Synthesis of the first diethylenetriaminepentahydroxamic acid (DTPH) bifunctional chelating agent.
Synthesis of a new pentahydroxamic acid bifunctional chelating agent (BCA), constructed on the aminoazaalkyl core of diethylenetriaminepentaacetic acid (DTPA), is reported. Rational modifications in the structure of DTPA, which could result in an enhancement of its chelation properties, add to the collection of diagnostic and therapeutic metals bound by this chelator, and might implement significant improvements in the in vivo behavior of this compound, are described. Further improvements in the stability of the ligand-metal complexes of DTPA may improve both diagnostic and therapeutic outcomes such as tumor-to-normal tissue ratios and target-delivered radioactivity. A combination of hydroxamate functions with the azaalkyl backbone of DTPA might be a suitable approach to generate such higher stabilities. This rationale may be justified by the well-known affinity of hydroxamates against different transition metals and favorable properties of DTPA as a versatile chelator. Thus, the N(4),N(alpha),N(alpha),N(epsilon),N(epsilon)-pentakis[[((N-hydroxy-N-methyl]carbonyl)methyl]-2, 6-diamino-4-azahexanoic hydrazide (5, DTPH) was designed and synthesized through a convergent synthesis and in 40.7% overall yield. Conjugation of this compound to the monoclonal antibody (MAb) Delta Ch2HuCC49, used as a model protein, was carried out to evaluate the efficiency of this molecule as a BCA. Radiolabeling of the DTPH-Delta CH2HuCC49 conjugate with lutetium-177 ((177)Lu) and biodistribution of the labeled conjugate in athymic nude mice, bearing LS174T human colon carcinoma xenografts, are reported.
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; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000276:immunology; D001372:Aza Compounds / Q000737:chemistry*; D002614:Chelating Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D005260:Female; D006834:Hydrazines / Q000737:chemistry*; D008187:Lutetium; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D004369:Pentetic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D011868:Radioisotopes
D000911:Antibodies, Monoclonal; 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; D011868:Radioisotopes; D008187:Lutetium; D004369:Pentetic Acid