The present invention relates to 18F-labeled choline analogs and to methods of using same as imaging agents (for example, as positron emission tomography (PET) imaging agents) for the noninvasive detection and localization of neoplasms and pathophysiologies influencing choline processing in the body. The invention further relates to methods of synthesizing 18F-labeled choline analogs and to compositions comprising such analogs.
Positron emission tomography (PET) is uniquely suited to evaluate metabolic activity in human neoplasms for diagnostic imaging purposes. The glucose analog, [18F]fluoro-2-deoxy-glucose (FDG), has proven successful as a PET imaging agent for detection and localization of many forms of cancer. The elevated rate of glycolysis in many types of tumor cells enhances the uptake of FDG in neoplasms relative to normal tissues (Weber et al, Strahlenther Onkol. 175:356-373 (1999), Delbeke, J. Nucl. Med. 40:591-603 (1999), Hoh et al, J. Urology 159:347-356 (1998)). However, FDG-PET has been found to have less sensitivity and/or specificity for assessment of some types of cancer, motivating efforts to develop new oncologic tracers for PET. Carbon-11 (Txc2xd=20 min) labeled choline (CH, trimethyl-2-hydroxyethylammonium) has shown potential utility in two applications: brain tumors (Hara et al, J. Nucl. Med. 38(6):842-847 (1997), Shinoura et al, Radiology 202(2):497-503 (1997)), where FDG has suboptimal specificity due to uptake by normal brain and some post-therapy responses (Marriott et al, J. Nucl. Med. 39(8):1376-1390)1998)), and prostate carcinoma (Hara et al, J. Nucl. Med. 39(6):990-995 (1998)), where FDG shows inadequate sensitivity (Hoh et al, J. Urology 159:347-356 (1998), Shreve et al, Radiology 199:751-756 (1996)). CH was initially synthesized and evaluated as a physiologic probe for choline uptake by normal tissues (Friedland et al, J. Nucl. Med. 24(9):812-815 (1983), Rosen et al, J. Nucl. Med. 26(12):1424-1428 (1985)). The practical advantages of working with the longer lived radioisotope fluorine-18 (Txc2xd=110 min) led Hara et al (J. Nucl. Med. 38:44P (1997)) to synthesize and preliminarily evaluate the choline analog, 2-[18F]fluoroethyl-dimethyl-2-hydroxyethyl-ammonium (designated herein HARA-1). This analog showed similar biodistribution of this tracer to CH in normal human subjects with the exception of more prominent urinary excretion of radioactivity. The more rapid accumulation of radioactivity in the urinary bladder with this 18F-labeled analog rendered it less preferable than CH for imaging of primary prostate carcinoma and metastatic prostate carcinoma in the pelvic lymph nodes (Hara et al, J. Nucl. Med. 38:44P (1997)).
The present invention provides 18F-labeled analogs of choline for imaging, including oncologic imaging with PET.
The present invention relates to 18F-labeled choline analogs and to methods of using same, for example, as PET imaging agents for the noninvasive detection and localization of neoplasms and pathophysiologies influencing choline processing in the body. The invention further relates to methods of synthesizing 18F-labeled choline analogs and to compositions comprising such analogs.
Objects and advantages of the present invention will be clear from the description that follows.
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USPTO Backgrounds