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BASICSCIENCES RADIOCHEMISTRY AND RADIOPHARMACEU11CALS [125I]IodobenzoylDerivativesof Acebutololas PotentialMyocardial Imaging Agents Robert N. Hanson, Michael A. Davis, and B. Leonard Holmat. HarvardMedical School and Northeastern University, Boston, Massachusetts Threenew Iodobenzoylderivativesof acebutolol,a cardioselectivebeta antago nist, were synthesized and labeled with iodine-125. The blodistrlbutlons of these labeled compoundswere determinedin normal rats and compared with that of thallium-201. Fifteen minutesfolloWingi.v. administration,the Iodlne-125-Iabeled meta- and para-iodobenzoylacebutololspossessedthe greatest ventricularup take and the highest ventricle-to-bloodand ventricle-to-lungratIos of the new agents.The correspondingvaluesfor thallium-201 were 2.5 to 3.0 tImes as high. The data in this studysuggestthat more lipophillcderivativesof the cardioselec tlve beta antagonists will possess increased uptake and cardloselectivity, and thereby will compare more favorably with thalllum-201 as myocardlal Imaging agents. J NucI Med 21: 846—851, 1980 The development of gamma-emitting radiopharma (4) andacebutolol(5), respectively,tendstoenhancethe ceuticals that could provide more accurate imaging of cardioselectivity of the drug. regional myocardial perfusion than thallium-20l would Since benzoylated analogs of practolol and acebutolol be useful in the early detection of coronary disease and are cardioselective (4,5), it seemed reasonable to expect assessment of therapy. Our approach to the development that the iodobenzoyl derivatives would also show this of such agents utilizes radiolabeled derivatives of drugs, pharmacologic selectivity. Derivatives of the beta an such as the beta-adrenergic antagonists, that exert a tagonists were synthesized in which the iodine-containing selective pharmacologic effect upon the heart. moiety is distal to the oxyisopropylaminopropanol The beta antagonists have the ability to decrease heart pharmacophore. These compounds should be more re rate, myocardial contractility, and myocardial metabo sistant to deiodination in vivo than the o-iodophenolic lism. As defined by Lands et al. (I ), these are beta-i beta antagonists previously prepared (6—8).To test the responses, and structure-activity relationship studies theory that derivatives of cardioselective antagonists (2,3) have demonstrated that selective inhibition of these would have better myocardial uptake and selectivity than beta- I responses can be achieved by the selective intro derivatives of noncardioselective antagonists, a series of duction of functional groups onto the parent 3-phe three 1-125-labeled beta antagonists was made (9). noxy- I-isopropylaminopropan-2-ol structure. For ex Meta-[' 25I]-iodobenzoyl practolol (m-IBP) and -ace ample, the placement of hydrogen-bonding moieties in butolol (m-IBA) were prepared as the cardioselective the para position of the phenoxy group, such as the derivatives, and 4'-['251]iodopropranolol (IP) was pre acetamido and butyramido groups present in practolol pared as a nonselective beta antagonist. The biodistri bution data indicated that m-IBP and m-IBA had sig nificantly better myocardial uptake and target-to-non Received March 30, 1979; revision accepted March 10, 1980. target ratios (T/NT) than the noncardioselective IP. For reprints contact: Robert N. Hanson, PhD, Dept. of Medicinal These data supported the decision to examine derivatives Chemistry and Pharmacology, Collegeof Pharmacy and Allied Health of the cardioselective beta-adrenergic antagonists as Professions, 360 Huntington Ave., Boston, MA 021 15. possible cardiovascular imaging agents. 846 THE JOURNAL OF NUCLEAR MEDICINE BASIC SCiENCES RADIOCHEMJSTRY AND RADIOPHARMACEUTICALS Pharmacokinetic studies with radiolabeled f3-adren chloride and rneta-iodobenzoic acid were obtained ergic antagonists have demonstrated that i.v. adminis commercially.* Sodium [125l]iodide in 0.08 N sodium trationofthedrugresultsina rapiddistributionphase hydroxide, and [201T1Jthallous chloride, were carrier followed by a slower elimination process that isconsistent free. The acebutolol hydrochloride was used without with a two-compartment body model. At doses less than puriuication.t 2 mg/kg there is little distribution to a tissue compart Chemical and radiochemical purity analyses. The ment with a slower equilibration constant (10,1!). This chemical and radiochemical purity of the products were is reflected in the biodistributional studies conducted by determined by thin layer chromatography using the other investigators (8,12—15),and by ourselves (9), following analytical systems: (a) Silica gel plates@(250 where the target- (heart) to-nontarget ratios for the ra @Lwith fluorescent indicator) and chloroform : methanol diolabeled /3-adrenergic antagonists remain relatively (85 : I 5); (b) Silica gel plates* (250 @zwith fluorescent constant between 5 mm and 2 hr after administration. indicator) and butanol:acctic acid:water (4: 1:2); and Therefore, for the purpose of comparing the uptake and (c) KC18 plates (200 /2 with fluorescent indicator) and selectivity of radiopharmaceuticals, we chose a single methanol : water :acetic acid (60 : 40 : 1). The unlabeled time interval that falls in the early elimination phase for starting materials were applied adjacent to the radiola the rat. beled products, the chromatograms were developed, and Because the myocardial uptake and heart-to-lung 0.5-cm segments of the adsorbent were removed and ratio for meta-['251]iodobenzoyl acebutolol were corn counted in a Nal(Tl ) well counter. In all three systems, parable to those of the corresponding practolol deriva 95-99% of the radioactivity was associated with a single tive, and because of the side effects reported in the component having an R1 value identical to that of the clinical use ofpractolol (16), the acebutolol derivatives unlabeled material. No other organic products could be were selected for primary consideration. A comparison visualized by ultraviolet light. The nonlabeled corn of the organ distribution with that of Tl-20l and the pounds were characterized by their infrared, nuclear elucidation of the effect of positional isomerism in the magnetic resonance, and mass spectra. Elemental iodobenzoyl prosthetic group upon iodine exchange, analyses (C, H, N, I) were performed commercially and biodistribution in normal rats at I 5 mm, and myocardial agreed to within ±0.4%of the theoretical values. selectivity were thought to be reasonable objectives. Chemicalsynthesisandexchange.Theortho-,meta-, These data would provide a basis for determining the and para-iodobcnzoyl derivatives of accbutolol (IBA) relative merits of the labeled beta antagonists vis-a-vis were prepared using the previously published procedure a currently used myocardial perfusion imaging agent. (Fig. I) (9). The radioisotopic exchange with the ortho-iodo isomer was achieved by autoclaving an am poule containing a buffered solution of the compound MATERIALS AND METHODS and sodium [‘251]iodide(5-9 mCi) at I30°Cfor 90 mm Chemical reagents. Ortho- and para-iodobenzoyl (17). Adjustment of the cooled solution to pH 10, fol 3 CH3 CR5 OH 2NHCI CH3 1H2 0 O@('@N'@CH3 CR5 ortho, meta,poro pH 5.5 HN@(I@ FIG. 1. Preparation of isomeric iodoben ortho, meto, poro zoyl derivatives of acebutolol. 355O@'/e overall yield Volume 21, Number 9 847 HANSON, DAVIS,AND HOLMAN CH3 [email protected] ortho8O90% 1300 meto,pora 1-4% .@ I No'251melt mete poro7OBO% l80 @ Na 1251 5 @9mCi ( 2 3 -4.1 nmol) FiG. 2. Radioisotopic labeling of isomeric @ IBA 0.5 - 1.0mg ( I -2jnnol) iodobenzoylderivatives of acebutolol. lowed by extraction with chloroform, gave the product, or Sprague—Dawleyoutbred rats. Fifteen minutes after which was virtually free of inorganic [‘25ljiodide. In administration the animals were killed by ether as corporation proceeded with an 89% yield, 99% purity, phyxiation and the organs of interest excised. Blood and specific activity of 3.2 Ci/millimole. The same samples were obtained from a vein in the thoracic cavity. procedure with the meta and para isomers gave only a The tissue samples were weighed, counted in a NaI(T1) 1—4%incorporation, and therefore exchange was well scintillation counter, and the percent of the dose per achieved by using the melt method (18) to give a 75—80% gram of tissue (% ID/g) and/or per organ (% ID/organ) incorporation and specific activities of 0.38 and I .9 determined. Ci/millimole, respectively (Fig. 2). RESULTS AND DISCUSSION Biodistribution. A solution of iodine- 125-labeled product or [201T1Jthallous chloride (0.1 ml, 10 zCi per The chemical syntheses for the three iodobenzoyl rat) was injected intravenously into 150-250 g Wistar acebutolol isomers resulted in yields adequate to provide TABLE1. TISSUECONCENTRATIONSOF RADIOPHARMACEUT1CALS15 MIN AFTERINTRAVENOUS ADMIN1STRATIONTO RATS TI (n = 6) o@lBAt(n = 3) m-IBA (n 6) p-IBA (n 5) Liver 0.72t 1.57 1.84 1.70 (0.49—0.93) (1.39—1.88) (1.54—2.04) (1.40—2.11) Spleen 0.86 0.60 0.65 0.91 (0.67—1.12) (0.49—0.70) (0.57—0.82) (0.67—1.16) Lungs 2.03 1.07 1.76 1.34 (1.79—2.70) (0.96—1.16) (1.45—2.63) (1.08—2.16) Kidneys 5.83 0.95 3.42 3.30 (4.23—7.49) (0.92—0.99) (2.57—4.03) (2.63—3.96) Pelt 0.19 0.19 0.15 0.19 (0.16—0.22) (0.06—0.26) (0.11—0.22) (0.16—0.23) Muscle 0.28 0.21 0.15 0.17 (0.24—0.33) (0.18—0.24) (0.12—0.17) (0.15—0.22) Bones 0.49 0.19 0.17 0.19 (0.36—0.71) (0.12—0.24) (0.14—0.21) (0.15—0.29) Blood 0.07 0.24 0.07 0.17 (0.05—0.08) (0.20—0.28) (0.05—0.09) (0.09—0.23) Thyroid 10.91 5.65 4.25 5.88 (7.83—16.32) (5.13—6.20) (2.39—6.29) (5.58—6.44) Atria 2.16 0.42 0.77 0.80 (1.45—3.46) (0.36—0.51) (0.59—1.02) (0.67—0.87) Ventricles (normal) 3.09 0.43 1.06 0.93 (1.90—4.11) (0.36—0.55) (0.74—1.19) (0.75—1.07) .

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