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Molecular Imaging and Contrast Agent Database (MICAD) [Internet].

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11C-Labeled rhodamine-123

[11C]Rhodamine-123
, PhD
National Center for Biotechnology Information, NLM, Bethesda, MD 20894

Created: ; Last Update: December 27, 2012.

Chemical name:11C-Labeled rhodamine-123image 126685671 in the ncbi pubchem database
Abbreviated name:[11C]Rhodamine-123
Synonym:
Agent Category:Compound
Target:P-glycoprotein transporter (P-gp)
Target Category:Transporter
Method of detection:Positron emission tomography (PET)
Source of signal / contrast:11C
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
Click on the above structure of Rhodamine-123 for more information in PubChem.

Background

[PubMed]

The P-glycoprotein (P-gp; also known as MDR1 or ABCB1) is a member of the ATP-binding cassette transporter family of proteins (the multi-drug resistance (MDR) protein and the breast cancer resistance protein (BCRP) are the other two members of this group of proteins) that is responsible for the rapid transportation of drugs across the cell membrane (uptake and efflux) (1). The structure, functions, and activities of P-gp have been discussed in detail by Giacomini et al. (2) and Sharom (3). Overexpression of these transporters, particularly P-gp, affects the distribution of drugs in various parts of the body, including the central nervous system (CNS), and is responsible for the development of drug resistance in cancer cells (4). In addition, reduced function and expression of P-gp have been suggested to cause slow or reduced clearance of neurotoxic peptides such as the amyloid-β peptide from the neuronal cells, and this has been hypothesized to contribute to the development of Alzheimer’s disease, Parkinson’s disease, or other such neurological conditions (5). There is much interest in studying the role of P-gp at the blood–brain barrier (BBB) with positron emission tomography (PET), using P-gp substrates such as [11C]verapamil and [11C]desmethyl-loperamide (6). These tracers can measure the decrease in transport function of the P-gp because this decrease results in the accumulation of the label in the brain; however, the uptake of these radiolabeled compounds in normal brain cells as such is very low, and an increase in P-gp function cannot be determined in the tissue with these labeled compounds. Therefore, it was hypothesized that radiolabeled substrates that have a low to moderate affinity for P-gp will probably accumulate in the brain and likely can be used to determine the expression level of this transporter in the tissue or organ (6).

Rhodamine-123 is a fluorescent dye that is used to measure the expression of P-gp in drug-resistant cells, and the National Cancer Institute of the United States uses it to screen for drugs that serve as substrates for MDR1 (6). This fluorescent dye has also been used to investigate the P-gp function in the blood–brain barrier of wild-type (WT) and knockout (KO) mice (mdr 1 a(-/-); these animals lack the P-gp transporter), and the KO rodents were shown to accumulate up to a 4-fold higher amount of rhodamine-123 in the brain compared with the WT animals (6). Similar results were obtained with the WT rodents when they were intravenously infused with rhodamine-123 in the presence of cyclosporine A, an inhibitor of P-gp (6). From these studies, it was concluded that rhodamine-123 was an in vivo substrate for P-gp in mice. The biodistribution of 131I-labeled rhodamine-123 has been studied in mice (7). On the basis of information reported in the studies mentioned above, rhodamine-123 was labeled with 11C ([11C]rhodamine-123; half-life of 11C is 20.4 min) and used to study the efflux transporters in WT and various efflux transporter KO mice (organic cation transporter (OCT) 1 and 2 (OCT1/2) KO mice, BCRP KO mice, and MDR-associated protein 1 (MRP1) KO mice; MRP1 is responsible for the cellular efflux of various anti-cancer drugs and contributes to the development of drug resistance) (6). In addition, the biodistribution of [11C]rhodamine-123 was investigated with PET in rats and mice (6).

Synthesis

[PubMed]

The synthesis of [11C]rhodamine-123 has been described by Bao et al. (6). The total time required for the synthesis of [11C]rhodamine-123 was 35 min. The radiochemical yield, radiochemical purity, and specific activity of the labeled compound (determined at the end of synthesis) were 4.4 ± 1.7%, >95% (as determined with reverse-phase high-performance liquid chromatography (HPLC)), and 13.4 ± 4.4 GBq/μmol (495.8 ± 62.9 mCi/μmol), respectively.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

[11C]Rhodamine-123 was reported to have a stability of 99.0 ± 0.9% for at least 1 h in sterile 0.9% sodium chloride at room temperature and for at least 2.5 h in 0.15 M sodium phosphate buffer (pH 7.4) at the same temperature (6). The labeled compound was reported to be stable in rat plasma, whole blood, and forebrain homogenates for at least 2.5 h at 37°C as determined with radio-HPLC (6).

The lipophilicity (LogD7.4) of [11C]rhodamine-123 was reported to be 0.85 ± 0.01 (n = 6 determinations) as determined with an n-octanol/0.15 M sodium phosphate buffer (pH 7.4) mixture (6).

The plasma-free fractions of [11C]rhodamine-123 in mouse and rat blood were determined to be 0.156 ± 0.007 (n = 3 determinations) and 0.09 ± 0.004 (n = 3 determinations), respectively (6).

Animal Studies

Rodents

[PubMed]

The biodistribution of [11C]rhodamine-123 was investigated with PET in WT mice and WT rats, efflux transporter KO mice, WT rats pretreated with (2R)-anti-5-{3-[4-(10,11-dichloromethanodibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}quinolone trihydrochloride (DCPQ; an inhibitor of P-gp; administered intravenously (i.v.) at the rate of 32 mg/kg body weight (BW)) or with cimetidine (an inhibitor of OCT; 30 mg/kg BW i.v.), and in P-gp KO mice pretreated with cimetidine (6). The rats were given 28.9 ± 5.9 MBq (1.07 ± 0.218 mCi) [11C]rhodamine-123 through a penile vein catheter, and the mice were injected with 18.1 ± 7.4 MBq (0.67 ± 0.27 mCi) [11C]rhodamine-123 through a tail vein catheter as described elsewhere (6). For some studies, the animals were treated with either DCPQ or cimetidine (i.v. administration) at least 30 min before administration of the tracer.

Time-activity curves generated from PET images of rats showed that the uptake of radioactivity in the brain of these animals (n = 3 rats) peaked within 1 min (<0.27 standardized uptake value (SUV)) after the administration of [11C]rhodamine-123 (6). A similar trend in tracer accumulation was observed with the mice (n = 3 animals). Rats pretreated with DCPQ (n = 3 animals) showed an ~2-fold increase in the SUV of the brain compared with the untreated animals, suggesting that the P-gp activity in the BBB of the WT rodents did not allow the accumulation of [11C]rhodamine-123 in the brain of the WT rats. At the initial time points, the uptake of radioactivity in the hearts of the DCPQ-pretreated rodents was ~5-fold higher than in the brain of the WT animals. Although the label was rapidly lost from the heart, accumulation was observed to remain ~3-fold higher in this organ than in the brain for up to 90 min postinjection (p.i.). The peak SUVs for the liver and kidney of the untreated rats were ~4 and ~8 at 20 min p.i., respectively, and in the DCPQ-treated animals these values increased to ~5 and ~12, respectively. The patterns of radioactivity uptake in the liver and kidney of the WT mice were similar to those of the organs in the WT rats, as described above.

The biodistribution of [11C]rhodamine-123 was studied in WT mice (n = 3 animals) and the various efflux transporter KO mice (P-gp KO, OCT1/2 KO, BCRP KO, and MRP1 KO; n = 3–4 rodents/transporter group) as described elsewhere (6). Data obtained from this study were presented as SUV of unchanged [11C]rhodamine-123 concentration (Table 1). The amount of unchanged [11C]rhodamine-123 present in the plasma and forebrain of the WT and KO mice was relatively low compared with the accumulation in the heart and kidney of the animals. Only the P-gp KO mice showed an increased concentration of the tracer in the forebrain compared with the organs of the WT animals or the other transporter KO rodents. In addition, the tissue/plasma [11C]rhodamine-123 concentration ratios (Table 1) for the forebrain, heart, and kidney were relatively higher in the P-gp KO group than in animals from the other groups. These results indicated that the P-gp transporter plays an important role in the uptake and efflux of [11C]rhodamine-123 in the various organs of these rodents.

Table 1: Standardized uptake values (SUV) of unchanged [11C]rhodamine-123 in various tissues of WT and efflux transporter KO mice at 30 min p.i (6).

TissuesSUV of unchanged [11C]rhodamine-123 concentrations
Wild-typeP-gp KOOCT1/2 KOBCRP KOMRP1 KO
Plasma0.031 ± 0.0320.008 ± 0.0040.026 ± 0.0030.022 ± 0.0080.014 ± 0.007
Forebrain0.071 ± 0.025
(3.0)*
0.168 ± 0.006
(12.0)*
0.029 ± 0.011
(0.5)*
0.031 ± 0.015
(2.0)*
0.042 ± 0.006
(4.0)*
Heart3.40 ± 0.69
(100.0)*
2.96 ± 0.29
(120.0)*
3.51 ± 0.41
(100.0)*
3.13 ± 1.66
(100.0)*
2.51 ± 0.013
(110.0)*
Kidney10.7 ± 2.23
(600.0)*
12.8 ± 4.9
(>1,000.0)*
12.7 ± 0.12
(700.0)*
11.7 ± 3.87
(750.0)*
12.1 ± 2.35
(>1,100.0)*

*Approximate tissue/plasma ratios of unchanged [11C]rhodamine-123 (6).

From these studies, the investigators concluded that P-gp and other such transporters play a very important role in the biodistribution of [11C]rhodamine-123 in the brain and peripheral organs of the rodents (6). Therefore, [11C]rhodamine-123 is not an ideal tracer to measure the level of P-gp activity in the BBB of these animals.

Other Non-Primate Mammals

[PubMed]

No reference is currently available.

Non-Human Primates

[PubMed]

No reference is currently available.

Human Studies

[PubMed]

No reference is currently available.

Supplemental Information

[Disclaimers]

No information is currently available.

NIH Support

Supported by the Intramural Research Program, National Institute of Mental Health, National Institutes of Health.

References

1.
Haar C.P., Hebbar P., Wallace G.C.t., Das A., Vandergrift W.A. 3rd, Smith J.A., Giglio P., Patel S.J., Ray S.K., Banik N.L. Drug resistance in glioblastoma: a mini review. Neurochem Res. 2012;37(6):1192–200. [PMC free article: PMC4518733] [PubMed: 22228201]
2.
Giacomini K.M., Huang S.M., Tweedie D.J., Benet L.Z., Brouwer K.L., Chu X., Dahlin A., Evers R., Fischer V., Hillgren K.M., Hoffmaster K.A., Ishikawa T., Keppler D., Kim R.B., Lee C.A., Niemi M., Polli J.W., Sugiyama Y., Swaan P.W., Ware J.A., Wright S.H., Yee S.W., Zamek-Gliszczynski M.J., Zhang L. Membrane transporters in drug development. Nat Rev Drug Discov. 2010;9(3):215–36. [PMC free article: PMC3326076] [PubMed: 20190787]
3.
Sharom F.J. The P-glycoprotein multidrug transporter. Essays Biochem. 2011;50(1):161–78. [PubMed: 21967057]
4.
Hitchcock S.A. Structural modifications that alter the P-glycoprotein efflux properties of compounds. J Med Chem. 2012;55(11):4877–95. [PubMed: 22506484]
5.
Bartels A.L. Blood-brain barrier P-glycoprotein function in neurodegenerative disease. Curr Pharm Des. 2011;17(26):2771–7. [PubMed: 21831040]
6.
Bao X., Lu S., Liow J.S., Morse C.L., Anderson K.B., Zoghbi S.S., Innis R.B., Pike V.W. [(11)C]Rhodamine-123: Synthesis and biodistribution in rodents. Nucl Med Biol. 2012;39(8):1128–36. [PMC free article: PMC3478417] [PubMed: 22898316]
7.
Vora M.M., Dhalla M. In vivo studies of unlabeled and radioiodinated rhodamine-123. Int J Rad Appl Instrum B. 1992;19(3):405–10. [PubMed: 1629029]

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