L- and D--(3-[F]fluoropropyl)homocysteine

High energy consumption and constant proliferation are the hallmarks of all cells with a malignant phenotype. To maintain a high pace of protein and DNA synthesis, such cells have an increased demand for various nutrients, glucose, and amino acids (aa). Therefore, radiotracers such as F-labeled fluorodeoxyglucose, which is taken up by the cell through the glucose transporter, are often used with positron emission tomography (PET) to detect cancerous tumors. This agent, however, is not able to distinguish between malignant tissue, inflammation, and tissues that normally have high glucose consumption, such as the brain (1). As an alternative, radiolabeled aa and their derivatives, such as those of phenylalanine and tyrosine, have been used to detect neoplastic tumors because these lesions show increased utilization of aa for the synthesis of proteins and other cellular components (2, 3). To accommodate the increased demand for aa, the malignant cells overexpress the aa transporters (phenylalanine and tyrosine use the l-type transporter), and this phenomenon promotes the rapid uptake and accumulation of the radiolabeled aa in the tumors. Therefore, noninvasive imaging with a radiolabeled aa can be used to detect cancerous lesions within a short time after administration of an aa tracer. Among the various radiolabeled aa tracers, [F]-α-methyl-tyrosine is often used in the clinic, but the low yield of the final labeled product prohibits the use of this labeled compound in most oncology centers (1). -(2-[C]methyl)-l-methionine ([C]MET; half-life of C = ~20 min) is another aa derivative that is widely used for the PET imaging of tumors, but because MET contributes to a diverse array of biosynthetic reactions such as DNA synthesis, protein synthesis, etc., the radiolabeled macromolecules derived from [C]MET along with the biodegradation products of the labeled molecules generate a high background signal in the tissues (4). As a consequence, the imaging of tumors with [C]MET has limited utility in the clinic and this tracer has been used primarily for the noninvasive visualization of gliomas in the brain, and very little information is available to indicate that labeled MET is suitable for the detection of tumors in other parts of the body (3, 4). Investigators developed -(2-[F]fluoroethyl)-L-homocysteine, an analog of MET, as a possible agent for the imaging of cancerous tumors, but this agent was unstable in aqueous media and could be used for the detection of these lesions (5). In a continued effort to develop an aa derivative that can be used for the imaging of non-glioma tumors, the d and l enantiomers of -(3-[F]fluoropropyl)homocysteine ([F]-d-FPHCys and [F]-l-FPHCys) were synthesized, and the biodistribution and tumor imaging properties of these compounds in nude mice bearing xenograft tumors derived from different non-glioma human cancer cell lines was investigated (4, 6).