De novo synthesis of a new diethylenetriaminepentaacetic acid (DTPA) bifunctional chelating agent.
Diethylene triamine pentaacetic acid (DTPA) has been in extensive use as a metal chelator in the development of radiopharmaceuticals and contrast agents. The former application uses DTPA mostly as a bifunctional chelating agent (BCA) conjugated to tumor-targeting vehicles (TTVs) such as monoclonal antibodies (MAbs) and receptor-directed peptides. A new bifunctional DTPA derivative was synthesized by a fully organic scheme. This compound, N(4),N(alpha),N(alpha),N(epsilon),N(epsilon)-[pentakis(carboxymethyl)]-N(4)-(carboxymethyl)-2,6-diamino-4-azahexanoic hydrazide (20) was prepared by a convergent synthesis strategy using N(alpha)-benzyloxycarbonyl-2,3-diaminopropionic acid as the starting compound. This commercially available material was used to build a functionalized triamine which served as the molecular core template for assembling the target molecule. To evaluate the conjugation and radiolabeling capabilities of this new molecule, it was covalently attached to the anti-TAG-72 MAb, Delta CH2HuCC49, and the conjugate was radiolabeled in near-quantitative yields with yttrium-90 ((90)Y) and lutetium-177 ((177)Lu). Biodistribution of the (177)Lu-labeled DTPA-Delta CH2HuCC49 in tumor-bearing nude mice demonstrated preservation of the immunoreactivity of the MAb as indicated by high tumor uptake. In addition to the introduction of a new bifunctional DTPA, this work reports on a novel synthetic approach for preparation of this useful metal chelator and introduces a new conjugation protocol.
Safavy
Ahmad
A
Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA. safavy@uab.edu
Smith
Dale C
DC
Bazooband
Alireza
A
Buchsbaum
Donald J
DJ
D000818:Animals; D001372:Aza Compounds / Q000737:chemistry*; D002614:Chelating Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D006834:Hydrazines / Q000737:chemistry*; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D004369:Pentetic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship; D015021:Yttrium Radioisotopes
D001372:Aza Compounds; D002614:Chelating Agents; D006834:Hydrazines; C460022:N(4),N,N,N,N-(pentakis(carboxymethyl))-N(4)-(carboxymethyl)-2,6-diamino-4-azahexanoic hydrazide; D015021:Yttrium Radioisotopes; D004369:Pentetic Acid