RADIOCHEMISTRY and RADIDPHARMACEUTICAL.S
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BASIC SCIENCES RADIOCHEMISTRY AND RADIDPHARMACEUTICAL.s Radlolodinated Derivatives of P Adrenoceptor Blockers for Myocardlal Imaging Victor W. Jiang, Raymond E. Gibson, Waclaw J. Rzeszotarski, William C. Eckelman, and Richard C. Reba George Washington University, Washington, D.C. and Frank Vieras and Philip 0. Alderson* Armed Forces Radiobiology Research Institute, Bethesda, Maryland Four new beta-adrenoceptor blocking agents carrying tyramine as the amino moiety were synthesized and the distribution of their 1-125-tagged derivatives evaluated in rats. This distribution was compared with the dis tribution of various agonists and antagonists labeled with H-3 and C-14, and with the in vitro binding affinity of the new derivatives. A radioiodinated derivative of a cardioselective blocker, alprenolol, showed poor blood clear ance and no cardiac selectivity. A derivative of another cardioselective blocker, practolol, showed a promising heart-to-blood ratio (ca. 19) and cardioselectivity with a heart-to-lung ratio of Ca. 2. Two additional practolol analogs showed no improvement over the practolol derivative; because of the increased lipophilicity of these derivatives, blood clearance and cardio selectivity were diminished. An inverse correlation is suggested between the dusociation constant for the beta adrenoceptor in the lung and the heart to-blood and heart-to-lung values. We conclude that polarity plays an im portant role in the blood clearance and cardioselectivity of these beta adrenoceptor derivatives. J NuciMed19: 918—924,1978 It may be difficult to follow the pathway of a bio myocardium by virtue of their specific and high chemical or a drug labeled with radioiodine or a affinity interaction with f3-adrenergic receptors. If radioactive metallic ion if the gamma-emitting ra derivatives of ,t@blockers can be prepared and labeled dionuclide is bound directly to the compound. The with gamma-emitting radionuclides, a unique pro native functional groups may be required to interact cedure for in vivo tracing of the distribution and with the active site responsible for compound lo concentration of the /3 receptors would be available, calization, and should the radiolabel interfere with not only in the heart but also in the cerebellum (1) this interaction, the normal behavior of the molecule and as a function of the aging process (2). would be altered and tracer studies would fail. These problems can be avoided by preparing biochemicals or drugs containing a radionuclide-carrying group Received Nov. 18, 1977; revision accepted Feb. 7, 1978. that does not interfere with the biologically active For reprintscontact: WilliamC. Eckelman,GeorgeWash functional groups in the molecule. ington University, Radiopharmaceutical Chemistry, 2300 The f3-adrenoceptor blocking agents are a class Eye Street, N.W., Washington, D.C. 20037. * Present address: Johns Hopkins Medical Institutions, of potential imaging agents that may localize in the Div. of Nuclear Medicine, Baltimore, MD. 918 THE JOURNAL OF NUCLEAR MEDICINE BASIC SCIENCES RADIOCHEMISTRY AND RADIOPHARMACEUTICALS To date, the methodsavailable to evaluatefi cases. The radioactivity of each compound was di blockers for therapeutic use have involved the cx luted to 50 @Ci/mlin 50% EtOH (equal volumes amination of a physiologic response such as change of 100% EtOH and 0.03 M phosphate buffer, pH in heart rate or muscle contraction (3,4). This is 7.4), and 0.1 ml of the solution was injected into carried out either in isolated systems or intact ani Sprague Dawley rats. Solutions of compounds No. mals. These systems measure to varying extents the 3, 5, and 6 also contained 10 @g/mlEDTA and 20 net effect of a series of interactions involving pro @&g/mlascorbic acid as antioxidant. The specific tein binding, metabolism, excretion, capillary per activity of each compound is shown in Table 2. meability, membrane transport, and interaction with 1-125-labeled compounds. All noniodinated pre the receptor. To help sort out the important struc cursors of the iodinated compounds listed in Table tural parameters involved in one aspect of the total 1 (Nos. 7—12),except lit and 12t, were synthe interaction—binding to the f3 receptor—we have sized in our laboratory and the results of elemental used an established in vitro method to determine the analyses were in agreement with the theoretical val relative affinity of the derivative for the f3-adrenergic ues (unpublished data). The chloramine-T method receptor. Because all f3-adrenergic drugs localize not (7) of iodination was used to label these compounds only in the heart but also in the lungs, we require with carrier-free Na 1-125. A standard procedure knowledge of the specific interaction of the synthetic was carried out as follows: 10 @g(0.03 @moles)of derivatives with adrenergic binding proteins in van the compound were mixed with 3 mCi of 1-125 and ous tissues. Consequently, a method that quantitates then 10 ;Lgof the chloramine-T was added to the both the th (heart) and /32 (lung) character of de mixture. The total volume of the mixture was 25 @l. rivatives was used (5,6). The solution was mixed for 3 mm before punifica We have prepared a number of derivatives labeled tion. Methanol was used as the solvent, since most with radioiodine by attaching a (3-iodo-4-hydroxy)- of the compounds are not water soluble. phenethyl group to the amino nitrogen of a parent The 1-125-labeled compound was separated from f3-adrenergic compound (unpublished data). These the unreacted 1-125 by thin-layer chromatography. compounds have been studied in isolated systems At least two different solvent systems were used to and in intact animals to determine their ability to identify the labeling product for each compound. concentrate in the heart. The 1-125-labeled compound was extracted from the silica-gel layer with methanol and the methanol then MATERIALS AND METHODS evaporated under vacuum at room temperature. The Preparation of labeled compounds. H-3 labeled dry 1-125-labeled compound was dissolved in 50% compounds. We procured these compounds (Table EtOH (equalvolumesof 100% EtOH and0.03 M 1) commercially' and they were used without fur phosphate buffer, pH 7.4) at activity 50 @Ci/mI. ther purification. They were stored at 2°C and ana Since carrier-free 1-125 was used in the preparation, lyzed by thin-layer chromatography on plastic sheets the specific activity of the 1-125-labeled compounds coated with silica gel (0.25 mm) together with a approaches the theoretical value of 2,200 Ci/mmol TLC radiochromatogram scanner. The radiochemi (Table 2). Starting material is still present in the cal purity was found to be greater than 97% in all product, however, and can compete for receptor TABLE 1. NOMENCLATURE No. ChemicalName Abbreviations 1-isopropylamino-3-(1-naphthyloxy)-propan-2-ol propranolol (‘NJPLP 2 1-isopropylamino-3-(2-allyl)phenoxy-propan-2-ol alprenolol [‘H]ALP 3 1-(3,4-dihydroxy)phenyl-2-isopropyl-amino-ethanol isoproterenol [°ii] IPL 4 1-omino-3-(2-allyl)phenoxy-propan-2-ol [3H] NHrALP 5 1-(3,4-dihydroxy)phenyl-2-methylamino-ethanol epinephrine [‘H]EPI 6 1-(3,4-dihydroxy)phenyl-2-amino-ethanol norephinephrine [‘H]NE 7 1-125 TYR-PRAC 8 1-125 TYR-ALP 9 i@ii@;, 1-125 TCC-PRAC 10 I-i 25 TC-PRAC 11 1-(3-iodo-4-hydroxy-5-methoxy)phenethylamino-3-(m-tolyloxy}-propan-2-ol 1-125PD-3 12 3-iodotyramine 1-125 TYR Volume 19, Number 8 919 JIANG, GIBSON, RZESZOTARSKI, ECKELMAN, REBA, VIERAS, AND ALDERSON TABLE2. PHYSICAL AND CHEMICAL PROPERTIESOF p-ADRENERGIC COMPOUNDS Partition' 20°!.ethyl vitrof activity No. Compound coefficientRttIn1%Cl/mmolllCH,OHNH4OH0.9°!. NaClBenzene acetate stabilitySpecific 1 [‘H]PLP 16.5 0.50 0 1 /./month 5 2 [‘H]ALP 19.1 0.57 0 1%/month 30 3 [‘H]IPL 0.11 0 0.10 1%/month 5 4 [‘H]NHS-ALP 1.3 0.48 0.31 23 5 (‘H]EPI 0.023 0.08 0.48 1%/mgnth 11 6 [‘H]NE 0028 0 0.91 0.5%/month 24 7 1-125 TYR-PRAC 6.3 0.79 0.10 1 @./day 98 8 1-125TYR-ALP 8.2 0.77 0 2°I./day 104 9 1-125 TCC-PRAC 17.8 0.83 0 0.81 1%/day 136 10 1-125 TC-PRAC 44.8 0.80 0 0.61 1%/day 130 11 1-125 PD3 18.9 0.90 0 1%/day 96 12 1-125 TYR 0.5 0.40 OJO 0.50 1%/day 62 . The partion coefficient was determined using octanol and phosphate buffer at pH 7.4. t Silica-gelTLCin indicatedsolvent. t % deiodinationasmeasuredbysilica-gelchromatographyin saline. IIThenumberofmmolstartingmaterialandtheiodinatedproduct. sites. Thus we included this material in our calcu centage of deiodination of I-i 25-labeled compounds lation of specific activity. was measured over a period of 3 days (Table 2). Radiochemical purity. At least two chromato Partition coefficient. The partition coefficient is graphic systems were used to ensure that the labeled used to indicate the distribution of the labeled corn compound contains only the desired species. One pound between a mixture of a hydrophilic and a percent NH4OH in methanol, 0.9% NaCl solution, hydrophobic solvent. Octanol was used as the hy or 20% ethyl acetate in benzene, were used as sol drophobic solvent and 0.03 M phosphate buffer, vent systems for silica-gel thin-layer chromatography. pH 7.4, was the hydrophiic. One milliliter of each @ The R@values of each labeled compound in these solvent was pipetted into a test tube and then 3 solvent systems are shown (Table 2) . The radio of the labeled compound was pipetted into the mix chemical purity of all compounds was >97% imme ture.