cypate-d: -(+)-glucosamine (cyp-GlcN), and d: -(+)-glucosamine-cypate-d: -(+)-glucosamine (cyp-2GlcN)

Increased nutritional requirements are a characteristic feature of neoplastic tumor cells, and because these lesions do not rely on mitochondrial oxidation for energy, most of the energy in these cells is generated through glycolysis (1). To keep up with the high nutritional and energy needs of a malignant tumor, the transformed cells in the lesion show a 20- to 30-fold higher rate of glucose uptake and glycolysis compared with normal cells. As a consequence, to meet the increased demand for glucose, the facultative glucose transport proteins (GLUTs; there are 14 known isoforms of these proteins, designated GLUT1 through GLUT14) that facilitate glucose uptake are upregulated on the plasma membranes of the tumor cells (2). In general, GLUT1 and GLUT3 are able to transport glucosamine (GlcN) in addition to glucose and are overexpressed in the different cancer types, including prostate cancer. In addition, an elevated expression of these transporters correlates with the malignant potential of the lesions and indicates a poor prognosis for the patient (2). Among the different glucose transporters, GLUT2 and GLUT4 can also transport GlcN, and both of these isoforms are transcriptionally repressed by the p53 protein, a tumor suppressor protein that regulates the cell cycle and promotes apoptosis (3). GLUT1 and GLUT4 exhibit a similar affinity for glucose and GlcN, but GLUT2 has an approximate 20-fold higher affinity for GlcN than for glucose (3). The PC3 human prostate cancer cell line does not express the p53 protein, and an increased expression of GLUT1 has been observed in these cells (3). Therefore, an imaging probe derived from GlcN would probably accumulate rapidly in tumors generated from the PC3 cells (3). Currently, 2-deoxy-2-[F]fluoro-d-glucose ([F]-FDG), a glucose analog, is commonly used with positron emission tomography (PET) to detect, stage, and monitor cancers after therapy [PubMed]. A major limitation of using [F]-FDG to detect and monitor cancers is that this probe often generates false positive results (4). The main disadvantages of imaging with PET are that this technique involves the use of radionuclides that have a very short half-life and that the radiolabeled compounds used for this procedure have very high specific activities, which may expose the patient to an abnormal dose of radiation. As an alternative, there is much interest to develop probes that contain cyanine fluorophores, such as the cypate dye (cyp), because these fluorophores are visible in the near-infrared (NIR) wavelength of light and can be used for the noninvasive optical imaging of targeted tissues. The advantages of using cyp are that the compound has very low autofluorescence, absorption, and scattering within the excitation and emission ranges of the wavelength and that photons emitted from the dye can travel several centimeters through the tissue (3). Korotcov et al. investigated the and applications of cypate conjugated either to a single molecule of GlcN (cypate-d-(+)-GlcN; cyp-GlcN) or to two molecules of GlcN (d-(+)-glucosamine-cypate-d-(+)-glucosamine; cyp-2GlcN) to visualize luciferase-expressing PC3 cell (PC3-luc) xexograft tumors in mice (3). The biodistribution of cyp-GlcN and cyp-2GlcN was also studied in these animals.