Synthesis and biological evaluation of novel macrocyclic ligands with pendent donor groups as potential yttrium chelators for radioimmunotherapy with improved complex formation kinetics.
Novel 1,4,7-triazacyclononane-N,N',N' '-triacetic acid (NOTA) based octadentate ligands [2-(4,7-biscarboxymethyl[1,4,7]triazacyclononan-1-ylethyl)carbonylmethylamino]acetic acid tetrahydrochloride (1) and [3-(4,7-biscarboxymethyl[1,4,7]triazacyclononan-1-yl-propyl)carbonylmethylamino]acetic acid tetrahydrochloride (2) with pendent donor groups as potential yttrium chelators for radioimmunotherapy (RIT) have been prepared via a convenient and high-yield cyclization route. The complexation kinetics of the novel chelates with Y(III) was investigated and compared to that of 1,4,7,10-tetraazacyclododecane-N,N',N' ',N" '-tetraacetic acid (DOTA), a macrocyclic chelating agent well recognized as forming very stable complexes with yttrium but also limited in usage because of slow Y(III) complex formation rates. The in vitro stability of the corresponding (88)Y-labeled complexes in human serum was assessed by measuring the release of (88)Y from the complexes over 14 days. The in vivo biodistribution of (86)Y-labeled 1 in mice was evaluated and compared to that of the (86)Y-DOTA complex. Formation of the Y complex of 1 was significantly more rapid than that of either 2 or DOTA. Serum stability of the (88)Y complex formed with 1 was equivalent to the DOTA complex, while the complex formed with 2 proved to be significantly unstable. The results obtained from a biodistribution study indicate that the (86)Y-1 complex possesses in vivo stability comparable to the analogous DOTA complex.
Chemistry Section, Radiation Oncology Branch, Building 10, Room B3B69, National Cancer Institute/NIH, Bethesda, MD 20892, USA.
Hyun-soon
HS
Chong
Kayhan
K
Garmestani
Dangshe
D
Ma
Diane E
DE
Milenic
Terrish
T
Overstreet
Martin W
MW
Brechbiel
D000085:Acetates / Q000138:chemical synthesis* / Q000737:chemistry; D000818:Animals; D002614:Chelating Agents / Q000138:chemical synthesis* / Q000737:chemistry; D004355:Drug Stability; D005260:Female; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D016499:Radioimmunotherapy; D014018:Tissue Distribution; D015019:Yttrium
C463502:(2-(4,7-biscarboxymethyl(1,4,7)triazacyclononan-1-ylethyl)carbonylmethylamino)acetic acid; C463519:(3-(4,7-biscarboxymethyl(1,4,7)triazacyclononan-1-ylpropyl)carbonylmethylamino)acetic acid; D000085:Acetates; D002614:Chelating Agents; D006571:Heterocyclic Compounds; D009942:Organometallic Compounds; D015019:Yttrium