18F-labeled choline analogs

Details 18F-labeled choline analogs 18F-labeled choline analogs

2001-04-30

2003-10-07

Hartley, Michael G. (Department: 1616)

Drug, bio-affecting and body treating compositions

Radionuclide or intended radionuclide containing; adjuvant...

In an organic compound

Reexamination Certificate

active

06630125

ABSTRACT:

TECHNICAL FIELD
The present invention relates to
18
F-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
18
F-labeled choline analogs and to compositions comprising such analogs.
BACKGROUND
Positron emission tomography (PET) is uniquely suited to evaluate metabolic activity in human neoplasms for diagnostic imaging purposes. The glucose analog, [
18
F]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 (T½=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 (T½=110 min) led Hara et al (J. Nucl. Med. 38:44P (1997)) to synthesize and preliminarily evaluate the choline analog, 2-[
18
F]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
18
F-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
18
F-labeled analogs of choline for imaging, including oncologic imaging with PET.
SUMMARY OF THE INVENTION
The present invention relates to
18
F-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
18
F-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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patent: 9-48747 (1997-02-01), None
patent: 2809145 (1998-07-01), None
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Hara et al, “Automated Synthesis of Fluorine-18 Labeled Choline Analogue 2-Fluoroethyl-Dimethyl-2-Oxyethylammonium”, Scientific Papers, Proceedings of the 44thAnnual Meeting, The Journal of Nuclear Medicine No. 156, p. 44P, Tuesday, Jun. 3, 1997.
Friedland et al, “Labeled Choline and Phosphorylcholine: Body Distribution and Brain Autoradiography: Concise Communication”, J. Nucl. Med. 24:812-815 (1983).
Roivainen et al, “Blood metabolism of [methyl-11C]choline; implications for in vivo imaging with positron emission tomography”, Eur. J. Nucl. Med. 27(1):25-32 (2000).
Hara et al, “Sensitive Detection of Mediastinal Lymph Node Metastasis of Lung Cancer with11C-Choline PET”, J. Nucl. Med. 41(9):1507-1513 (2000).
Shinoura et al, “Brain Tumors: Detection with C-11 Choline PET”, Radiology 202(2):497-503 (1997).
Rosen et al, “Carbon-11 Choline: Synthesis, Purification, and Brain Uptake Inhibition by 2-Dimethylaminoethanol”, J. Nucl. Med. 26(12):1424-1428 (1985).
Hara et al, “PET Imaging of Prostate Cancer Using Carbon-11-Choline”, J. Nucl. Med. 39(6):990-995 (1998).
Kobori et al, “Positron Emission Tomography of Esophageal Carcinoma Using11C-Choline and 18f-Fluorodeoxyglucose”, Cancer 86:1638-1648 (1999).
Hara et al, “PET Imaging of Brain Tumor with [methyl-11C]Choline”, J. Nucl. Med. 38(6):842-847 (1997).
Translation of Hara et al, “Fluorine-18-Labeled Fluorine-Containing Choline Derivatives, Methods For Their Preparation, And Their Use As Diagnostic Agents For Positron Emission Computed Tomography”, Japanese Patent Office, Patent Journal (A), Kokai Patent Application No. HEI 9[1997]-48747.

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