99mTc-Labeled tetraethylenepentamine-folate

Excerpt

Folic acid (FA; folate) belongs to the B group of vitamins, and its activity is mediated through the membrane-bound folate receptor (FR; also known as the folate-binding protein), which has two isoforms (α and β). A third constitutively secreted form of the receptor (γ) has also been identified in some hematopoietic cells (1). The α and β isoforms of FR show a high affinity for FA and have a restricted expression in certain tissues. FR-α is found in the lungs, glandular tissue, and choroid plexus of the brain. A functional β form is present only in activated monocytes and macrophages, although it is also borne by mature neutrophils and CD34⁺ cells (as an inactive form) (1). Low amounts of FR-α are expressed in normal tissue, but it has been shown to be overexpressed in several cancerous tumors such as those of the breast, colon, head and neck, kidneys, and lungs (2). In addition, overexpression of the FR in tumors indicates a poor prognosis for the patient (3, 4). Therefore, the FR has been targeted in clinical trials for the detection, diagnosis, and treatment of cancers. Several folate-based imaging agents that use techniques such as magnetic resonance imaging, optical imaging, computed tomography, positron emission tomography, and single-photon emission tomography (SPECT) have been developed and evaluated for the noninvasive detection of malignant tumors that overexpress the FR (2). However, except for SPECT-based agents, all imaging agents had limitations and were determined to be unsuitable for the detection of tumors overexpressing the FR as detailed by Sega et al. (2).

An indium (¹¹¹In)-labeled folate-based SPECT agent with a good tumor specificity was developed earlier and evaluated in clinical trials, but the nuclide is expensive to produce, has a high γ energy emission (171 and 245 keV) and a long half-life (~68 h) (2), and the detection of recurrent cancer with this agent is difficult (5). To overcome the problems associated with the use of ¹¹¹In, some investigators developed and evaluated the use of technetium (^99mTc)-labeled FR imaging agents because this nuclide has a low energy emission (140 keV), has a short half-life (~6 h), is inexpensive to produce and, compared with ¹¹¹In, produces high-quality images (6-10). Among the ^99mTc-labeled FR imaging agents, only the peptide-based agent ^99mTc-EC20 has been evaluated preclinically (10) and more recently in the clinics (11). In an effort to develop an alternate FR imaging agent, Panwar et al. synthesized and evaluated ^99mTc-tetraethylenepentamine-folate (^99mTc-TEPA-folate) for scintigraphy in nude mice bearing FR-overexpressing tumors (12). The biodistribution of this radiolabeled compound was also studied in these animals.