DTPA-bisamide-Based MR Sensor Agents for Peroxidase Imaging Manuel Querol, John W. Chen, Ralph Weissleder, and Alexei Bogdanov, Jr.* Center for Molecular Imaging Research, Massachusetts General Hospital and HarVard Medical School, Building 149, 13th Street, Charlestown, Massachusetts 02129 abogdanoV@helix.mgh.harVard.edu Received February 1, 2005 ABSTRACT The synthesis and some properties of two novel DTPA-bisamides are reported. These derivatives were designed as enzyme-activated contrast agents (CA) for magnetic resonance imaging. Both derivatives bear tyramido or 5-hydroxytryptamido groups that could be oligomerized in situ in the presence of peroxidase/H 2 O 2 pair resulting in a net increase in longitudinal (R1) relaxivity. Over the last two decades, magnetic resonance imaging (MRI) has become the leading tool for imaging fine details of anatomy as well as physiology (functional imaging). Due to high tissue contrast and excellent spatial resolution, Magnetic Resonance Imaging (MRI) is being used in many applications where optical methods fail to provide informa- tion due to light scattering and absorption by the tissue (usually, beyond the depth of 250 μm). 1 In both clinical and research settings, MRI techniques benefit from the wide use of biocompatible Contrast Agents (CAs), which further enhance the image contrast. Currently, about 35% of all clinical MRI protocols include the use of several approved CAs. The main application of CAs relies on the shortening of proton relaxation times (T 1 and T 2 ) of water molecules. The resultant subtle local MR signal changes can be easily detected giving rise to better signal-to-noise ratios and providing exact spatial locations if mapped versus nonin- fluenced water molecules in target tissue volume. 2 To be applicable for imaging in vivo, CAs have to exhibit high atomic relaxivities (r lp ) defined as the shortening of water proton relaxation rates in the presence of the CA normalized per concentration of the paramagnetic element. High relax- ivites are essential to keep the dose of CA low while achieving high levels of contrast. In addition, pharmacoki- netic properties of CAs have to be fine-tuned in order to achieve adequate in vivo retention and clearance times. In general, CAs, once administered, show the tendency to rapidly equilibrate between intravascular and interstitial compartments. 3 Fine-tuning of these properties should result in lower doses of paramagnetic metal and potential decrease in toxicity. Relaxivity increase and minimization of vascular permeability by using various macromolecular CAs have been goals of a large number of studies. In a broad sense, this research could be divided into two main categories. First, the increase in size has been achieved by covalent binding of CA to preformed macromolecules such as proteins, polypeptides, 4 dendrimers, 5 and graft-copolymers. 6 Second, tailored noncovalent association of CA with proteins, mainly (1) Keller, E. H. Handbook of Biological Confocal Microscopy, 2nd ed.; Pawley, J. B., Ed.; Plenum: New York, 1995; p 111. (2) Caravan, P.; Ellison, J. J.; McMurry, T. J.; Lauffer, R. B. Chem. ReV. 1999, 99, 2293-352. (3) Koenig, S. H.; Kellar, K. E. Acad. Radiol. 1998, 5 (Suppl 1), S200- S205; discussion S226-S227. (4) Merbach, A. E.; Toth, E. The Chemistry of Contrast Agents in Medical Magnetic Resonance Imaging; John Wiley & Sons: Chichester, 2001; Chapter 5. (5) Stiriba, S.-E.; Frey, H.; Haag R. Angew. Chem., Int. Ed. 2002, 41 (8), 1329-1334. (6) Weissleder, R.; Bogdanov, A., Jr.; Tung C.-H.; Weinmann H.-J. Bioconjugate Chem. 2001, 12, 213-219. ORGANIC LETTERS 2005 Vol. 7, No. 9 1719-1722 10.1021/ol050208v CCC: $30.25 © 2005 American Chemical Society Published on Web 03/25/2005