MEDICINAL CHEMISTRY RESEARCH
Med Chem Res (2013) 22:3459–3465 DOI 10.1007/s00044-012-0360-z
ORIGINAL RESEARCH
Extraction, radiolabeling, and biodistribution of thebaine in rats ¨ nak • F. Yurt Lambrecht • H. Enginar • P. U F. Zu¨mru¨t Biber Mu¨ftu¨ler • B. Seyitog˘lu • A. Yurt S. Yolcular • E. I˙. Medine • I˙. Bulduk
•
Received: 8 June 2012 / Accepted: 8 November 2012 / Published online: 23 November 2012 Ó Springer Science+Business Media New York 2012
Abstract The goal of this study was to determine the radiopharmaceutical potential of radioiodinated thebaine. Thebaine was extracted from dry capsules of opium poppy (Papaver somniferum L.), purified using high-performance liquid chromatography, and characterized with nuclear magnetic resonance and infrared spectroscopy. The purified thebaine was labeled with 131I using the iodogen method. Normal and receptor-blockage biodistribution studies were performed in male Albino Wistar rats. The results of the tissue distribution studies showed that the uptake of 131I-thebaine in the stomach, large intestine, spinal cord, and prostate was higher than in the other tissues. A greater uptake of radiolabeled thebaine in the rat brain was observed in the midbrain and hypothalamus. We concluded that (1) the labeling yield of 131I-thebaine was high, (2) a large amount of 131I-thebaine remained in the midbrain and hypothalamus, and (3) 131I-thebaine had enough stability for diagnostic scanning. Keywords Thebaine Biodistribution Rat I Iodogen
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H. Enginar Department of Chemistry, Afyon Kocatepe University, Afyonkarahisar, Turkey ¨ nak F. Y. Lambrecht (&) F. Z. Biber Mu¨ftu¨ler P. U B. Seyitog˘lu A. Yurt S. Yolcular E. I˙. Medine Institute of Nuclear Science, Department of Nuclear Applications, Ege University, Bornova, Izmir, Turkey e-mail:
[email protected] I˙. Bulduk Bolvadin Alkaloid Factory, Bolvadin, Afyonkarahisar, Turkey
Introduction Opium, a dried latex material that leaks out of the cut seed capsules of the opium poppy Papaver somniferum (Booth, 1996; Bruneton, 1995), contains several types of morphine alkaloids. Of these, thebaine (Fig. 1) is biosynthesized from two molecules of L-tyrosine by way of several intermediaries, e.g., norcoclaurine, coclaurine, reticuline, and salutaridine (Spenser, 1968; Stadler et al., 1987; Loeffler et al., 1987; Battersby et al., 1964. Barton et al., 1965). In plants, morphine is formed from thebaine after transitioning through codeine and oripavine (Brochmann-Hanssen, 1985). Thebaine occurs in opium at concentrations of 0.1–2.5 %, with less than 1 % being common (Bruneton, 1995). Thebaine, though not used medicinally, is important as a substrate in the semisynthesis of other compounds (Paul and Schiff, 2002). Oxycodone is produced by oxidation of the conjugated diene system of thebaine. Demethylation of oxycodone through the production of hydrobromic acid readily affords oxymorphone. The mixed agonist–antagonist nalbuphine may be formed semisynthetically from oxymorphone, in addition to the antagonists naloxone and naltrexone. Various agonists such as etorphine (a powerful veterinary analgesic/sedative being 5,000–10,000 more potent than morphine) or compounds with mixed agonist–antagonist properties such as buprenorphine are synthesized by the conjugated diene system (Bruncton, 1995; Dewick, 1997; Cordell, 1981). Etorphine, a semisynthetic thebaine derivative, is lipophilic and has a greater affinity for opioid receptors compared with morphine (Swan, 1993). Thebaine also displays some physiological and pharmacological effects. It has slight analgesic and depressant effects, but does not elicit physical dependence (Krueger, et al., 1943; WHO Advisory Group, 1980). However, it can stimulate the central nervous system and
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Fig. 1 Structure of thebaine
cause muscle contractions (Corrado and Longo, 1961; Gilbert and Martin, 1975; Tortella et al., 1984). The analgesic effect of thebaine is thought to be a consequence of its interaction at the l receptor. In biochemical radioligand binding studies, the opioid receptors in the brain of mammals have been identified since 1971 (Pugsley, 2002). These receptors were found throughout the brain as well as in the spinal medulla and spinal cord (Gutstein and Akil, 2001; Mikus et al., 1991). In the study performed by Mikus et al. (1991), oripavine was shown to be a major metabolite of thebaine and the total intrinsic clearance of thebaine to oripavine was high in Sprague-Dawley rats. According to Kodaira et al. (1989), thebaine was transformed to oripavine, codeine, and morphine in the rat liver, kidney, and brain microsomes in the presence of an NADPH-generating system. Kodaira et al. (1989) showed that the presence of thebaine in the ovine brain provided strong evidence that the morphine and codeine found in various mammalian tissues are of endogenous origin and are actually biosynthesized from a precursor. The aim of this study was to label thebaine with 131I and to determine the radiopharmaceutical potential of radioiodinated thebaine.
Materials and methods Reagents All reagents were commercially available and were of analytical grade. 131I was obtained from the Department of Nuclear Medicine of Ege University. Extraction of thebaine Plant materials were harvested near localities of Afyonkarahisar, Turkey. 10 g of opium poppy was cut into small pieces (5 mm) and put into a beaker with 1 L of
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10 % Ca(OH)2 solution and stirred using a mechanical mixer for 2 h. The pH of the mixture was reduced to 6.5 using 98 % H2SO4. The mixture was filtered and pH was increased to 9.0 using NH4OH (1 N). Waste products were separated as a precipitate. The pH of solution was adjusted to 7–7.5 with 1 N acetic acid and the precipitated substances were filtered. Lead acetate (1 mL) was added to the filtrate; the mixture was allowed to precipitate completely and was then filtered. The filtrate was cleared off lead using 20 mL H2SO4 (98 %). The pH was adjusted to 10 with 1 N NH4OH, and thebaine was precipitated, filtered, and dried at 80 °C in the oven. These procedures produced 0.025 g of thebaine, and the overall yield was 0.25 %. Chromatography A low-pressure gradient high-performance liquid chromatography (HPLC) system (LC-10ATvp quaternary pump and SPD 10A/V UV detector), a syringe injector equipped with a 1 mL loop and 7 lm RP-C-18 column (250 9 4.6 mm I.D., Macharey-Nagel), was used for preparative procedures. The elution was collected with a FRC-10A fraction collector (Shimadzu). The flow rate was set at 5 mL/min. Column was eluted with 100 % 10 mM tetraethyl ammonium hydroxide. UV detection was achieved at 254 and 280 nm. Labeling procedure 1 mg thebaine was dissolved in 1 mL acetic acid solution (0.5 %) and pH of the thebaine solution was adjusted to 2 using 0.1 N HCl. The labeling of thebaine (50 lg) was carried out with 131I using the iodogen (1,3,4,6-tetrachloro3a,6a-diphenylglucoluril) (Enginar et al., 2009; Lambrecht et al., 2006; Yilmaz et al., 2007; Akat et al., 2008; Seyitoglu et al., 2009; Lambrecht et al., 2009). Morphine glucuronide solution and 200 lCi of Na131 were added into the iodogencoated tube. This reaction mixture was kept at room temperature without stirring for 15 min. At the end of this period, the mixture was transferred to another tube by a syringe and then checked for quality. The quality control studies were performed by thin-layer radiochromatography (TLRC) and paper electrophoresis to confirm the labeling efficiency of 131I-thebaine. The TLRC procedure Each TLRC cellulose-coated sheet was covered by a celloband after its development and cut into 0.5 cm widths. Various solvent mixtures were used as developers (solvent A: ethyl acetate:ethanol, 1:1, v/v; solvent B: chloroform:acetic acid, 9:1, v/v; solvent C: isopropyl alcohol, n-butanol, 0.2 M ammonium hydroxide, 2:1:1, v/v/v). Then the developed sheet was dried and cut into 0.5 cm
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width. The pieces were counted using the Cd(Te) detector equipped with a RAD 501 single-channel analyzer. The TLRC chromatograms were obtained from these figures by plotting counts versus distance. The Rf values and labeling efficiencies were derived from these chromatograms. Paper electrophoresis Electrophoresis was conducted using a Gelman electrophoresis chamber. The cathode and anode poles and application points were indicated on the cellulose acetate strips which were moistened by buffer solution (n-butanol/ water/acetic acid; 4/2/1; v/v/v). After each compound was set onto the strips, they were placed in the electrophoresis chamber. The standing time and voltage applied were 2 h and 300 V, respectively. The developed strips were dried and cut into 1 cm pieces and each one was counted using a Cd(Te) detector.
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150–180 g. To block the uptake of iodine by the thyroid gland, 10 mg of potassium iodide was added to 1 L of drinking water. The 131I-labeled compound was sterilized by membrane filtration and then injected into the tail vein of the animals (1 lg 131I-thebaine per rat). The rats were killed at 15, 60, or 180 min under ether anesthesia and the tissues of interest were removed. All tissues were weighed and assessed for radioactivity using a Cd(Te) detector. The percentage of radioactivity per gram tissue weight (in percentage injected activity/g tissue) was determined. For the blocked-receptor studies, 10 lg thebaine was given to each rat 15 min before administering 131I-thebaine. For the in vivo blocking experiments, 10 lg of non-labeled thebaine were prepared under the same conditions as 131I-thebaine to determine whether the uptake in the receptor-expressing target tissues was specific. The same procedures were repeated as indicated above.
Lipophilicity
Results and discussion
A 100 lL volume of 131I-thebaine was added to a test tube containing 3 mL each of n-octanol and water. It was vortexed for 1 h at room temperature and centrifuged at 3,000 rpm for 5 min. Following this, 0.5 mL aliquots of each phase were taken for counting. The partition coefficient was determined by the following function: partition coefficient = LogP (counts in n-octanol layer/counts in aqueous layer). The experiment was repeated five times.
The structural parameters of thebaine were obtained using nuclear magnetic resonance (1H-NMR), infrared (IR) spectroscopy, and HPLC. Figures 1 and 2 show the molecular structure and the HPLC chromatogram of thebaine, respectively. The characteristics of thebaine were as follows: IR (KBr, cm-1): 3500 (hydroxyl, OH), 2950 (alkyl, CH), 1600 (alkenyl, C=C), 1300 (N–C), and 1250 (ether, C–O–C); 1 H-NMR: 1H-NMR (DMSO) d (ppm) values: 6.66 (d, 1H, 9-H), 6.58 (d, 1H, 8-H), 5.55 (d, 1H, 3-H), 5.28 (s, 1H, 1-H), 5.02 (d, 1H, 5-H), 3.84 (s, 1H, 12-OCH3), 3.60 (s, 1H, 11-OCH3), 3.30 (d, 2H, 4-H), 2.83 (t, 2H, 7-H) 2.46 (s, 3H, NCH3), 2.20 (t, 1H, 2-H), 1.72 (t, 2H 6-H), dH 37.4, 43.1, 47.6, 45.1, 46.5, 55.1, 56.8, 61.3, 89.2, 96.1, 112.2, 113.7, 119.8, 128.1, 132.7, 133.6, 143.2, 145.3, 153.1. As seen in Table 1, the Rf value in solvent C is distinctive. Rf values were 0.83 and 0.95 for Na131I and 131 I-thebaine, respectively. Paper electrophoresis showed that 131I-thebaine has a neutral structure (Fig. 3) as 131 I-thebaine remained at the application point. The results
Serum stability of
131
I-thebaine
The 131I-thebaine (300 lL) was incubated with fresh human serum (600 lL) in duplicate at 37 °C for 4 h. During incubation, the sample was analyzed at 15 min and 1, 3 and 24 h by TLRC. Besides, effects of pH and iodogen amount on labeling percentage on thebaine were investigated. Stability of
131
I-thebaine
The 131I-thebaine (300 lL) was incubated with physiological serum (600 lL) in duplicate at 37 °C for 24 h. During incubation, the sample was analyzed at 15 min and 1, 3 and 24 h by TLRC. Biodistribution studies in rats The animal experiments were approved by the Institutional Animal Review Committee of Ege University. The biodistribution data are expressed as the percentage of injected radioactivity per gram of tissue for selected organs as the mean value from three rats. The experiments were performed on albino Wistar rats weighing approximately
Fig. 2 HPLC chromatogram of thebaine
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Table 1 Rf values of Na131I, Oxidized 131
I
131
I and
Oxidized
131
I-thebaine
131
I
131
I-thebaine
Mobile phase
Na
A
0.07
0.00
1.00
B
0.07
0.07
1.00
C
0.83
0.20
0.95
A ethyl acetate:ethanol, 1:1, v/v; B chloroform:acetic acid, 9:1, v/v; C isopropyl alcohol, n-butanol, 0.2 M ammonium hydroxide, 2:1:1, v/v/v Fig. 5 Effect of amount of iodogen on labeling yield of 131I-thebaine
Fig. 3 Electrophoresis chromatogram of
131
I-thebaine Fig. 6 In vitro stability of
Fig. 4 Effect of pH on labeling yield of
131
I-thebaine
indicated that the labeling yield of 131I-thebaine was 86 ± 5.8 %. Lipophilicity was found to be 0.49 ± 0.3 experimentally. The theoretical lipophilicities of thebaine and iodothebaine were 2.51 ± 0.81 and 3.55 ± 0.88, respectively, according to the program. The experimental lipophilicity of 131I-thebaine is less than theoretical. To determine the effect of pH on the radiolabeling yield, mixtures were tested with pH between 2 and 7. The amounts of thebaine (1 mg) and iodogen (1 mg) were fixed during investigation of the effect of pH. The highest labeling yield, 86 ± 5.8 %, was obtained at pH 2. Figure 4 shows that the labeling yield decreases with increasing pH (77.5 ± 4.6 % at pH 4, 40.2 ± 2.8 % at pH 7). The effect of the amount of iodogen (0.10, 0.50, 1 mg) on radiolabeling yield is summarized in Fig. 5. During the experiment, the amount of thebaine (1 mg) and pH (pH 2) were fixed. Radiolabeling yield was observed to increase according to the amount of iodogen. Labeling yields were
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131
I-thebaine
62.1 ± 3.4, 78.1 ± 4, and 86 ± 5.8 % when using 0.10, 0.50, and 1 mg of iodogen, respectively. In vitro stability results show that radioiodinated thebaine deiodinates with time. The labeling percentages were determined to be 86 ± 5.8, 85.2 ± 2.5, 83.3 ± 3.3, 77.2 ± 2.2, and 68.5 ± 3.5 % at 15, 30, 60, and 180 min, and 24 h, respectively (Fig. 6). The stability decreased rather slowly with time. The data on serum stability were also similar. According to the data, radiolabeling yield was 86 ± 5.8, 80 ± 1, 69.9 ± 4.1, 60.1 ± 2, and 45.1 ± 5 % at 15, 30, 60, and 180 min, and 24 h, respectively (Fig. 7). This time is suitable for imaging. The biodistribution data of 131I-thebaine in normal rats are shown in Fig. 8. High uptake of radiolabeled thebaine was observed in the large intestine (%ID = 0.85), stomach (%ID = 0.53), prostate (%ID = 0.81), and spinal cord (%ID = 0.73) at 60 min. A significantly positive correlation
Fig. 7 Stability in human serum of
131
I-thebaine
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Fig. 8 Biodistribution of 131 I-thebaine in rats. Results are expressed as mean ± standard deviation
of 131I-thebaine was indicated in lung–liver (r = 0.80, p \ 0.02), lung–pancreas (r = 0.80, p \ 0.02), small intestine–fat (r = 0.84, p \ 0.005), large intestine–blood (r = 0.09, p \ 0.002), large intestine–prostate (r = 0.89, p \ 0.003), and stomach–testis (r = 0.85, p \ 0.003) combinations. The highest uptake of radioiodinated codeine (131Icodeine) was observed in the lung, liver, kidney, small intestine, stomach, and prostate in rats 15 min postinjection (Enginar et al., 2009). Chen et al. showed that the maximum plasma codeine concentration was reached about 1.0 h after a single dose. Uptake of morphine, another opioid, was observed in the intestine, liver, kidney, blood, and brain 1.0 h postinjection (Donnerer et al., 1987). We obtained results similar to other reports. Some reports indicated that the clearance of opioids was via the urinary and hepatobiliary systems. Our results agreed with these reports based on the evidence of increased hepatobiliary excretion (0.32 ± 0.02 %ID/g in the liver and 0.31 ± 0.10 %ID/g in the small intestine at 15 min) and reduced renal excretion (0.18 ± 0.06 %ID/g in kidney at 60 min) (Enginar et al., 2009; Jackson and Stanford, 2004; Chen et al., 1991). When the receptors were blocked, the %ID/g values of 131 I-thebaine in the small intestine, large intestine, prostate,
and spinal cord were 0.63, 0.44, 0.89, and 0.13, respectively, at 180 min as the maximum (Fig. 9). The uptake of 131 I-thebaine decreased in these organs when the receptors were unblocked. After receptor blocking, 131I-thebaine indicated positive correlation in the heart–lung (r = 0.89, p \ 0.007), heart–spleen (r = 0.82, p \ 0.007), lung–large intestine (r = 0.85, p \ 0.003), lung–spleen (r = 0.82, p \ 0.02), liver–kidney (r = 0.80, p \ 0.03), liver–right testis (r = 0.90, p \ 0.005), and the large intestine–spleen (r = 0.92, p \ 0.003) combinations. Receptor blockage and unblockage of 131I-thebaine showed positive correlation in the large intestine–rec. pancreas (r = 0.85, p \ 0.008) and blood–rec. pancreas (r = 0.92, p \ 0.000) combinations. A negative correlation of 131I-thebaine was seen in the thyroid– rec. heart (r = -0.89, p \ 0.003), thyroid–rec. lung (r = -0.83, p \ 0.04), thyroid–rec. large intestine (r = -0.89, p \ 0.02), thyroid–rec. spleen (r = -0.89, p \ 0.02), and blood–rec. large intestine (r = -0.86, p \ 0.02) combinations. However, the uptake of 131I-codeine by receptors blocked with codeine decreased in similar organs (lung, liver, stomach, prostate, and spinal cord) (Enginar et al., 2009). Figure 10 shows that 131I-thebaine accumulated in some regions of the brain. As seen in the results, the highest uptake of radioiodinated thebaine in the midbrain and hypothalamus was 69.70 ± 10.9 %ID/g at 15 min and
Fig. 9 Biodistribution of 131 I-thebaine receptor-blocked studies in rats. Results are expressed as mean ± standard deviation. Different superscripts indicate significant differences according to groups and time
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Fig. 10 Biodistribution of 131Ithebaine in rats’ brain. Results are expressed as mean ± standard deviation
Fig. 11 Biodistribution of 131 I-thebaine in receptorblocked studies in rats’ brain. Results are expressed as mean ± standard deviation. Different superscripts indicate significant differences according to groups and to time
32.83 ± 09.6 %ID/g at 180 min. While the uptake of 131Ithebaine increased in the hippocampus, hypothalamus, and striatum, the uptake values decreased significantly in the cerebellum, midbrain, and frontal cortex over 180 min. Possible correlations range from positive (?) to negative (-). A zero correlation indicates that there is no relationship between the variables. A correlation of (-) indicates a perfect negative correlation, meaning that as one variable goes up, the other goes down. A correlation of (?) indicates a perfect positive correlation, meaning that both variables move in the same direction together. According to the results, a positive correlation was indicated in the cerebellum–temporal cortex (r = 0.92, p \ 0.001), hippocampus–middle pons (r = 0.82, p \ 0.007), and hippocampus–temporal cortex (r = 0.72, p \ 0.04) combinations. A significantly negative correlation was observed in the striatum–midbrain (r = 0–0.79, p \ 0.06), hypothalamus–midbrain (r = 0–0.79, p \ 0.03), and temporal cortex–midbrain (r = 0–0.79, p \ 0.05) combinations. When the receptors were blocked, 131I-thebaine showed maximum uptake in the hypothalamus (42.93 ± 10.21 %ID/ g) at 60 min and midbrain (50.79 ± 11.45 %ID/g) at 15 min (Fig. 11). While the uptake of 131I-thebaine increased in the cerebellum, hippocampus, midbrain, hypothalamus, and
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striatum, it decreased in the middle pons and temporal cortex with time. A positive correlation was found between the brain w?>regions (rec. cerebellum–rec. middle pons (r = 0.73, p \ 0.026), rec. cerebellum–rec. middle pons (r = 0.73, p \ 0.026), and rec. middle pons–rec. frontal cortex (r = 0.84, p \ 0.005). A negative correlation was seen between the rec. hypothalamus–rec. midbrain (r = -0.93, p \ 0.001) and rec. cerebellum–rec. midbrain (r = -0.77, p \ 0.017). When the receptor was blocked, the uptake of radiolabeled thebaine decreased in the midbrain, temporal cortex, and frontal cortex. Receptor blockage and unblockage studies data demonstrated a positive correlation between the rec. temporal cortex and frontal cortex (r = 0.74, p \ 0.023) of rat brains. In our study, we assumed that the maximum uptake in the regions of interest will occur at 15 min. However, the uptake of 131I-codeine was high in middle pons, hypothalamus, and midbrain 180 min after the injection in our previous study. Morphine accumulation has been observed in the cortex, midbrain, pons, medulla, and cerebellum in biodistribution studies in rats (Donnerer et al., 1987; Evans et al., 1992). In addition, opioid receptors were observed in nerve cells located throughout the brain and spinal medulla (Pugsley et al., 2002; Kodaira et al., 1989; Fries, 1995; Rice, 1985). We found similar results in our study.
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In conclusion, the original goal of this study was to evaluate the biodistribution of 131I-thebaine in rats. In addition, we showed that the labeling yield of 131I-thebaine was high and that 131I-thebaine accumulation was high in the brain. Finally, 131I-thebaine has enough stability for diagnostic scanning. If thebaine is radiolabeled with 123 I instead of 131I, it can possibly prove to be a radiopharmaceutical target for brain imaging in SPECT. Acknowledgments The authors thank for the financial supports from The Scientific and Technical Research Council of Turkey (TUBITAK, Project number 2004-104T187) and T.R Prime Ministry State Planning Organization (DPT, Project Number 2006 DPT 06).
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