Synthesis of hexa aza cages, SarAr-NCS and AmBaSar and a study of their metal complexation, conjugation to nanomaterials and proteins for application in radioimaging and therapy

• Published in: Dalton transactions : an international journal of inorganic chemistry 2013-10, Vol.42 (40), p.14402-14410
• Main Authors: Mume, Eskender, Asad, Ali, Di Bartolo, Nadine M, Kong, Linggen, Smith, Christopher, Sargeson, Alan M, Price, Roger, Smith, Suzanne V
• Format: Article
• Language: English
• Subjects: Antibodies; Aza Compounds - chemical synthesis; Aza Compounds - chemistry; Cages; Cobalt - chemistry; Complexation; Computing time; Conjugation; Copper - chemistry; Copper Radioisotopes - chemistry; Derivatives; Hydrogen-Ion Concentration; Ligands; Molecular Structure; Nanostructures - chemistry; Nanostructures - therapeutic use; Organometallic Compounds - chemical synthesis; Organometallic Compounds - therapeutic use; PARTICLE ACCELERATORS; Positron-Emission Tomography; Proteins - chemistry; Radiopharmaceuticals - chemistry; Radiopharmaceuticals - therapeutic use; Silicon Dioxide - chemistry; Synthesis (chemistry); Zinc - chemistry
• ISSN: 1477-9226; 1477-9234
• DOI: 10.1039/c3dt51199e

A novel hexa aza cage, N(1)-(4-isothiocyanatobenzyl)-3,6,10,13,16,19-hexaazabicyclo[6.6.6]icosane-1,8-diamine (SarAr-NCS) was synthesized in good yield and characterized by (1)H NMR and electrospray mass spectrometry. A new method for the synthesis of the related N(1)-(4-carboxybenzyl)-3,6,10,13,16,19-hexaazabicyclo[6.6.6]icosane-1,8-diamine (AmBaSar) using the p-carboxybenzaldehyde is reported. The complexation of Cu(2+), Co(2+) and Zn(2+) by the two ligands over a range of pHs was found to be similar to the parent derivative SarAr. SarAr-NCS was conjugated to both silica particles (≈90 nm diam.) and the model B72.3 murine antibody. The SarAr-NCSN-silica particles were radiolabeled with Cu(2+) doped (64)Cu and the number of ligands conjugated was calculated to be an average of 7020 ligands per particle. Conjugation of SarAr-NCS to the B72.3 antibody was optimized over a range of conditions. The SarAr-NCSN-B72.3 conjugate was stored in buffer and as a lyophilized powder at 4 °C over 38 days. Its radiolabeling efficiency, stability and immunoreactivity were maintained. The development of a high yielding synthesis of SarAr-NCS should provide an entry point for a wide range of Cu and Zn radiometal PET imaging agents and potentially radiotherapeutic agents with (67)Cu.