Evaluation of the Stability and Animal Biodistribution of Gadolinium(III) Benzylamine-Derivatized Diethylenetriaminepentaacetic Acid

• Published in: Journal of medicinal chemistry 1996-08, Vol.39 (16), p.3096-3106
• Main Authors: Deal, Kim A, Motekaitis, Ramunas J, Martell, Arthur E, Welch, Michael J
• Format: Article
• Language: English
• Subjects: Animals; Binding, Competitive; Biological and medical sciences; Bone and Bones - metabolism; Chelating Agents - chemical synthesis; Chelating Agents - chemistry; Chelating Agents - pharmacokinetics; Chromatography, Thin Layer; Cross-Linking Reagents - metabolism; Drug Stability; Feces - chemistry; Female; Gadolinium; Galactose; General pharmacology; Glycine - analogs & derivatives; Glycine - chemical synthesis; Glycine - chemistry; Glycine - pharmacokinetics; Hydrogen-Ion Concentration; Indium; Mannose; Medical sciences; Molecular Structure; Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions; Pharmacology. Drug treatments; Phenylalanine - analogs & derivatives; Phenylalanine - chemical synthesis; Phenylalanine - chemistry; Phenylalanine - pharmacokinetics; Rats; Rats, Sprague-Dawley; Serum Albumin, Bovine - pharmacokinetics; Tissue Distribution
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm9602118

The need for a readily available Gd(III) bifunctional chelate for protein conjugation has led to the development of LDTPA (N,N-bis[2-[N‘,N‘-bis(carboxymethyl)amino]ethyl]-4-amino-l-phenylalanine). The benzylamine group is readily converted to the isothiocyanato group (SCN-LDTPA) by treatment of the lithium salt of LDTPA with thiophosgene. SCN-LDTPA was successfully conjugated to three proteins, BSA (bovine serum albumin), mannose BSA, and galactose BSA. All protein conjugates were labeled with 111In3+ or 153Gd3+. Competition of Gd-LDTPA with DTPA (diethylenetriaminepentaacetic acid) resulted in a log stability constant of 21.2. The thermodynamic stability constant of Gd-LDTPA was also measured. The log Gd(III) stability constant (log K) is 21.99, and the log protonation constants (pK a's) are 10.16, 8.92, 5.35, 3.93, 2.71, and 1.89. Comparison of the thermodynamic stability constants for Gd(LDTPA)2- with other DTPA derivatives indicates that the stability of Gd(LDTPA)2- is similar to Gd(DTPA)2- (log K = 22.4), and higher than DTPA derivatives with one or more carboxylate arm(s) functionalized. The biodistribution of 153Gd-LDTPA−protein conjugates is consistent with the in vitro stability measurements. By monitoring the bone accumulation of 153Gd3+, 153Gd-LDTPA−protein shows a higher in vivo stability than 153Gd-DTPA−protein, the radiolabeled protein conjugate formed by the reaction of DTPA dianhydride with proteins.