title: Investigations of N-linked macrocycles for 111In and 90Y labeling of proteins.
abstract: To simplify the synthesis of macrocyclic chelators, commercially available macrocyclic amines were condensed with halogenated acetic acid to prepare the five chelators 12N4 (DOTA), 14N4 (TETA), 15N4, 9N3 and 12N3. Only 12N4 and 9N3 showed efficient labeling of the free chelator with 111In and 90Y. Serum stability studies at 37 degrees C with In-labeled DTPA, 12N4 and 9N3 showed no loss of label over 2 days whereas, with 90Y, only 12N4 showed stabilities comparable to DTPA. The 12N4 chelator was derivatized by attaching biotin on one N-acetate group to stimulate the attachment to protein. The serum stability for both 111In and 90Y was identical to that of biotin derivatized DTPA and lower than that of the free chelators. Biodistribution studies in normal mice of a model protein (avidin) labeled with 90Y via biotinylated 12N4 and biotinylated DTPA showed identical distribution at 1 day except in bone where the %ID/g for the macrocyclic-conjugated protein (3.4 +/- 0.5, N = 8) was significantly (P less than 0.001) lower than that of the DTPA-conjugated protein (9.4 +/- 0.9, N = 7). In conclusion, macrocycles may be readily synthesized from the macrocyclic amines and several show useful stabilities with In and Y. When N-linked to a protein, the Y biodistribution was found to be superior to that of the corresponding DTPA-coupled protein.
authors.affiliation: University of Massachusetts Medical Center, Worcester 01655.
authors.forename: C
authors.initials: C
authors.lastname: Wu
authors.forename: F
authors.initials: F
authors.lastname: Virzi
authors.forename: D J
authors.initials: DJ
authors.lastname: Hnatowich
mesh_terms: D000588:Amines / Q000097:blood / Q000493:pharmacokinetics*; D000818:Animals; D001360:Avidin / Q000097:blood / Q000493:pharmacokinetics; D001710:Biotin / Q000097:blood / Q000493:pharmacokinetics; D002614:Chelating Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D004355:Drug Stability; D006571:Heterocyclic Compounds / Q000097:blood / Q000493:pharmacokinetics; D006573:Heterocyclic Compounds, 1-Ring; D007205:Indium Radioisotopes; D051379:Mice; D004369:Pentetic Acid / Q000032:analysis / Q000493:pharmacokinetics; D011506:Proteins / Q000378:metabolism*; D014018:Tissue Distribution; D015021:Yttrium Radioisotopes
chemical_list: D000588:Amines; D002614:Chelating Agents; D006571:Heterocyclic Compounds; D006573:Heterocyclic Compounds, 1-Ring; D007205:Indium Radioisotopes; D011506:Proteins; D015021:Yttrium Radioisotopes; D001360:Avidin; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D001710:Biotin; D004369:Pentetic Acid