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Quantitative in Vivo Receptor Binding 0270-6474/85/0502-0421$02.00/O The Journal of Neuroscience Copyright 0 Society for Neuroscience Vol. 5, No. 2, pp. 421-428 Printed in U.S.A. February1985 QUANTITATIVE IN VIVO RECEPTOR BINDING I. Theory and Application to the Muscarinic Cholinergic Receptor’ K. A. FREY, R. L. E. EHRENKAUFER, S. BEAUCAGE, AND B. W. AGRANOFF3 Neuroscience Laboratory, Department of Biological Chemistry and Division of Nuclear Medicine, The University of Michigan, Ann Arbor, Michigan 48109 Received April 2, 1984; Revised July 13, 1984; Accepted July 23, 1984 Abstract A novel approach to in vivo receptor binding experiments is presented which allows direct quantitation of binding site densities. The method is based on an equilibrium model of tracer uptake and is designed to produce a static distribution proportional to receptor density and to minimize possible confounding influences of regional blood flow, blood-brain barrier permeability, and nonspecific binding. This technique was applied to the measurement of regional muscarinic cholinergic receptor densities in rat brain using [3H]scopolamine. Specific in vivo binding of scopolamine demonstrated saturability, a pharmacologic profile, and regional densities which are consistent with interaction of the tracer with the muscarinic receptor. Estimates of receptor density obtained with the in vivo method and in vitro measurements in homogenates were highly correlated. Furthermore, reduction in striatal muscarinic receptors following ibotenic acid lesions resulted in a significant decrease in tracer uptake in vivo, indicating that the correlation between scopolamine distribution and receptor density may be used to demonstrate pathologic conditions. We propose that the general method presented here is directly applicable to investigation of high affinity binding sites for a variety of radioligands. Extensive attempts in the past to demonstrate the in vivo neurotransmitter receptors and other high affinity binding sites distribution of radiolabeled drugs within the central nervous in human brain utilizing positron and single-photon emission system encompassed a variety of approaches. The goals of tomography (Eckelman et al., 1979, 1984; Raichle, 1979; Wag- initial studies were to demonstrate the regional distributions of ner et al., 1983). The approach holds the promise of directly labeled drugs and neurotoxins at their presumed sites of action testing hypotheses implicating receptor alterations in a number in the brain (Roth and Barlow, 1961). With the development of neurologic and psychiatric diseases. Design strategies for of receptor binding techniques, a second application of in vivo such clinical applications differ from previous in vivo studies tracer distribution emerged: tracer distribution experiments in that accurate quantitation of receptor numbers and/or affin- were employed to reveal the anatomic localization of high ities in discrete brain regions is necessary. Thus, requirements affinity drug-binding sites previously detected in tissue homog- for these in vivo tracer experiments exceed those of earlier enates (Yamamura et al., 1974; Hollt et al., 1977; Chang and localization studies in that they impose additional constraints Snyder, 1978; Kuhar et al., 1978). Autoradiographic localization associated with modeling of tracer distribution and binding. of drug binding revealed anatomic detail at the light (Kuhar Correlation between muscarinic receptor distribution in the and Yamamura, 1976; Murrin et al., 1977; Murrin and Kuhar, brain and the in vivo distribution of [3H]quinuclidinyl benzilate 1979) and electron microscopic (Kuhar et al., 1981) levels, was originally reported by Yamamura et al. (1974) following beyond that available by tissue punch and homogenate binding bolus injection of the tracer into the tail vein of the rat. techniques. Attempts in this laboratory as well as in those of others (Drayer Recently, there has been renewed interest in in vivo ligand et al., 1982; Vora et al., 1983) to extend these findings to lower distribution experiments with the ultimate goal of imaging drug doses compatible with eventual clinical imaging protocols have demonstrated poorer correlation between receptor density and tissue radioactivity and have prompted a re-examination 1 This work was supported by National Institutes of Health Grant of the design of in vivo receptor binding experiments. In this NS 15655 and by a grant from the Michigan Memorial Phoenix Fund, University of Michigan. K. A. F. was a trainee under National Institutes report we describe a quantitative approach to in vivo measure- of Health Grant 1 T32 GM07863, and S. B. was supported by Grant ment of regional receptor densities based on the equilibrium 51‘32 CA09015. distribution of radiolabeled tracers. The feasibility of this ap- ’ Present address: Beckman Instruments, Inc., P. 0. Box 10200,1117 proach has been examined using [3H]scopolamine to label the California Avenue, Palo Alto, CA 94304. muscarinic receptor in the rat brain. The ultimate purpose of 3 To whom correspondence should be addressed, at Neuroscience these experiments is to identify a suitable positron-labeled Laboratory Building, The University of Michigan, 1103 East Huron, imaging agent for human studies. Additional experiments in- Ann Arbor, MI 48109. dicating the suitability of scopolamine for this purpose are in 421 422 Frey et al. Vol. 5, No. 2, Feb. 1984 progress (K. A. Frey, R. L. E. Ehrenkaufer, R. D. Hichwa, and binding parameters from the time courses of regional brain and B. W. Agranoff, manuscript in preparation). blood tracer levels under non-equilibrium conditions. Theory Materials and Methods Tracer distribution in samples of brain tissue involves two Scopolamine, methylscopolamine, atropine, and di-isopropylfluoro- anatomic compartments: the intravascular and extravascular phosphate (DFP) were purchased from Sigma Chemical Co. (St. Louis, spaces. The total extravascular tracer concentration, CE, may MO). Ibotenic acid was obtained from Regis Chemical Co. (Morton be determined from total tissue tracer concentration, CT, and Grove, IL). Unlabeled (+)-quinuclidinyl benzilate (QNB) was provided by Dr. Charlotte Otto, University of Michigan (Dearborn, MI). Triti- blood tracer levels, Ca, when the tissue blood volume, VB ated CH,I (specific activity, 10 to 13 Ci/mmol) was purchased from (expressed as milliliters of blood per milliliter of tissue), is Amersham (Arlington Heights, IL). Tritiated (-)-QNB (specific activ- known: ity, 33.1 Ci/mmol) was obtained from New England Nuclear (Boston, MA). Male Sprague-Dawley rats weighing between 180 and 200 gm CE = (CT - cBvB)/(1 - VB) (1) were purchased from Harlan Sprague-Dawley Inc. (Indianapolis, IN). This correction for intravascular tracer is frequently ignored, Synthesis of [3Hlscopohmine. Scopolamine was tritiated by meth- since brain blood volumes are estimated to be 1 to 5% (Kuhl et ylation of (-)-norscopolamine (Werner and Schickfluss, 1969) with [3H]CH,I using a modification of the method of Schmidt et al. (1965). al., 1980; Cremer and Seville, 1983). It has been omitted from The product was purified by thin layer chromatography on silica gel analysis of the data in the present study since tissue tracer using the solvent system tetrahydrofuran-di-isopropylethylamine, 95:5. levels were found to be greater than or equal to blood tracer Radiochemical purity of the product was routinely greater than 97% levels at all times examined. and it remained stable for several months when stored at -20°C in The extravascular tracer consists of three components: LE, ethanol solution. The specific activity of the product was determined N& and SE, representing free, nonspecific, and specifically by comparison of its in vitro receptor-binding capacity compared to that obtained with ?HlQNB of known snecific activitv. The snecific bound tracer, respectively. 1- activity of [3H]scopolamine determined inthis manner agreed to kithin CE = LE + NSE + SE (2) 10% with the stated specific activity of the precursor [3H]CHJ. In vitro binding. In uitro scopolamine binding to homogenates of rat If it is assumed that free and nonspecifically bound tracer brain was measured with a filtration assay (Kloog and Sokolovsky, concentrations at equilibrium are proportional to the plasma 1978). Rat forebrains were homogenized in 25 vol of phosphate-buffered ligand concentration, an apparent tissue-to-blood partition saline (NaCl, 124 mM; KCl, 2.7 mM; Na,HPO,, 7.7 mM; KH,PO,, 1.5 coefficient, X, may be defined: mM, pH 7.4). A crude particulate fraction was obtained by centrifuga- tion at 20,000 x g for 10 min. The pellet was resuspended and the X = (LE + N&)/& (3) centrifugation was repeated before final reconstitution in buffer and subsequent storage at -20°C. In regional QNB binding capacity exper- and, by substitution into equation 2 and rearrangement of iments, centrifugation was omitted and determinations were carried terms: out on the total homogenate. Binding of [3H]scopolamine was determined by incubating aliquots s, = c, - h cg (4) of the homogenates (80 to 160 pg of protein) with various ligand Equation 4 can be used to determine the amount of tracer in concentrations (0.1 to 10 nM) in 1 ml of buffer for 30 min at 25°C. tissue specifically bound to the receptor site at equilibrium Incubations were terminated by rapid vacuum filtration through glass fiber filters (Whatman GF/C), followed by three washes with 2-ml when CE and CB are measured and the local value of X is known. portions of ice-cold buffer. Nonspecific binding
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