2-[(4-{[(2-amino-4-oxohydropteridin-7yl)methyl]amino}phenyl) carbonylamino]-4-{ N-[(2-[18F]-fluoro(4-pyridyl))carbonylamino] carbamoyl}butanoic acid

Excerpt

Folic acid (FA; also known as folate or vitamin B₉) is a water-soluble vitamin that is required for the synthesis and repair of DNA in the cell. FA also acts as a cofactor for many biological reactions and has an important role in cell maintenance and proliferation. Although the folate receptor (FR) is expressed at low levels in normal cells, this receptor is known to be upregulated in cancers such as those of the ovary, lung, breast, brain, colon, and the hematopoietic lineage cells (1). Therefore, the FR system has been targeted with radiolabeled folate and its derivatives, such as ⁶⁷Ga-deferoxamine (DF)-folate, ¹¹¹In-diethylenetriamine pentaacetic acid-folate, ^99mTc-mercaptoacetyldiglycine-folate-methotrexate, etc., for the noninvasive detection of malignancies with single-photon emission computed tomography (2). Mathias et al. showed that ^66/67Ga-DF-folate can be used with positron emission tomography (PET) for the imaging of FR-positive cancerous tumors in mice (3). However, although these tracers could detect the FR-rich tumors, they were deemed unsuitable for imaging lesions in the abdominal regions because high levels of radioactivity were observed to accumulate in the liver and the intestines of the animals (4). In addition, ^66/67Ga-labeled tracers are known to produce low-resolution images due to their high positron energy (4.15 MeV and 1.89 MeV for ⁶⁶Ga and ⁶⁷Ga, respectively. ⁶⁷Ga-labeled agents are used for single photon emission computed tomography imaging) compared to ¹⁸F (0.64 MeV), which generates superior images and is often used to radiolabel PET imaging agents in the clinic (4). In another study, it was shown that ¹⁸F-fluorobenzylamine derivatives of folate can detect tumors that had a high expression of FR, but the radioactivity from these labeled compounds accumulated mainly at the rim of the tumor, and large amounts of the label were retained in the liver and intestines of the animals (4, 5).

In an ongoing effort to generate radiolabeled agents for the imaging of tumors that express high levels of FRs that would be superior to those developed and evaluated earlier, a ¹⁸F-fluorobenzene derivative of folic acid ([¹⁸F]-folate-1), a pyridinecarbohydrazide-folate derivative of folic acid ([¹⁸F]-folate-2), a ¹⁸F-fluorobenzene/methotrexate (MTX) conjugate of folic acid ([¹⁸F]-folate-MTX-8), and a ¹⁸F-pyridinecarbohydrazide-folate/methotrexate conjugate of folic acid ([¹⁸F]-folate-MTX-9) have been synthesized (2). The biodistribution of these tracers was investigated in healthy mice. On the basis of results obtained from these studies, [¹⁸F]-folate-2 was evaluated for the PET imaging of human KB cell line xenograft tumors (have a high expression of FR) in mice. This chapter describes the results obtained with [¹⁸F]-folate-2. Separate chapters in MICAD (http://www.micad.nih.gov/) discuss the studies performed with [¹⁸F]-folate-1 (6), [¹⁸F]-folate-MTX-8 (7), and [¹⁸F]-folate-MTX-9 (8).