Hepatobiliary delivery of polyaminopolycarboxylate chelates: synthesis and characterization of a cholic acid conjugate of EDTA and biodistribution and imaging studies with its indium-111 chelate.
A conjugate in which the steroid nucleus of cholic acid was linked to EDTA via an 11-atom spacer was obtained by reacting the succinimidyl ester of cholic acid with the amine formed by reaction of a benzyl isothiocyanate derivative of EDTA with N-(tert-butoxycarbonyl)ethylenediamine and subsequent deprotection. Potentiometric titration studies with model complexes showed that the EDTA moiety retained the ability to form 1:1 chelates of high thermodynamic stability, although formation constants were some 3-4 log K units lower for complexes of the conjugate than for the analogous chelates with underivatized EDTA. A complex formed between the cholic acid-EDTA conjugate and 111InIII was clearly rapidly into the liver when injected iv into mice, with subsequent excretion from the liver into the gastrointestinal tract being complete within 1 h of injection. Radioscintigraphic imaging studies conducted in a rabbit given the 111In-labeled conjugate also showed early liver uptake followed by rapid clearance from the liver into the intestine, with good visualization of the gallbladder in images obtained at 20-25 min postinjection. It is concluded that conjugation to cholic acid provides a useful means for the hepatobiliary delivery of EDTA chelates that otherwise exhibit predominantly extracellular distribution and renal clearance.
Betebenner
D A
DA
Abbott Laboratories, Department 90M, Abbott Park, Illinois 60064.
Carney
P L
PL
Zimmer
A M
AM
Kazikiewicz
J M
JM
Brücher
E
E
Sherry
A D
AD
Johnson
D K
DK
D000818:Animals; D001659:Biliary Tract / Q000000981:diagnostic imaging / Q000378:metabolism*; D002614:Chelating Agents / Q000378:metabolism*; D002793:Cholic Acids / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D004492:Edetic Acid / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000031:analogs & derivatives; D005260:Female; D007205:Indium Radioisotopes; D007553:Isotope Labeling; D008099:Liver / Q000000981:diagnostic imaging / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D011199:Potentiometry; D011817:Rabbits; D011877:Radionuclide Imaging; D013816:Thermodynamics; D014018:Tissue Distribution
D002614:Chelating Agents; D002793:Cholic Acids; D007205:Indium Radioisotopes; C070256:N-carboxymethyl)-N-(2-(bis(carboxymethyl)amino)ethyl)-3-(4-(N'-(2-((3,7,12-trihydroxycholan-24-oyl)amino)ethyl)(thioureido)phenyl)alanine; D004492:Edetic Acid