{"entity":{"id":"macropa-chelation","kind":"technology","name":"Macropa chelation","aka":["H2macropa","bp18c6"],"tldr":"Macropa is a newer ring-shaped molecule built specifically to grip large radioactive metal atoms, such as the alpha-emitter actinium-225, quickly and at room temperature, which older molecules like DOTA cannot do well.","summary":"Macropa (N,N'-bis[(6-carboxy-2-pyridyl)methyl]-4,13-diaza-18-crown-6) is an 18-membered diaza-crown-6 macrocycle with two pendant picolinate arms, first reported by Thiele et al. in 2017. Unlike DOTA, whose rigid octadentate cavity favours small lanthanide-sized ions, macropa shows 'reverse size selectivity': it binds large ions (Ac3+, Pb2+, La3+, Ra2+) markedly more tightly than small ones, matching Ac3+'s large 1.12 Å ionic radius. In side-by-side testing, macropa complexed essentially all of a 26 kBq 225Ac spike within 5 minutes at room temperature at submicromolar ligand concentration, whereas DOTA complexed only around 10% under the same conditions and required 80°C to go to completion.\n\nBifunctional derivatives (macropa-NCS) have been conjugated to antibodies (trastuzumab, the GPC3-targeting antibody codrituzumab/GC33) and to the PSMA-targeting small molecule RPS-070, and the resulting 225Ac complexes were stable for 7-8 days against human serum and excess La3+ challenge. Rigidified analogues (H2BZmacropa, H2BZ2macropa) trade some thermodynamic stability for improved synthetic access. Macropa also complexes 212Pb, 133La, 213Bi, 223Ra and 224Ra with varying efficiency, making it one of two chelators (alongside DOTA) most discussed for 225Ac-based targeted alpha therapy as of 2026; it does not solve the separate daughter-recoil problem that follows 225Ac decay.","asOf":"2026-09-22","links":[{"label":"Thiele et al., Angew. Chem. Int. Ed. 2017: An eighteen-membered macrocyclic ligand for actinium-225 targeted alpha therapy","url":"https://onlinelibrary.wiley.com/doi/am-pdf/10.1002/anie.201709532"},{"label":"Kadassery et al., Bioconjugate Chem 2022: H2BZmacropa-NCS, a bifunctional chelator for 225Ac TAT","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC9362842/"},{"label":"Equilibrium thermodynamics of macropa complexes with radiopharmaceutical metals (Inorg. Chem. 2023)","url":"https://pubs.acs.org/doi/10.1021/acs.inorgchem.3c01983"},{"label":"Advancing chelation strategies for large metal ions for nuclear medicine (UC eScholarship dissertation)","url":"https://escholarship.org/content/qt8hr5w9j2/qt8hr5w9j2.pdf"}],"tags":["chemistry","chelator","alpha therapy"],"related":["dota-chelation","alpha-daughter-redistribution","targeted-alpha-therapy","ac225-psma","ac-225","ra-223","pb-212","bi-213","ra-224"],"indications":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":["cyclotron-isotope-production"],"notes":[],"principle":"An 18-membered diaza-crown-6 macrocycle with two picolinate arms has a cavity sized for large metal ions, so it shows 'reverse size selectivity' and binds large ions such as Ac3+, Pb2+ and La3+ far more tightly and far faster (minutes, at room temperature) than it binds small lanthanide-sized ions, the opposite preference to DOTA.","strengths":[],"limitations":[],"since":"2017 (first report); bifunctional NCS derivative and antibody conjugates 2019-2022"},"route":"/technologies/macropa-chelation/","neighbours":{"technology":[{"id":"alpha-daughter-redistribution","kind":"technology","name":"Alpha-emitter daughter redistribution ('free daughter' problem)","route":"/technologies/alpha-daughter-redistribution/"},{"id":"cyclotron-isotope-production","kind":"technology","name":"Cyclotron isotope production (F-18, Ga-68, Cu-64, Zr-89, At-211)","route":"/technologies/cyclotron-isotope-production/"},{"id":"dota-chelation","kind":"technology","name":"DOTA chelation","route":"/technologies/dota-chelation/"},{"id":"targeted-alpha-therapy","kind":"technology","name":"Targeted alpha therapy","route":"/technologies/targeted-alpha-therapy/"}],"drug":[{"id":"ac225-psma","kind":"drug","name":"Actinium-225 PSMA agents","route":"/drugs/ac225-psma/"}],"isotope":[{"id":"ac-225","kind":"isotope","name":"Actinium-225","route":"/isotopes/ac-225/"},{"id":"bi-213","kind":"isotope","name":"Bismuth-213","route":"/isotopes/bi-213/"},{"id":"pb-212","kind":"isotope","name":"Lead-212","route":"/isotopes/pb-212/"},{"id":"ra-223","kind":"isotope","name":"Radium-223","route":"/isotopes/ra-223/"},{"id":"ra-224","kind":"isotope","name":"Radium-224","route":"/isotopes/ra-224/"}]}}