Review Article Amplification Strategies in MR Imaging: Activation and Accumulation of Sensing Contrast Agents (SCAs) Manuel Querol, PhD, and Alexei Bogdanov, Jr., PhD * We review new strategies for the development of Gd 3+ - based T1-relaxation agents and paramagnetic chemical ex- change saturation transfer (PARACEST) “sensing” contrast agents (SCAs) designed specifically to detect small mole- cules or enzymatic activity in living systems. The first class of agents exhibits molecular “sensing” properties as a re- sult of water coordination sphere effects, cleavage, or syn- thesis of reactive precursor compounds that recombine with macromolecules with the resultant formation of im- mobilized or rotationally constrained paramagnetic cat- ions. This effect results in changes of water proton relax- ation times. The second class (PARACEST) comprises a family of lanthanide-based paramagnetic compounds suit- able for CEST imaging. The need for both types of MR agents is justified by efforts to utilize magnetic resonance imaging (MRI) to visualize fine structures in living tissue, and to increase the molecular specificity of MRI. Key Words: molecular imaging; sensing contrast agents; gadolinium; paramagnetic; CEST; relaxivity J. Magn. Reson. Imaging 2006;24:971–982. © 2006 Wiley-Liss, Inc. THE SENSITIVITY OF POSITRON EMISSION TOMOG- RAPHY (PET) and other radionuclide-tracer modalities enables molecular imaging of multiple biological tar- gets, including disease-specific molecules present in submicromolar concentrations in the tissue. The trade- off in resolution and the lack of anatomical imaging map usually requires the registration of PET or single photon emission computed tomography (SPECT) im- ages to CT images. Unlike radionuclide-based modali- ties, MRI offers a combination of high anatomical reso- lution and a variety of contrast agents (CAs), including emerging chemical exchange saturation transfer (CEST and paramagnetic CEST (PARACEST) agents) (reviewed in Ref. 1 and below) and hyperpolarized 129 Xe, 13 C, and 15 N nuclei (2), as well as traditional paramagnetic (based primarily on Gd 3+ mediated water proton T1- relaxation effects) and superparamagnetic (primarily based on T2-relaxation effects) agents (reviewed in Refs. 3 and 4). The advantages of “molecular” MRI have yet to be fully explored because of its intrinsically low sensi- tivity to CAs compared to radionuclide-based methods. Here we summarize the various works that have been directed toward increasing the sensitivity of MR CAs and related applications in molecular imaging. WATER PROTON RELAXATION AGENTS The first convincing experimental evidence of tissue- specific contrast enhancement with the use of para- magnetic metal cations ex vivo and in vivo was provided in the early 1980s (5,6). The initial success of the use of gadolinium (Gd) as a CA for in vivo MRI (7) was due to its relatively high longitudinal molar relaxivity (r1), the key parameter that reflects the ability of a given CA to gen- erate imaging signal contrast (8). Relaxivity is defined as the relaxation rate of water protons in a 1-mmol/L solution of CA, according to the following equation: 1/T OBS 1,2 = 1/T D +r[C] (where T OBS 1,2 is the measured relaxation time, T D is the diamagnetic contribution to either T1 or T2, and [CA] is the concentration). The total free water proton relaxation rate increase (R1) is the result of one diamagnetic and two paramagnetic con- tributions (inner and outer coordination spheres). The paramagnetic contribution of the inner coordination sphere is due to the exchange of inner coordination sphere water molecules with the bulk of the water, whereas outer-sphere effects are associated with the diffusion of water molecules in the outer coordination sphere of the paramagnetic center. Most efforts to improve relaxivity have focused on the tuning of various parameters associated with the inner- sphere relaxation value, which is usually treated as a combined effect of rotational correlation time of the CA (  i.e., the tumbling time of the CA in the water bulk, water proton residence time (  ), which reflects the ex- change rate of a single inner-coordinated water mole- cule at the paramagnetic center with the bulk water Department of Radiology, University of Massachusetts Medical School, Worcester, Massachusetts, USA. Contract grant sponsor: NIH; Grant numbers: P50-CA86355; R01 EB000858. *Address reprint requests to: A.B., S2-804, Department of Radiology, University of Massachusetts Medical School, 55 Lake Ave. North, Worcester, MA 01655. E-mail: Alexei.Bogdanov@umassmed.edu Received December 21, 2005; Accepted July 17, 2006. DOI 10.1002/jmri.20724 Published online 5 October 2006 in Wiley InterScience (www. interscience.wiley.com). JOURNAL OF MAGNETIC RESONANCE IMAGING 24:971–982 (2006) © 2006 Wiley-Liss, Inc. 971