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68Ga-1,4,7-Triazacyclononane,1-glutaric acid-4,7-acetic acid-1,2-diaminoethane-γ-folate (P3246).

Authors

Leung K.

Source

Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.
2012 Jun 14 [updated 2012 Sep 20].

Excerpt

Folic acid (folate) is a water-soluble B vitamin (1) that is essential for methylation and DNA synthesis. The primary pathway for entry of folate into cells is through the facilitated transporter, which has a low affinity for folate (Michaelis constant (Km) = 1–5 μM). Some cells in the choroid plexus, kidney, lung, thyroid, spleen, placenta, and thymus also possess a higher-affinity receptor (dissociation constant (Kd) = 0.5 nM) that allows folate uptake via receptor-mediated endocytosis. Some human epithelial tumor cells have been found to overexpress folate receptors (2). More than 90% of human ovarian and endometrial cancers express the high-affinity folate receptor, which is absent in the corresponding normal tissues. Breast, colorectal, renal, and lung carcinomas also overexpress the high-affinity folate receptor but at lower frequencies (20%–50%). Activated macrophages, but not resting macrophages, have also been found to have the high-affinity folate receptor (3). Several folate-based conjugates (111In-DTPA-folate, 99mTc-EC-folate, and [18F]FBA-folate) have been studied in tumor imaging (4-8). Deferoxamine (DF), a chelating agent, was conjugated to folic acid to form a mixture of two isomers, DF-α-folate and DF-γ-folate. Only the DF-γ-folate isomer was able to displace [3H]folic acid from its receptors, with a 50% inhibition concentration similar to that of folic acid (2.5 nM versus 2.4 nM) (9). Fani et al. (10) prepared a γ-folate conjugate with tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA) and 1,2-diaminoethane as a spacer to form P3026, which was labeled with 68Ga for positron emission tomography (PET) imaging of folate receptors in tumors. To further the quest for a 68Ga-folate conjugate for clinical application, folic acid was conjugated to 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA) via 1,2-diaminoethane as a linker between the NODAGA and folic acid (P3246) (11). 68Ga-P3246 was evaluated as a PET agent for imaging folate receptor expression in a mouse tumor model. 67/68Ga-P3246 exhibited a higher tumor/blood ratio than 67/68Ga-P3026 in the same tumor model.

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