An Eighteen‐Membered Macrocyclic Ligand for Actinium‐225 Targeted Alpha Therapy

Abstract

The 18-membered macrocycle H macropa was investigated for Ac chelation in targeted alpha therapy (TAT). Radiolabeling studies showed that macropa, at submicromolar concentration, complexed all Ac (26 kBq) in 5 min at RT. [ Ac(macropa)] remained intact over 7 to 8 days when challenged with either excess La ions or human serum, and did not accumulate in any organ after 5 h in healthy mice. A bifunctional analogue, macropa-NCS, was conjugated to trastuzumab as well as to the prostate-specific membrane antigen-targeting compound RPS-070. Both constructs rapidly radiolabeled Ac in just minutes at RT, and macropa-Tmab retained>99 % of its Ac in human serum after 7 days. In LNCaP xenograft mice, Ac-macropa-RPS-070 was selectively targeted to tumors and did not release free Ac over 96 h. These findings establish macropa to be a highly promising ligand for Ac chelation that will facilitate the clinical development of Ac TAT for the treatment of soft-tissue metastases.

Sensing Zn2+ in Aqueous Solution with a Fluorescent Scorpiand Macrocyclic Ligand Decorated with an Anthracene Bearing Tail

“…Scorpiand type aza-macrocyclic ligands, that is aza-macrocyclic ligands with coordinating tails [1], and their metal complexes have attracted considerable interest thanks to the numerous uses they have been tested for, including but not limited to various biomedical applications [2,3] (MRI contrast agents [4,5], radioisotopes complexation and radiolabelling [6][7][8][9], radiotherapy [10][11][12][13][14], chelation therapy [15][16][17], antiproliferative treatments [18][19][20][21], enzyme mimicking [22][23][24][25][26][27][28][29]), catalysis [30][31][32][33][34][35][36] and chemosensing [37][38][39][40][41][42][43].…”

An Appendix of Radionuclides Used in Targeted Alpha Therapy

“…However, its thermodynamics require long reaction time at elevated temperature [28]. Larger ligands, HEHA and Macropa, have been explored for high in vitro and in vivo stability conjugates obtained at room temperature [29,30]. One of the major concerns with 225 Ac is the presence of multiple daughters after decay having relatively long half-life and different chemistry.…”

Radiolabelled Peptides for Positron Emission Tomography and Endoradiotherapy in Oncology

“…Again, the use of [ 225 Ac]Ac-DOTA-derivatives as prosthetic groups is suggested to solve this problem [111]. Recently, N,N'-bis[(6-carboxy-2-pyridil)methyl]-4,13-diaza-18-crown-6 (H 2 macropa) and its bifunctional analogue H 2 macropa-NCS have been proposed [112]. This chelator allows labelling with actinium-225 at room temperature within several minutes at submicromolar precursor concentrations.…”