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The Distribution of the Muscarinic Acetyichoiine Receptor Antagonists

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The Distribution of the Muscarinic Acetyichoiine Receptor Antagonists The Distribution of the Muscarinic Acetyichoiine Receptor Antagonists, Quinuciidinyi Benziiate and Qulnuciidinyi Benziiate Methiodide (both tritiated), in Rat, Guinea Pig, and Rabbit Raymond E. Gibson, William C. Eckelman, Frank Vieras*, and Richard C. Reba School of Medicine, George Washington University Medical Center, Washington, D.C. and *Armed Forces Radiobiology Research institute , Bethesda, Maryland The distribution of [3Hjquinuclidinyl benzilate and its methiodide salt was deter mined in rat, guinea pig, and rabbit. Accumulation in the myocardium of up to 2% of the injected dose per gram of tissue was obtained with both compounds, providing heart-to-blood ratios of @—‘3Oand heart-to-lung ratios of @4.The accumulation in the heart was blocked (89%) by preinjection of atropine. The distribution of tritium in rabbit heart corresponds to the muscarinic receptor densities determined in vitro. Cakulation of the theoretical maximum for the bound-to-free ratio, based on in-vitro equilibrium binding isotherms, resulted in ratios in reasonable agreement with the experimental results. Because of the high accumulation in the heart with low serum concentration, we conclude that the methiodide salt of quinuclidinyl benzilate repre sents an ideal parent structure for the design of a receptor-binding gamma-emitting radiopharmaceuticalfor imaging of the myocardium. J NuciMed20:865—870,1979 Current methods for external imaging of the myo gand concentrations in the target tissue and work cardium are based on the metabolic requirements able. target-to-blood ratios. of the heart [Tl-201 (1), (11C)palmitic acid (2)], or Two receptors are present in the myocardium in metabolic trapping [2-('8F)fluoro-2-deoxy-D-glu sufficiently high concentration to make localization cose (3)], or the deposition of technetium [Tc-99m feasible: a) the .beta-adrenoceptor (8), and b) the Ppm (4)] and certain lipophilic drugs [1-131 tetracy muscarinic acetylcholine receptor (9). Both are cell dine (5)]. An alternate mechanism that may prove surface receptors that are present in concentrations useful is the localization of a radiolabeled ligand of 10 to 20 pmole/gram of heart tissue. For these exhibiting a specific, high-affinity interaction with receptors there are a limited number of drugs that a receptor present in the myocardium (6). The the have sufficient affinity (K,, of 10@to 10'°M1) to oretical requirements have been described (7) for deliver the desired radioactivity to the target and to both the quantity of receptor needed in the tissue provide sufficiently large target-to-blood ratios. The and the affinity required to give adequate radioli investigation of beta-adrenoceptor antagonist local ization in the myocardium has been the subject of Received Dec 28, 1978; revision accepted March 19, 1979. several previous communications (10,11). This re For reprints contact: Raymond E. Oibson, George Washing ton University Medical Center, School of Medicine, 2300 Eye port describes results on the myocardial localiza St., N.W., Washington, D.C. 20037 tion of two high-affinity, tritiated antagonists of the Volume 20, Number 8 865 GIBSON, ECKELMAN, VIERAS, AND REBA H suesfrom the heart, lungs,and liver wereexcised, blotted to remove excess blood, solubilized in NCS tissue solubilizer in capped vials, and counted in a liquid-scintillation counter. Blood samples were similarly solubilized and counted. Samples were dark-adapted for at least 4 hr and counted through two cycles to ensure reproducible values. Quench ing corrections were made with an external stand ard and calibrated curve. The results are expressed as %dose/g of tissue and were obtained from at least five animals. The affinity of [3H]QNB and [3H]MQNB for guinea pig heart muscarinic receptor was deter mined using the heavy-membrane fraction of the * ventricular muscle. H In two rabbits, 50 @Ciof [3H]MQNB was injected through an ear vein and the animals were killed at 30 mm by a blow to the neck. Blood was taken by R=H@ UNB cardiac puncture, and the heart, lungs, and liver R = CH3; MQNB were removed. The heart was dissected into the left and right atrial and ventricular muscle (VM), yen FIG. 1. Structures of quinuclidinyl benzylate (QNB) and its tricular septum, and papillary muscle. In one rabbit methyl quaternary derivative (MONB). Counter ion (x) for MONB is iodide. the left ventricular muscle was cut into 16 sections. Three 20-mg samples of each tissue were solubi lized and counted as above. muscarinic acetylcholine receptor: [3H]quinucidinyl In-vivo drug displacement studies. Various con benzilate ([3H]QNB) and its methiodide salt centrations of unlabeled muscarinic agents were in ([3H]MQNB) (Fig. 1). jected 15 to 30 mm before the injection of [3HJMQNB. Quantities ofunlabeled drug were cho MATERIALS AND METHODS sen to provide initial serum concentrations of I @M, [3HIQNB (32 Cilmmole) was purchased commer 10 @M,or 100 @M,assuming that the volume of ciallyt. The molecule is nominally labeled in the distribution is 3.5% of the animal's weight (see 4' ,4'-positions of the benzilate moiety (Fig. 1). The Table 3). radiochemical purity is specified as greater than 98%. [3H]MQNB, the N-methyl derivative of RESULTS [3H]QNB, was prepared by mixing 1 mCi of Distribution in rat. Distribution of tritium in rat [3H]QNB with 1 ml CH3I at room temperature for and guinea pig VM, lung, and blood, following in 2 hr in the dark. The excess CH3I was removed jection of [3H]QNB and [3HIMQNB, is summarized under a stream of dry N2, and the methiodide salt in Table 1. There is no significant difference in the was solubilized in 95% EtOH. The product exhib accumulation of tritium in the rat VM between 15 ited one radioactive peak on TLC in butanol, water, mm and 2 hr with [3H]QNB, but the methyl qua acetic acid (60:20: 10; ml ofeach) and ethanol, acetic ternary salt suffers a reduction in activity of ½to acid, water (60:30: 10), with R1 values of 0.32 and ‘/4between 15 mm and 2 hr. The heart-to-blood 0.36, respectively. In the same two systems, ratio (H/B) for [3H]MQNB is somewhat higher than E3HIQNB exhibits Rf values of 0.65 and 0.73. The that for [3HJQNB at 15 mm, whereas the reverse is [3H]MQNB was stored at —25°C and was used the case at 2 hr. The quaternary salt exhibits a large within 5 days of preparation. Unlabeled atropine, heart-to-lung (H/L) ratio at 15 mm (12.7), whereas pilocarpine, oxotremorine, and nicotine were pur that of [3HIQNB is modest (1.6). We therefore used chased commercially. [3H]MQNB for the remainder of our studies. Distribution studies used male Charles River Distribution in guinea pigs. During studies on the guinea pigs (400 g), Sprague-Dawley rats (350 g), tissue distribution of a radioiodinated tyramine de and New Zealand Albino rabbits (6 kg). In rats and rivative of practolol (9), large species-related dif guinea pigs anesthetized with sodium pentobarbital, ferences were observed in the accumulation of the 4 @Ciof E3HIQNB or [3H]MQNB was injected via radiolabel in the VM of rat and guinea pig. We have the femoral vein and the animals were killed by therefore used guinea pigs as a second animal model exsanguination at various times after injection. Tis in this study. The %dose/g in the guinea pig VM 866 THE JOURNAL OF NUCLEAR MEDICINE BASIC SCIENCES RADIOCHEMISTRY AND RADLOPHARMACEUTICALS TABLE 1. DISTRIBUTION OF TRITIUM RADIOACTIVITY AFTER INJECTION OF 4 @Cl(0.13 pmol) OF [3H]QNBAND [‘H}MQNBIN RATS AND GUINEA PIGS* . % dose/g s.d.t Ti me Animal Compound (hr) Heart Blood Lung H/B H/L Rat QNB ¼ 1.89±0.24 0.103 ±0.008 1.25 ±0.37 18.4 01.6 2 1.88±0.57 0.076 ±0.014 0.34 ±0.13 24.6 6.0 MQNB ¼ 2.35 ±0.49 0.075 ±0.015 0.184 ±0.017 31.5 12.7 2@ 0.60±0.06 0.064 ±0.005 0.103 ±0.018 9.3 6.0 MQNB 2@ 0.88±0.16 0.072 ±0.007 0.17 ±0.02 12.2 5.3 4 0.46 ±0.20 0.075 ±0.006 0.14 ±0.04 6.3 3.7 Guinea pig MQNB ¼ 1.61 ±0.24 0.050 ±0.004 0.55 ±0.14 32.2 3.0 ½ 1.57±0.18 0.057 ±0.005 0.51 ±0.17 27.3 3.3 ¾ 2.74±0.83 0.070 ±0.005 0.86 ±0.09 38.7 3.2 1 1.38±0.25 0.058 ±0.009 0.49 ±0.08 23.9 2.8 2@ 0.82±0.24 0.036 ±0.015 0.32±0.15 28.4 3.0 2@ 0.80±0.15 0.026 ±0.003 0.30 ±0.14 31.6 2.7 * ONB = quinuclidinyl benzilate, MONB = N-methyl quinuclidinyl benzilate. t Each group contained at least five animals. 1@Determinedduringdifferentweeksto demonstratereplicability. following injection of [3H]MQNB compares favor distribution of tritium in the blood and lungs of two ably with the results for rat VM at both 15 mm and rabbits, the %dose/g in various regions of the heart 2 hr (Table 1). The accumulation in the lung is was determined (Table 2). The concentration of trit higher at 15 mm, resulting in a relatively low H/L ium in the atrial muscle is 1.5 to two times that in value, but at 2 hr the HIL ratio is not significantly the ventricular muscle.
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