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| Chemical name: | [N-methyl-11C]4-(4-(4-Chlorophenyl)-4-hydroxypiperidin-1-yl)-2,2-diphenyl-N-dimethyl-butanamide |  |
| Abbreviated name: | [11C]Lop | |
| Synonym: | [11C]Loperamide | |
| Agent category: | Compound | |
| Target: | P-glycoprotein multidrug transporter, MDR-1 | |
| Target category: | Transporter | |
| Method of detection: | PET | |
| Source of signal: | 11C | |
| Activation: | No | |
| Studies: |
| Click on the above structure for additional information in PubChem. |
[PubMed]
One of the mechanisms of tumor cells to escape the cytotoxic effects of chemotherapeutic agents, such as adriamycin, vinca alkaloids, epipodophyllotoxins, actinomycin D, and paclitaxel, is to limit their presence inside the cells by way of a multidrug resistance (MDR-1) gene protein (1, 2). The MDR-1 gene encodes a transmembrane P-glycoprotein (P-gp) as an ATP-dependent multidrug transporter that is capable of actively pumping a variety of agents out of the cells. Injection of unlabeled efflux pump substrates increases the retention of the radioactivity in the tumor by blocking the efflux rather than reducing radioactivity as seen with receptor-binding radiotracer blocking studies. Overexpression of P-gp in tumor cells (such as renal carcinoma, hepatoma, pheochromocytoma, and colon carcinoma) leads to resistance to anticancer drugs (3). P-gp is also present in a variety of normal cells, such as intestinal mucosal cells, hepatocytes, renal proximal tubule epithelial cells, and endothelial cells of the blood–brain barrier (BBB) (4, 5). Calcium channel blockers, cyclosporin, and its non-immunosuppressive analog PSC 833 are MDR modulators that inhibit the transport of P-gp substrates out of the cells (6, 7).
99mTc-sestamibi (MIBI) has been approved by the United States Food and Drug Administration as a myocardial perfusion imaging agent for use with single-photon emission computed tomography to assess the risk of future cardiac events (9). It is also used as a tumor-imaging agent in breast, lung, thyroid, and brain cancers (9-11). But sestamibi (MIBI) is a substrate for P-gp (4, 8). Loperamide (Lop) is an opiate agonist (12) and an avid substrate for P-gp at the BBB (13). Therefore, 11C-labeled Lop ([11C]Lop) is being developed as a positron emission tomography (PET) agent for the non-invasive study of the P-gp function and MDR in tumors and normal tissues (14).
[PubMed]
[11C]Lop was synthesized by reaction of 4-(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)-2,2-diphenyl-N-methyl-butanamide (dLop) with [11C]methyl iodide for 6 min at 80°C (14). The radiochemical purity of purified [11C]Lop was >99% with specific activities of 42.6 ± 23.9 GBq/µmol (1.15 ± 0.65 Ci/µmol) at the end of synthesis. The total synthesis time was 37 min with a radiochemical yield of 11% (decay-corrected).
[PubMed]
In vitro binding studies using cloned receptors with Lop exhibited inhibition constant (Ki) values of 0.31, 47, and 116 nM for µ, δ, and κ opiate receptors, respectively (14). The measured log D7.4 of [11C]Lop was 3.04.
[PubMed]
Biodistribution studies with [11C]Lop with PET imaging in normal and P-gp knockout mice showed 2.7-fold and 1.9-fold higher accumulation of radioactivity in the forebrain and cerebellum, respectively, in the knockout mice than in the wild-type mice (14). Four radiometabolites were detected with high-performance liquid chromatography (HPLC) in the plasma and brains. The most lipophilic radiometabolite was putatively found to be dLop on HPLC. In the knockout mice, the fraction of unchanged [11C]Lop in the plasma and brain as determined with HPLC was 22% and 50%, respectively, at 60 min after injection. In the wild-type mice, the fraction of unchanged [11C]Lop in the plasma and brain was 25% and 13%, respectively, at 60 min after injection. The ex vivo brain concentrations of [11C]Lop and [11C]dLop were ~16-fold greater in the knockout mice than in the wild-type mice, whereas no differences were observed in the plasma of these mice. There was a 4-fold increase in total radioactivity ([11C]Lop plus its radiometabolites) in the forebrain in the knockout mice as compared with the wild-type mice. No studies with known P-gp blockers were reported.
[PubMed]
Zoghbi et al. (14) showed that pretreatment with DCPQ and tariquidar (P-gp blockers) in three rhesus monkeys enhanced brain [11C]Lop PET radioactivity by 3.7-fold and 3-fold, respectively. The increase in brain radioactivity was not caused peripherally because DCPQ and tariquidar insignificantly changed the plasma concentration and plasma protein binding of [11C]Lop as well as metabolism prolife of [11C]Lop. At least six radiometabolites were detected in monkey arterial plasma at 15 min after injection. One of the metabolites was putatively found with HPLC to be dLop (2.6%). Demethylation of [11C]Lop to [11C]dLop precludes quantification of the P-gp function with PET if [11C]dLop is also an avid substrate for P-gp. Also, the number of metabolites in the brain, when only 511 keV gamma rays are being detected also confounds the interpretation.
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