An Evaluation of Cage Amine Sarcophagine Ligands for the Synthesis of Cobalt Radiopharmaceuticals

Positron-emitting cobalt-55 (t1/2 = 17.53 h, β+ = 77%, Eγ = 931.1 keV, Iγ = 75%) has the potential to be used for PET imaging and Auger electron-emitting cobalt-58m (t1/2 = 9.10 h, IC= 100%) has the potential to be used in targeted radionuclide therapy. Sarcophagines are a family of macrobicyclic cage amine ligands that form stable complexes with cobalt(III). This work investigates the potential of a derivative of sarcophagine with a pendent carboxylic acid functional group, 5-(8-methyl-3,6,10,13,16,19-hexaaza-bicyclo[6.6.6]icosan-1-ylamino)-5-oxopentanoic acid (known as MeCOSar), to serve as a ligand for cobalt-55. The cobalt(III) complex, [CoIII(MeCOSar)]3+, was synthesized and characterized as well as a complex where the MeCOSar ligand is conjugated to tumor-targeting peptide Tyr3-ocreotate, [CoIII(SarTATE)]3+. The MeCOSar and SarTATE ligands were radiolabeled with cobalt-55 to give [55Co][CoIII(MeCOSar)]n+ and [55Co][CoIII(SarTATE)] respectively and their biodistribution was evaluated in non tumor-bearing mice. The tumor uptake of [55Co][CoIII(SarTATE)] was then further evaluated in AR42J tumor-bearing mice and compared to the copper-64 complex, [64Cu][CuII(SarTATE)]. Radiolabeling SarTATE with cobalt-55 requires higher temperatures when compared to copper-64, and [55Co][CoIII(SarTATE)] has lower tumor uptake and higher liver uptake in tumor-bearing mice when compared to [64Cu][CuII(SarTATE)].