First Advisor

Mark Woods

Term of Graduation

Fall 2021

Date of Publication


Document Type


Degree Name

Doctor of Philosophy (Ph.D.) in Chemistry







Physical Description

1 online resource (xxx, 236 pages)


Magnetic resonance imaging (MRI) revolutionized diagnostic imaging and modernized the characterization of numerous diseases. The clinical success of MRI is in large part due to the employment of gadolinium-based contrast agents (GBCAs). Due to sensitivity limitations, GBCAs are indicated at markedly high dosages (~1 g Gd3+ per exam). The routine use of such large quantities of gadolinium poses significant health and environmental risks. There are growing concerns over the effects of dechelation of the metal in vivo and the possible effect of resulting gadolinium deposition. Concurrently, there is a rising awareness of gadolinium anomalies borne by GBCAs which undergo water treatment to be emitted into oceans, surface and potable waters. With increasing reports of gadolinium in the aquatic environment and negative effects on marine life, there are clear potential long-term health and environmental implications if this pollution is not properly addressed. To decrease gadolinium emission into the environment, improving GBCA efficacy to reduce dosage and devising a strategy for selective interception of GBCAs is essential.

To address effectiveness, safety and environmental concerns, a series of new gadolinium chelates has been developed. The α-carbon of the pendant arms of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) was substituted with benzoate groups in a new ligand design, DOTBA. Benzoate-substituted ligands were prepared through new diastereoselective and enantioselective synthetic routes to offer simple solutions toward the advancement of safer and more effective GBCAs. The effectiveness of DOTBA was characterized and found to behave similarly to previous work by our group, demonstrating an agent wherein tumbling, water exchange and hydration state are optimized in concert to achieve an efficacy over two times that of current clinically available GBCAs. The r1 (efficacy) of DOTBA and clinical agents = 11.7 mM-1s-1 and 4 -- 5 mM-1s-1, respectively (20 MHz, 298 K). Of significant note is the exceptional performance of DOTBA at clinical field strengths (1.5 T -- 3 T) where it is at least twice and up to three times as effective as current clinical agents. The high performance of DOTBA at clinical field strengths offers an agent which could decrease the dosage of Gd3+ by more than one-half, significantly reducing the consumption and emission of Gd3+.

To further reduce the amount of Gd3+ pollution, we envisaged collection of the first urine pass post contrast-enhanced examination wherein nearly all of the dose is eliminated. To retrieve the Gd3+ from the urine matrix, a chelate was designed to incorporate a bioorthogonal handle that we envisioned to interact selectively with a reaction partner functionalized on a polystyrene support bead. Proof of principle for selective interception of bioorthogonally functionalized GBCAs was established utilizing strain-promoted azide-alkyne cycloaddition (SPAAC) reaction partners. Near quantitative 98% Gd3+ removal was demonstrated in aqueous systems with an organic cosolvent and 73% removal was achieved in simulated urine. The incorporation of bioorthogonal moieties onto the improved DOTBA ligand framework offers a class of safer, more effective and environmentally responsible GBCAs.


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Available for download on Wednesday, November 23, 2022