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* ,† † 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, Universitä t 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, H 2 bispox 2 and its complexes with medicinally useful radiometal nuclides ( 111 In 3+ and 177 Lu 3+ ), including their X-ray diffraction single crystal structures with the stable isotopes. 111 InCl 3 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 [ 111 In(bispox 2 )] + 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 H 2 bispox 2 as a useful chelator for 111 In and 177 Lu-based radiopharmaceuticals. ■ INTRODUCTION Since the first clinical study in 1925 using bismuth-214 as a radiotracer to measure blood flow from arm to opposite arm, 1,2 the increasingly diverse use of radionuclides has been expanding the field of nuclear medicine, both in terms of diagnostic imaging (e.g., single photon emission computed tomography, SPECT, and positron emission tomography, PET) and targeted therapy (e.g., alpha (α), beta (β − ), and Auger electron-therapy). 3 A wide range of metallic radionuclides with varying physical (e.g., half- life, specific activity, emission type) and chemical (e.g., hardness, acidity) properties can be produced by cyclotrons, nuclear reactors and/or generators to afford a “nuclear chocolate box” that can be consulted and carefully selected from, depending on the desired application or need. 4 Indium-111 is an attractive SPECT radionuclide that decays with a half-life of 2.8 days via electron capture (100% EC) and emits two high intensity γ-rays (245 and 172 keV) with near- ideal energy for diagnostic purposes. This radionuclide is widely available as it is commonly cyclotron-produced via 111 Cd- (p,n) 111 In and is clinically FDA approved for use in drugs such as Octreoscan ( 111 In-pentetreotide), Prostascint ( 111 In-capro- mab), CEA-Scan ( 111 In-arcitumonab), MPI indium DTPA In111 (111In- DTPA), and indium In111 oxyquinoline (111In-oxyquinoline). 5 In addition, 111 In emits Auger electrons that can potentially be used for radiotherapy. 6,7 Lutetium-177 is a reactor-produced therapeutic radiometal ion ( 176 Lu(n, γ) 177 Lu) 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 <2 mm, which provides better irradiation of small tumors. 10 The medicinal application of radiometal nuclides usually requires a bifunctional chelator to bind the radiometal ion in order to form a thermodynamically stable and kinetically inert metal complex, which can then be delivered to the desired site in vivo via an attached targeting vector for imaging or therapy. 11 Besides the clinical relevance of these radionuclides, it is of utmost importance to understand the fundamental coordination chemistry of these metal complexes and the influence of the structural differences on their biological behavior. 12 In terms of the coordination chemistry of In 3+ , owing to its relatively large ionic size of 62−92 pm, it usually attains a coordination number of 7−8 in its complexes. 13 Although hydrated In 3+ has a high pK a of 4.0, 14 it is usually considered as a borderline acidic metal ion (I A = 6.3) with affinity for soft donor groups, such as thiols, 15,16 as well as hard donor groups, such as phenolates and carboxylates. 17,18 While the lanthanide Lu 3+ is a larger metal ion with an ionic radius of 86−103 pm and Received: April 9, 2019 Article pubs.acs.org/IC Cite This: Inorg. Chem. XXXX, XXX, XXX-XXX © XXXX American Chemical Society A DOI: 10.1021/acs.inorgchem.9b01016 Inorg. Chem. XXXX, XXX, XXX−XXX Downloaded by UNIV OF SOUTHERN INDIANA at 19:20:39:180 on June 18, 2019 from https://pubs.acs.org/doi/10.1021/acs.inorgchem.9b01016.