, 58, 8685−8693

Article

Inorganic Chemistry (4) Blower, P. J. A nuclear chocolate box: the periodic table of nuclear medicine. Dalton Trans. 2015, 44, 4819−4844. (5) Cyclotron Produced Radionuclides. Physical Characteristics and Production Methods; An International Atomic Energy Agency Publication: Vienna, 2009. (6) Kostelnik, T. I.; Orvig, C. Radioactive Main Group and Rare Earth Metals for Imaging and Therapy. Chem. Rev. 2019, 119, 902−956. (7) Kersemans, V.; Cornelissen, B.; Minden, M. D.; Brandwein, J.; Reilly, R. M. Drug-Resistant AML Cells and Primary AML Specimens Are Killed by 111In-Anti-CD33 Monoclonal Antibodies Modified with Nuclear Localizing Peptide Sequences. J. Nucl. Med. 2008, 49, 1546− 1554. (8) Holland, J. P.; Williamson, M. J.; Lewis, J. S. Unconventional nuclides for radiopharmaceuticals. Mol. Imaging 2010, 9, 1−20. (9) Emmett, L.; Willowson, K.; Violet, J.; Shin, J.; Blanksby, A.; Lee, J. Lutetium 177 PSMA radionuclide therapy for men with prostate cancer: a review of the current literature and discussion of practical aspects of therapy. J. Med. Radiat. Sci. 2017, 64, 52−60. (10) Banerjee, S.; Pillai, M. R. A.; Knapp, F. F. Lutetium-177 Therapeutic Radiopharmaceuticals: Linking Chemistry, Radiochemistry, and Practical Applications. Chem. Rev. 2015, 115, 2934−2974. (11) Price, E. W.; Orvig, C. Matching chelators to radiometals for radiopharmaceuticals. Chem. Soc. Rev. 2014, 43, 260−290. (12) Heppeler, A.; Froidevaux, S.; Mäcke, H. R.; Hennig, M.; Jermann, E.; Béhé, M.; Powell, P. Radiometal-Labelled Macrocyclic ChelatorDerivatised Somatostatin Analogue with Superb Tumour-Targeting Properties and Potential for Receptor-Mediated Internal Radiotherapy. Chem. - Eur. J. 1999, 5, 1974−1981. (13) Shannon, R. D. Revised Effective Ionic Radii and Systematic Studies of Interatomie Distances in Halides and Chaleogenides. Acta Crystallogr., Sect. A: Cryst. Phys., Diffr., Theor. Gen. Crystallogr. 1976, A32, 751−767. (14) Wadas, T. J.; Wong, E. H.; Weisman, G. R.; Anderson, C. J. Coordinating Radiometals of Copper, Gallium, Indium, Yttrium and Zirconium for PET and SPECT Imaging of Disease. Chem. Rev. 2010, 110, 2858−2902. (15) Sun, Y.; Anderson, C. J.; Pajeau, T. S.; Reichert, D. E.; Hancock, R. D.; Motekaitis, R. J.; Martell, A. E.; Welch, M. J. Indium(III) and Gallium(III) Complexes of Bis(aminoethanethiol) Ligands with Different Denticities: Stabilities, Molecular Modeling, and in Vivo Behavior. J. Med. Chem. 1996, 39, 458−470. (16) Briand, G. G.; Cooper, B. F. T.; MacDonald, D. B. S.; Martin, C. D.; Schatte, G. Preferred bonding motif for indium aminoethanethiolate complexes: structural characterization of (Me2NCH2CH2S)2InX/SR (X = Cl, I; R = 4-MeC6H4, 4-MeOC6H4). Inorg. Chem. 2006, 45, 8423−8429. (17) Hunt, F. C. Potential Radiopharmaceuticals for the Diagnosis of Biliary Atresia and Neonatal Hepatitis: EHPG and HBED Chelates of 67Ga and 111In. Int. J. Radiat. Appl. Instrumentation. Part B. Nucl. Med. Biol. 1988, 15, 659−664. (18) Price, E. W.; Ferreira, C. L.; Adam, M. J.; Orvig, C. High-denticity Ligands Based on Picolinic Acid for 111In Radiochemistry. Can. J. Chem. 2014, 92, 695−705. (19) Stimmel, J. B.; Kull, F. C. Samarium-153 and Lutetium-177 Chelation Properties of Selected Macrocyclic and Acyclic Ligands. Nucl. Med. Biol. 1998, 25, 117−125. (20) Mjos, K. D.; Orvig, C. Metallodrugs in Medicinal Inorganic Chemistry. Chem. Rev. 2014, 114, 4540−4563. (21) Boros, E.; Packard, A. B. Radioactive Transition Metals for Imaging and Therapy. Chem. Rev. 2019, 119, 870−901. (22) Price, E. W.; Zeglis, B. M.; Cawthray, J. F.; Ramogida, C. F.; Ramos, N.; Lewis, J. S.; Adam, M. J.; Orvig, C. H4octapa-Trastuzumab: Versatile Acyclic Chelate System for 111In and 177Lu Imaging and Therapy. J. Am. Chem. Soc. 2013, 135, 12707−12721. (23) Ferdani, R.; Stigers, D. J.; Fiamengo, A. L.; Wei, L.; Li, B. T. Y.; Golen, J. A.; Rheingold, A. L.; Weisman, G. R.; Wong, E. H.; Anderson, C. J. Synthesis, Cu(II) complexation, 64Cu-labeling and biological evaluation of cross-bridged cyclam chelators with phosphonate pendant arms. Dalton Trans. 2012, 41, 1938−1950.

(24) Wang, X.; Jaraquemada-Peláez, M. de G.; Rodríguez-Rodríguez, C.; Cao, Y.; Buchwalder, C.; Choudhary, N.; Jermilova, U.; Ramogida, C. F.; Saatchi, K.; Häfeli, U. O.; Patrick, B. O.; Orvig, C. H4octox: Versatile Bimodal Octadentate Acyclic Chelating Ligand for Medicinal Inorganic Chemistry. J. Am. Chem. Soc. 2018, 140, 15487−15500. (25) Comba, P.; Kerscher, M.; Rück, K.; Starke, M. Bispidines for radiopharmaceuticals. Dalton Trans. 2018, 47, 9202−9220. (26) Comba, P.; Kerscher, M.; Schiek, W. Bispidine coordination chemistry. Prog. Inorg. Chem. 2008, 55, 613. (27) Comba, P.; Fukuzumi, S.; Koke, C.; Martin, B.; Löhr, A.-M.; Straub, J. A bispidine iron(IV) oxo complex in the entatic state. Angew. Chem., Int. Ed. 2016, 55, 11129−11133. (28) Comba, P.; Merz, M.; Pritzkow, H. Catalytic Aziridination of S t y r e n e w i th C o p p e r C o m p l ex e s o f Su b s t i tu t e d 3 , 7 Diazabicyclo[3.3.1]nonanones. Eur. J. Inorg. Chem. 2003, 9, 1711− 1718. (29) Comba, P.; Haaf, C.; Lienke, A.; Muruganantham, A.; Wadepohl, H. Synthesis, Structure, and Highly Efficient Copper-Catalyzed Aziridination with a Tetraaza-Bispidine Ligand. Chem. - Eur. J. 2009, 15, 10880−10887. (30) Roux, A.; Nonat, A. M.; Brandel, J.; Hubscher-Bruder, V.; Charbonnière, L. J. Kinetically Inert Bispidol-Based Cu(II) Chelate for Potential Application to 64/67 Cu Nuclear Medicine and Diagnosis. Inorg. Chem. 2015, 54, 4431−4444. (31) Comba, P.; Grimm, L.; Orvig, C.; Rück, K.; Wadepohl, H. Synthesis and Coordination Chemistry of Hexadentate Picolinic Acid Based Bispidine Ligands. Inorg. Chem. 2016, 55, 12531−12543. (32) Juran, S.; Walther, M.; Stephan, H.; Bergmann, R.; Steinbach, J.; Kraus, W.; Emmerling, F.; Comba, P. Hexadentate Bispidine Derivatives as Versatile Bifunctional Chelate Agents for Copper(II) Radioisotopes. Bioconjugate Chem. 2009, 20, 347−359. (33) Comba, P.; Jermilova, U.; Orvig, C.; Patrick, B. O.; Ramogida, C. F.; Rück, K.; Schneider, C.; Starke, M. Octadentate Picolinic AcidBased Bispidine Ligand for Radiometal Ions. Chem. - Eur. J. 2017, 23, 15945−15956. (34) Comba, P.; Lienke, A. Bispidine Copper(II) Compounds: Effects of the Rigid Ligand Backbone Peter. Inorg. Chem. 2001, 40, 5206− 5209. (35) Imbert, D.; Comby, S.; Chauvin, A.-S.; Bünzli, J.-C. G. Lanthanide 8-Hydroxyquinoline-Based Podates with Efficient Emission in the NIR Range. Chem. Commun. 2005, 11, 1432−1434. (36) Mouralian, C.; Buss, J. L.; Stranix, B.; Chin, J.; Ponka, P. Mobilization of Iron from Cells by Hydroxyquinoline-Based Chelators. Biochem. Pharmacol. 2005, 71, 214−222. (37) Comba, P.; Jakob, M.; Kerscher, M. The tetradentate bispidine ligand 3,7-dimethyl-9-oxo-2,4-bis(2-pyridyl)-3,7-diazabicyclo[3.3.1]nonane-1,5-dicarboxylate methylester, and its copper(II) complex. Inorg. Synth. 2010, 35, 70−73. (38) Samhammer, A.; Holzgrabe, U.; Haller, R. Synthese, Stereochemie Und Analgetische Wirkung von 3,7-Diazabicyclo[3.3.1]nonan9-Onen Und 1,3-Diazaadamantan-6-onen1). Arch. Pharm. 1989, 322, 551−555. (39) Comba, P.; Kanellakopulos, B.; Katsichtis, C.; Lienke, A.; Pritzkow, H.; Rominger, F. Synthesis and Characterisation of manganese(II) Compounds with Tetradentate Ligands Based on the Bispidine Backbone. J. Chem. Soc., Dalton Trans. 1998, 3997−4002. (40) Serdyuk, O. V.; Evseenko, I. V.; Dushenko, G. A.; Revinskii, Y. V.; Mikhailov, I. E. Synthesis, Structure, and Luminescent Properties of 2[2-(9-Anthryl)vinyl]quinolines. Russ. J. Org. Chem. 2012, 48, 78−82. (41) Walkup, G. K.; Imperiali, B. Stereoselective Synthesis of Fluorescent α-Amino Acids Containing Oxine (8-Hydroxyquinoline) and Their Peptide Incorporation in Chemosensors for Divalent Zinc. J. Org. Chem. 1998, 63, 6727−6731. (42) Börzel, H.; Comba, P.; Hagen, K. S.; Katsichtis, C.; Pritzkow, H. A copper(I) oxygenation precursor in the entatic state: Two isomers of a copper(I) compound of a rigid tetradentate ligand. Chem. - Eur. J. 2000, 6, 914−919. 8692

DOI: 10.1021/acs.inorgchem.9b01016 Inorg. Chem. 2019, 58, 8685−8693

Article

Inorganic Chemistry (43) Braun, F.; Comba, P.; Grimm, L.; Herten, D.-P.; Pokrandt, B.; Wadepohl, H. Ligand-sensitized lanthanide(III) luminescence with octadentate bispidines. Inorg. Chim. Acta 2019, 484, 464−468. (44) Comba, P.; Kerscher, M.; Merz, M.; Müller, V.; Pritzkow, H.; Remenyi, R.; Schiek, W.; Xiong, Y. Structural Variation in TransitionMetal Bispidine Compounds. Chem. - Eur. J. 2002, 8, 5750−5760. (45) Martell, A. E.; Smith, R. M.; Motekaitis, R. J. NIST Database 46; National Institute of Standards and Technology: Gaithersburg, MD, 2001. (46) Spreckelmeyer, S.; Ramogida, C. F.; Rousseau, J.; Colpo, N.; Jermilova, U.; Dias, G. M.; Dude, I.; Jaraquemada-Pelaéz, M. d. G.; Benard, F.; Schaffer, P.; Orvig, C.; et al. p-NO2−Bn−H4neunpa and H4neunpa−Trastuzumab: Bifunctional Chelator for Radiometalpharmaceuticals and 111In Immuno-Single Photon Emission Computed Tomography Imaging. Bioconjugate Chem. 2017, 28, 2145−2159. (47) Eder, M.; Schäfer, M.; Bauder-Wüst, U.; Hull, W.-E.; Wängler, C.; Mier, W.; Haberkorn, U.; Eisenhut, M. 68Ga-complex lipophilicity and the targeting property of a urea-based PSMA inhibitor for PET imaging. Bioconjugate Chem. 2012, 23, 688−697. (48) Sarkar, S.; Bhatt, N.; Ha, Y. S.; Huynh, P. T.; Soni, N.; Lee, W.; Lee, Y. J.; Kim, J. Y.; Pandya, D. N.; An, G. Il; Lee, K. C.; Chang, Y.; Yoo, J. High in Vivo Stability of Cu-64-Labeled Cross-Bridged Chelators Is a Crucial Factor in Improved Tumor Imaging of RGD Peptide Conjugates. J. Med. Chem. 2018, 61, 385−395. (49) Comba, P.; Jakob, M.; Rück, K.; Wadepohl, H. Tuning of the properties of a picolinic acid-based bispidine ligand for stable copper(II) complexation. Inorg. Chim. Acta 2018, 481, 98−105. (50) Dolomanov, O. V.; Bourhis, L. J.; Gildea, R. J.; Howard, J. A. K.; Puschmann, H. OLEX2: a complete structure solution, refinement and analysis program. J. Appl. Crystallogr. 2009, 42, 339−341. (51) Sheldrick, G. M. Crystal structure refinement with SHELXL. Acta Crystallogr., Sect. C: Struct. Chem. 2015, C71, 3−8. (52) Burla, M. C.; Caliandro, R.; Camalli, M.; Carrozzini, B.; Cascarano, G. L.; Giacovazzo, C.; Mallamo, M.; Mazzone, A.; Polidori, G.; Spagna, R. SIR2011: a new package for crystal structure determination and refinement. J. Appl. Crystallogr. 2012, 45, 357−361. (53) Spek, A. L. PLATON SQUEEZE: a tool for the calculation of the disordered solvent contribution to the calculated structure factors. Acta Crystallogr., Sect. C: Struct. Chem. 2015, C71, 9−18.

8693

DOI: 10.1021/acs.inorgchem.9b01016 Inorg. Chem. 2019, 58, 8685−8693