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Abstract

Two novel gadolinium-based magnetic resonance (MR) contrast agents for molecular imaging were designed and
synthesized. They have the potential to trace physiological changes of extracellular pH, calcium concentration, and
enzymatic activity.
DO3A-EP; 1,4,7 tris(carboxymethyl)-10-(2-phosphono-ethyl)-1,4,7,10-tetraazacyclododecane (L1) and DO3A-EA-P5P;
1,4,7 tris(carboxymethyl)-10-2-[(3-hydroxy-2-methyl-5-phosphonooxymethyl-pyridin-4-ylmethylene)-amino]-ethyl-
1,4,7,10-tetraazacyclododecane (L2) were synthesized from 1,4,7,10-tetraazacyclododecane (Cyclen) by reaction with
tert-butyl bromoacetate, giving an excellent yield of 80.
L1 was prepared by reaction with diethyl 2-bromoethyl phosphonate. L2 was prepared by the reaction of 1,4,7-tris
(carbobutoxymethyl)-10-(4-aminoethyl)-1,4,7,10-tetraazacyclododecane and pyridoxal 5’ phosphate monohydrate. The
corresponding carboxylate derivative was obtained by cleaving the tert-butyl group by trifluoroacetic acid and anisole at
0ºC. All the derivatives and final chelates were characterized on the basis of 1H, 13C, and 31P NMR and ESI-MSn mass
spectrometry.
For initial MR results, the gadolinium complex of DO3A-EP was prepared in aqueous conditions at pH 6.3. In vitro MR
relaxivity studies were performed at 300 MHz to probe relaxivity changes with different pH. For Gd-DO3A-EP at 21ºC,
r1 increased by 70 from 2.3 to 3.9 s-1mM-1 (pH 7.5 to pH 5.5) and r2 increased by 57 from 2.8 to 4.4 s-1mM-1 (pH
7.5 to pH 5.5).