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Synthesis and Renal Excretion of Technetium 99M-Labeled Organic Cations

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Synthesis and Renal Excretion of Technetium 99M-Labeled Organic Cations Synthesis and Renal Excretion of Technetium 99m-Labeled Organic Cations Kevin M. Herzog, Edward Deutsch, Karen Deutsch, Edward B. Silberstein, Rangaprasad Sarangarajan and William Cacini CollegeofPharmacyand BiomedicalChemistryResearchCenter,DepartmentofChemistry, Universityof Cincinnati, Cincinnati, Ohio ERPF determination. The unfavorable radiation proper Organic cations are excreted more efficiently than organic ties of ‘@‘I(fi, 364 keY “@‘)are a distinct disadvantage anions in uremia suggesting superiority as renal imaging clinically, particularly in patients with obstructed urine agents. In this study, three @TC-1abeIedcationic cydam flow. Although a hippurate labeled with 1231(no beta complexesweresynthesizedandtheirrenalclearancequan emission, 159 keV, gamma emission) offers improved tified in rats. The complexes are deared at a rate of about characteristics, its cost is much higher. An agent labeled 2.5—3times that of inulin and about 60% that of p-aminohip with @Tc(no beta emission, 140 keY, gamma emission) purate. Inhibitionof @“Tc-cydamexcretion by quinine mdi would be more desirable and the anionic @mT@@MAG3 cates transport by the organic cation process. Comparative in vivoimagingexperiments demonstrated that in normal rats agent has been developed to this end (1-3). However, a @Fc-cyciamreached peak renal activity I .8 ±0.6 mm after second problem often little appreciated, is the general injection, a value intermediate between that for [131l]OlH decline in renal secretory efficiency of organic anions as (1.0 ±0) and @“Tc-MAG3(2.8 ±0.6). In rats injected with uremia develops (4,5). This arises from the progressive the acute nephrotoxin cisplatin, the times to peak were length buildup in plasma of organic anions formed as a conse ened with the relative order being @Tc-cydam> @Tc quence ofthe uremic state (6,7). The accumulated anions MAG3 > [131110IH.The results demonstrate that cationic can competitively inhibit renal tubular transport (reducing complexes may be useful for renal imaging diagnostic appli clearance rate) of anionic substrates like the hippurates @ cations. leading to artifactually low estimates of ERPF and tubular J NucI Med 1992; 33:2190-2195 function in uremic patients. Because uremic plasma fac tors do not interfere with tubular excretion of positively charged organic molecules, an attractive alternative is to use efficiently cleared organic cations as ERPF agents (5). ccurate assessment of renal functional status is a The purpose of this study was to determine the feasibility necessary part of the development of an appropriate ther ofestimating renal function through the assessment of the apy for the kidney patient. Among the oldest and most renal clearances of novel @“Tc-labeledorganic cations. widely employed techniques for renal function evaluation Some of these results have been previously presented in are the renal clearance methods, the most fundamental of abstract form (8). which is directed toward determination of glomerular fil tration rate (GFR) as indicated by inulin or creatinine MATERIALS AND METhODS clearance. In addition, the clearance of compounds that undergo extensive tubular secretion in addition to filtra Radlolabeling tion allow evaluation of functional tubular mass and esti All organicligandswere purchasedfrom Strem chemicaland mation of effective renal plasma flow (ERPF). The stand used without further purification. @TcO@was obtained from a ard for ERPF determination is p-aminohippurate (PAH) commercial @Mofl@mTcgenerator upon elution with normal which is about 90% extracted from renal arterial plasma saline.Radiolabelingwas carried out as follows: @mTc@l,4,8,ll@ in a single pass through the renal parenchyma. An ‘@‘Itetraazacyclotetradecane(cyclam)and 99mTcl,4,8,ll-tetraazaun labeled structural analog, ortho-iodohippurate ([‘31I]OIH;decane (@“Tc-TAU):0.060 mmol cyclamor 1,4,8,1l-TAU was added to 2.0 ml of [99m]TcO@solution. This solution was then Hippuran), had been the clinical standard for the past 25 degassed with argon for 5 mm, after which 0.150 ml of6 x l0@ yr. Although it is rapidly and efficiently cleared by the M stannoustartratein 0.01M HC1wasadded.The solutionwas kidney, [13s1]OIHis not an ideal radiopharmaceutical for then quickly capped and allowed to stand at room temperature for 45 mm. Technetium-99m-l,4,8,ll-tetramethyl-l,4,8,l 1-te traazacyclotetradecane (@‘Tc-tetramethylcyclam, TMC): TMC ReCeiVedNov. 29, 1991 ; revision accepted Jul. 10, 1992. Forreprintscontact:WilliamCacini,PhD.,CollegeofPharmacy.Lkilversity (0.06 mmol)wasadded to 2.0 ml [@mTcJO;solutionwhichwas of Cincinnati,Ck@clnnati,OH45267-0004. degassed with argon for 5 mm, afterwhich 0.150 mlof6 x l0@ 2190 The Journal of Nuclear Medicine •Vol. 33 •No. 12 •December 1992 @ @II@N@H M stannous tartrate in 0.01 M HC1was added. The solution was versity of Cincinnati Institutional Animal Care and Use Com then cappedas quicklyas possibleand heatedfor 2 hr at 120°C. mittee. Radiochemical purity was routinely assessed by the paper To furthercharacterizethe renal handlingof@mTc@cyclam,its chromatographymethod of Colombettiet al. (9). The accuracy renal handlingwas comparedto that of @“Tc-MAG3and [‘@‘I] ofthis method was confirmed by high pressure liquid chromato OIHin bothnormaland renallyimpairedSprague-Dawleyrats graphicanalysisof samplesas describedby Volkert et al. (10). of 250—400g BW. Renal impairment was induced by a single 5 Technetium-99m-pertechnetatewas the only detectable impurity. mg/kg i.p. injection of the nephrotoxin cisplatin. Normal rats were injected with saline vehicle. Degree of impairment was Electrophoresis indicated by blood urea nitrogen (BUN) level four days after A 15mm X 1.0m strip of Whatman chromatographypaper cisplatin injection (14). BUN was determined colorimetrically wassoakedin a Tris-barbital-sodiumelectrophoresisbuffer(Gel with a commercially available kit (Sigma procedure 640). On the man Sciences,Inc., product No. 51104)composedof 32.1%w/ fourth day after injection of cisplatin or saline, the rats were w Tris [2-amino-2-(hydroxymethyl)-1,3-propanediol, l37% w/w anesthetized with pentobarbital (40 mg/kg i.p.). Technetium barbital,and 54.2%w/w sodiumbarbital.The ends ofthe paper 99m-cyclam(200 @iCi),@mTc@MAG3(200 sCi)or [‘311]OIH(50 werethen connectedto the electrodesof the chamber(Gelman). @zCi)was injectedinto a lateraltail vein and the animal imaged Thecenterofthe stripwasspottedwitha smallamount ofsample for 30—45mm with a 37-photomultipliertube gamma camera solution, current was applied and the strip was allowed to develop with computer interface. Areas of interest were drawn around for 2 hr. The strip was serially cut into eight equal sections, each kidney, liver and heart from a posterior viewand time-activity of whichwas assayedin an LKB Wallac 1282gamma counter. curvesproduced. These procedures have been reviewed and approved by the Uni versityof CincinnatiRadiationSafetyCommittee. Statistics Statistical significance (p < 0.05) was assessed using Student's RenalClearanceExperiments t-test Male Sprague-Dawleyrats (250—400g BW) were used. All animals were housed in temperature and light cycle-controlled RESULTS quarters and were given free access to food and water. Anesthesia was induced with chloral hydrate (350 mg/kg i.p.), and the rat Synthesis and Protein Binding of Radiolabeled then placed on a heating pad. The urinary bladder, ajugular vein Organic Cations (for drug infusions) and a carotid artery (for blood sampling) Radiolabeling of the polyamine ligands in very high were cannulated with polyethylene tubing and a slow (50 @d/min) yields (>98%) without further purification was readily infusion ofchloral hydrate (25 mg/kg BW/min.) in 5% mannitol achieved (15—17). The cyclam and TMC complexation in normal saline was initiated to induce adequate urine flow and reactions were conducted at room temperature while that maintainanesthesia. for TAU required elevated temperature. TLC and HPLC Aftercollectionofblank urine and blood samples,the chloral results consistently indicated the lack of measurable hydrate/mannitol solution was stopped and a priming injection TcO@ and Tc02 impurities in 99mTc4abeled cyclam deriv ofinulin (20 mg in I ml) was administered. A sustaining infusion (50 @il/min)containing the labeled cation (50—100sCi total), atives. Electrophoresis results for these same compounds inulin (20mg/mI),PAH(5 mg/mI),and chioralhydrate(25 mg/ showed a single strong cationic peak and no anionic peaks. kg BW/ml) in 5% mannitol/saline was begun. Preliminarycx The chemical structures of the complexes are assigned on periments showed that 60 mm of such an infusion was adequate the basis of literature characterizations (12—14)and are to allow attainment of steady state plasma concentrations of inulin, PAH and all labeledcations. Three consecutive 12-mm urinecollectionswereobtained;a midpointarterialbloodsample wasdrawnforeachcollection.The volumeofeach bloodsample wasreplacedwithan equalvolumeofsaline.The renalclearances r#— \II/ for inulin, PAH and the labeledcation during each of the three @Tc periods were calculated using the conventional formula U x Nil j v/P whereU = urineconcentration,V = urinevolume(ml/min) H /j,@JN H and P = plasmaconcentration.Plasmaconcentrationswerecor rected for protein binding which was determined by ultrafiltration usingthe AmiconCentrifreesystem. +1 Concentrations of inulin (11) and PAH (12) in plasma and H urine samples were determined colorimetrically. Radioactivity
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