Synthesis and Evaluation of a Macrocyclic Actinium‐225 Chelator, Quality Control and In Vivo Evaluation of ²²⁵Ac‐crown‐αMSH Peptide

Abstract

Targeted alpha‐therapy (TAT) has great potential for treating a broad range of late‐stage cancers by delivering a focused and lethal radiation dose to tumors. Actinium‐225 (225Ac) is an emerging alpha emitter suitable for TAT; however, the availability of chelators for Ac remains limited to a small number of examples (DOTA and macropa). Herein, we report a new Ac macrocyclic chelator named ‘crown’, which binds quantitatively and rapidly (<10 min) to Ac at ambient temperature. We synthesized 225Ac‐crown‐αMSH, a peptide targeting the melanocortin 1 receptor (MC1R), specifically expressed in primary and metastatic melanoma. Biodistribution of 225Ac‐crown‐αMSH showed favorable tumor‐to‐background ratios at 2 h post injection in a preclinical model. In addition, we demonstrated dramatically different biodistrubution patterns of 225Ac‐crown‐αMSH when subjected to different latency times before injection. A combined quality control methodology involving HPLC, gamma spectroscopy and radioTLC is recommended.

Overview of the Most Promising Radionuclides for Targeted Alpha Therapy: The “Hopeful Eight”

“…New chelating agents based on structures bearing picolinic acid arms [ 25 , 38 , 39 ] including aza-crown-ether macrocycles [ 40 , 41 ] have recently emerged for complexation of 225 Ac ( Figure 2 ). Among all the reported chelators, the 18-membered macrocycle macropa [ 40 ], the new “crown” aza-macrocycle [ 41 ] and the undecadentate pyridyl-based H 4 py4pa [ 39 ] showed an efficient complexation at room temperature as well as an interesting stability against competing ions or in serum. After conjugation to a peptide or an antibody of interest, they all showed a promising in vivo stability highlighted by a high uptake in tumor and a low accumulation in other organs such as liver or bones.…”

Targeted Alpha Therapy: Progress in Radionuclide Production, Radiochemistry, and Applications

“…Recently developed 225 Ac chelators such as H 4 py4pa and H 4 py4pa-phenyl-NCS have demonstrated excellent in vivo stability and tumor specificity [53]. Another novel chelator, 225 Ac-crown, was shown to be stable over an extended period of time, while binding rapidly to 225 Ac at ambient temperature [45].…”

The Evolving Coordination Chemistry of Radiometals for Targeted Alpha Therapy

“…Acyclic picolinates H 4 neunpa [20,21] N 5 O 4 RT, 1 h, pH 5.5, 10 À3 M G H 4 phospa [21] N 4 O 4 77 D RT, 1 h, pH 5.5, 10 À3 M H 4 noneunpa [20] N 4 O 5 90 D RT, 1 h, pH 5.5, 10 À6 M H 4 octapa [21] N 4 O 4 20.13 93 D RT, 1 h, pH 5.5, 10 À5 M H 4 CHXoctapa [21] PSMA; [25][26][27][28][29][30] tetrazine-TCO [31] H 4 DOTP [24] N 4 O 4 Capped inverted square prism 408C, 30 min, pH 10, 10 À2 M 18-Crown-6-based H 2 macropa [32,33] N 4 O 6 Irregular tridecahedron 14.99 99 E RT, 5 min, pH 6, 10 À7 M PSMA; [14,34] trastuzumab [14] H 4 crown N 4 O 6 90 RT, 10 min, pH 5-7, 10 À6 M aMSH [35] A From the La 3þ X-ray crystallographic structure.…”