title: Modular syntheses of H₄octapa and H₂dedpa, and yttrium coordination chemistry relevant to ⁸⁶Y/⁹⁰Y radiopharmaceuticals.
abstract: The ligands H2dedpa, H4octapa, p-SCN-Bn-H2dedpa, and p-SCN-Bn-H4octapa were synthesized using a new protection chemistry approach, with labile tert-butyl esters replacing the previously used methyl esters as protecting groups for picolinic acid moieties. Additionally, the ligands H2dedpa and p-SCN-Bn-H2dedpa were synthesized using nosyl protection chemistry for the first time. The use of tert-butyl esters allows for deprotection at room temperature in trifluoroacetic acid (TFA), which compares favorably to the harsh conditions of refluxing HCl (6 M) or LiOH that were previously required for methyl ester cleavage. H4octapa has recently been shown to be a very promising (111)In and (177)Lu ligand for radiopharmaceutical applications; therefore, coordination chemistry studies with Y(3+) are described to assess its potential for use with (86)Y/(90)Y. The solution chemistry of H4octapa with Y(3+) is shown to be suitable via solution NMR studies of the [Y(octapa)](-) complex and density functional theory (DFT) calculations of the predicted structure, suggesting properties similar to those of the analogous In(3+) and Lu(3+) complexes. The molecular electrostatic potential (MEP) was mapped onto the molecular surface of the DFT-calculated coordination structures, suggesting very similar and even charge distributions between both the Lu(3+) and Y(3+) complexes of octapa(4-), and coordinate structures between 8 (ligand only) and 9 (ligand and one H2O). Potentiometric titrations determined H4octapa to have a formation constant (log K(ML)) with Y(3+) of 18.3 ± 0.1, revealing high thermodynamic stability. This preliminary work suggests that H4octapa may be a competent ligand for future (86)Y/(90)Y radiopharmaceutical applications.
authors.affiliation: Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC V6 T 1Z1, Canada.
authors.forename: Eric W
authors.initials: EW
authors.lastname: Price
authors.forename: Jacqueline F
authors.initials: JF
authors.lastname: Cawthray
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Adam
authors.forename: Chris
authors.initials: C
authors.lastname: Orvig
mesh_terms: D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry; D005021:Ethylamines / Q000138:chemical synthesis* / Q000737:chemistry; D007204:Indium / Q000737:chemistry; D008024:Ligands; D008187:Lutetium / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000737:chemistry*; D013816:Thermodynamics; D015019:Yttrium / Q000737:chemistry*
chemical_list: D056831:Coordination Complexes; D005021:Ethylamines; D008024:Ligands; C000596869:N,N'-((6-carboxylato)pyridin-2-yl)methyl)-1,2-diaminoethane; C000596870:N,N'-((6-carboxylato)pyridin-2-yl)methyl)-N,N'-diacetic acid-1,2-diaminoethane; D011725:Pyridines; D019275:Radiopharmaceuticals; D007204:Indium; D015019:Yttrium; D008187:Lutetium