Towards the stable chelation of radium for biomedical applications with an 18-membered macrocyclic ligand

Abstract

The therapeutic alpha-emitter 223Ra can be stably complexed in vivo, creating opportunities for the development of targeted radiopharmaceutical agents with this radionuclide.

Design and Evaluation of 223Ra-Labeled and Anti-PSMA Targeted NaA Nanozeolites for Prostate Cancer Therapy—Part II. Toxicity, Pharmacokinetics and Biodistribution

“…Nevertheless, despite the established clinical efficacy and safety, as well as availability, 223 Ra has not yet found application in receptor-targeted therapy because of the lack of effective bifunctional chelating agents [14]. Recently, Abou et al [15] developed a biologically stable radiocomplex of [ 223 Ra]Ra 2+ with the 18-membered bis-picolinate diazacrown macrocyclic chelator MACROPA and demonstrated its efficient conjugation to a single amino acid βalanine and to a glutamate-urea-glutamate (DUPA) PSMA-targeting vector. Unfortunately, upon conjugation of MACROPA to DUPA, stability of radiocomplex was lost.…”

The Evolving Coordination Chemistry of Radiometals for Targeted Alpha Therapy

“…Radiolabelling with 131 Ba (t 1/2 11.5 days, g 123.8 keV, 30 %) proceeded over 1 h at RT and pH 6 at concentrations above 10 À4 M to achieve radiolabelling efficiency .95 %. [179] Radiolabelling of H 2 macropa with 223 Ra 2þ proceeded in 5 min at ambient temperature and physiological pH (7.4), giving .80 % radiolabelling efficiency at concentrations .10 À5 M. [180,185] The high purity of [ 223 Ra][Ra(Hmacropa)] þ eliminates the need for further purification before in vivo administration. The [ 223 Ra] [Ra(Hmacropa)] þ complex was stable in buffer and human serum at 378C, with 90 % remaining intact over 12 days.…”

“…The [ 223 Ra] [Ra(Hmacropa)] þ complex was stable in buffer and human serum at 378C, with 90 % remaining intact over 12 days. [180] Biodistribution of [ 223 Ra][Ra(Hmacropa)] þ indicated decreased bone uptake (1.6 % ID g À1 after 24 h) in vivo in a healthy rodent model when compared with [ 223 Ra][RaCl 2 ] (22 % ID g À1 after 24 h), demonstrating the absence of free 223 Ra in circulation. [180] The similarity between the biodistributions of the H 2 macropa 223 Ra and 131 Ba complexes supports the use of 131 Ba as a matched pair imaging agent for 223 Ra a-therapy applications.…”

“…[180] Biodistribution of [ 223 Ra][Ra(Hmacropa)] þ indicated decreased bone uptake (1.6 % ID g À1 after 24 h) in vivo in a healthy rodent model when compared with [ 223 Ra][RaCl 2 ] (22 % ID g À1 after 24 h), demonstrating the absence of free 223 Ra in circulation. [180] The similarity between the biodistributions of the H 2 macropa 223 Ra and 131 Ba complexes supports the use of 131 Ba as a matched pair imaging agent for 223 Ra a-therapy applications. H 2 macropa functionalised with b-alanine and the PSMA binding small molecule (((S)-5-tert-butoxy-4-(3-((S)-1,5-di-tertbutoxy-1,5-dioxopentan-2-yl)ureido)-5-oxopentanoic acid) (DUPA)) were radiolabelled with 223 Ra under the same conditions as H 2 macropa with radiolabelling efficiency .90 %.…”

“…H 2 macropa functionalised with b-alanine and the PSMA binding small molecule (((S)-5-tert-butoxy-4-(3-((S)-1,5-di-tertbutoxy-1,5-dioxopentan-2-yl)ureido)-5-oxopentanoic acid) (DUPA)) were radiolabelled with 223 Ra under the same conditions as H 2 macropa with radiolabelling efficiency .90 %. [180] The radiolabelled conjugates [ 223 , indicating that the construct was unstable in vivo and highlighting the significant impact that targeting vectors can have on the chemical properties and biodistribution.…”