Date of Award

Fall 2010

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Chemistry

First Advisor

Hank F. Kung

Second Advisor

Datta E. Ponde

Abstract

Malignant tumors can be detected with high sensitivity and specificity by imaging their increased metabolic rate for glucose, amino acids and fatty acids. Positron emission tomography (PET) with glucose analog [18F]FDG, which utilizes increased glucose metabolism, has become a routine clinical test for diagnosis, staging and restaging a variety of cancers. Despite the tremendous success of PET-FDG, there are some well-known limitations of [18F]FDG such as high cerebral uptake, uptake in inflammatory tissues, high excretion through urinary tract and low or negligent uptake in certain type of tumors. Decades of nuclear medicine research have lead to development of other PET imaging agents to overcome such limitations.

We examined two series of tracers targeting two different altered metabolic processes in the tumor cells in order to improve on imaging properties of existing clinically utilized PET ligands. One series is 18F labeled tyrosine and phenylalanine derivatives, which targets altered amino acid metabolism – increased amino acids uptake and protein synthesis rate in cancer cells. We synthesized three new 18F labeled fluoroalkyl tyrosine derivatives, in vitro studies in human glioblastoma cells of these tyrosine derivatives indicated they were not very promising tumor-imaging agents since in comparison to clinically utilized imaging agent O-(2-[18F]fluoroethyl)-L-tyrosine (FET), their uptake was much lower. We also synthesized and evaluated L- and D-isomers of new phenylalanine derivatives, p-(2-[18F]fluoroethyl)-phenylalanine (FEP) and p-(3-[18F]fluoropropyl)-phenylalanine (FPP) in comparison to clinically utilized FET and its D-isomer. In vitro studies in 9L glioma cells as well as biodistribution and small animal PET imaging studies demonstrated that L- isomer of FEP is comparable to FET and it is a potential useful tracer for tumor imaging with PET. Comparison of L- and D-isomers of phenylalanine derivatives showed that D-isomers did not have improved imaging properties than their corresponding L-isomers. Of all new aromatic amino acid derivatives, L- isomer of FEP had the best outcome and is comparable to clinically established FET in imaging rats bearing 9L tumor model.

The other series of tracers is 11C labeled ethanolamine amine derivatives, which targets the altered lipid metabolism associated with increased cellular proliferation in tumors. Here, we developed 11C labeled ethanolamine and two ethanolamine derivatives — N-methyl ethanolamine and N,N-dimethyl ethanolamine. In vitro studies demonstrated that they could be more sensitive PET tracers than clinically utilized [11C]choline for the imaging of phospholipids biosynthesis in tumors.

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