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The objective of this study was to evaluate the potential of a high-relaxivity macromolecular gadolinium (Gd) chelate to target folate receptors (FRs). P866 is a dimeric high-relaxivity Gd chelate coupled to a folate moiety. Binding affinity, in vivo biodistribution studies in KB tumor-bearing mice at 1, 4, and 24 h, and dynamic contrast-enhanced (DCE) Key words: high-relaxivity gadolinium chelates; folate; MRI; tumor; molecular imaging; folate receptor Folic acid plays a major role in cell division for DNA synthesis. Cells are not able to synthesize folic acid, and thus folate transport systems through the cell membrane are necessary for cell survival to internalize external folic acid (1).-Folate transporters (reduced folate carriers [RFCs]) typically have a low affinity toward folate (in micromolar [ M] range). They have been identified by their sensitivity and ability to internalize dihydrofolate reductase inhibitors (antifolate cancer chemotherapeutics). While folate transport into the cytoplasm is ultimately mediated by a transporterbased mechanism, membrane folate receptors (FRs) that bind folate at nanomolar affinities will certainly increase membrane proximal concentrations of folates in the vicinity of the transporters. This is likely to substantially enhance the efficiency of delivery of folates into cells (2). The human membrane FR has three isoforms. The ␣-and ␤-isoforms belong to a special class of membrane proteins, namely GPI-anchored proteins, whereas the ␥-isoform is a soluble protein (3).The development of new and improved tumor-selective contrast agents is clinically desirable for detecting and/or confirming the presence and location of primary and metastatic lesions, probing biochemical features of neoplastic tissue that have implications for tumor staging, and/or treatment planning and monitoring tumor response to treatment (4).Because of its overexpression in many types of human tumors and its relative absence in most normal tissues, the FR (mainly the ␣-isoform) constitutes a promising target for tumor-specific contrast agents (5), and folate imaging agents have been investigated for nuclear medicine in human clinical trials (6,7). Compounds combining folic acid with either monomeric or polymeric gadolinium (Gd) chelates (8 -13) or nanoparticles, such as iron oxide nanoparticles (14,15), and microemulsions of Gd-chelates (16 -18) have already been studied. While the proof of principle has been demonstrated, the efficacy of such an approach in clinical practice has yet to be confirmed since it depends of the in vivo avidity of the compound to its receptor, its accessibility to the tumor, and the sensitivity of the contrast moiety.The potential of FR-targeted imaging depends on the rate of the folate-Gd compound binding to the cancer cell surface, the dose of folate-Gd chelate that will saturate the tumor cell surface FR in vivo, the rate of FR internalization, unloading and recycling back to the tumor cell surface for another round of product uptake, and the residence time of the folate co...

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