Evaluation of the serum stability and in vivo biodistribution of CHX-DTPA and other ligands for yttrium labeling of monoclonal antibodies.
Serum stability and in vivo biodistribution of both A and B isomers of the 2-(p-isothiocyanatobenzyl) (p-SCN-Bz)-cyclohexyldiethylenetriaminepentaacetic acid ligand (CHX-DTPA), a recently developed backbone-substituted derivative of DTPA, were evaluated and compared to those of 2-(p-SCN-Bz)-6-methyl-DTPA (1B4M-DTPA) and 2-(p-SCN-Bz)-1,4,7,10-tetraazacyclododecane tetra-acetic acid (2B-DOTA).


METHODS
Stability of 88Y-labeled ligands (0.1 microM) was evaluated in serum for up to 17 days. For biodistribution, ligands were conjugated to monoclonal antibody (Mab) B3, a murine IgG1k, and labeled with 88Y at 0.1-0.3 mCi/mg. Nontumor-bearing nude mice were injected intravenously with 1-2 microCi/4-10 micrograms of 88Y-labeled B3-conjugates and killed at 6 hr and daily up to 168 hr postinjection. Indium-111-(1B4M)-B3 was co-injected in all mice as internal control.


RESULTS
Serum stability of 88Y-DOTA failed to show any significant release of activity, whereas pseudo-first-order dissociation rate constants of 3.97 x 10(-3), 2.54 x 10(-3) and 1.46 x 10(-2) (day-1) were calculated for 88Y-1B4M, 88Y-CHX-A and 88Y-CHX-B, respectively. Accordingly, cortical bone uptake of 88Y was significantly higher for all DTPA-derivative chelates than for DOTA.


CONCLUSIONS
While none of the DTPA-derivative chelates could challenge DOTA in its ability to hold the radioytrium, significant differences were observed in the kinetic inertness of the A and B isomers of CHX, indicating that the CHX-B ligand is not as suitable for 90Y-labeling of Mabs.
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Department of Nuclear Medicine, Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, MD 20892.
Kinuya
S
S
Garmestani
K
K
Wu
C
C
Brechbiel
M W
MW
Pai
L H
LH
McMurry
T J
TJ
Gansow
O A
OA
Pastan
I
I
Paik
C H
CH
D000818:Animals; D001842:Bone and Bones / Q000378:metabolism; D002614:Chelating Agents / Q000493:pharmacokinetics*; D004355:Drug Stability; D005260:Female; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000493:pharmacokinetics; D007205:Indium Radioisotopes; D017879:Isothiocyanates / Q000737:chemistry / Q000493:pharmacokinetics; D008024:Ligands; D051379:Mice; D008819:Mice, Nude; D004369:Pentetic Acid / Q000031:analogs & derivatives / Q000737:chemistry / Q000493:pharmacokinetics; D016499:Radioimmunotherapy; D014018:Tissue Distribution; D015021:Yttrium Radioisotopes
C087160:2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid; D002614:Chelating Agents; D006571:Heterocyclic Compounds; D007205:Indium Radioisotopes; D017879:Isothiocyanates; D008024:Ligands; D015021:Yttrium Radioisotopes; C077295:2-(4-isothiocyanatobenzyl)-6-methyldiethylenetriaminepentaacetic acid; C085678:N-(2-amino-3-(4-isothiocyanatophenyl)propyl)cyclohexane-1,2-diamine-N,N',N',N'',N''-pentaacetic acid; D004369:Pentetic Acid