relatively low energy of its emitted photon and from itspoor dosimetric properties, MPIAS based on @9@chaverecently been developed and proposed for clinical use(6,7). The first such @“FcMPIA was @‘@Tc-sestamibi,introduced in the late 1980s and now widely used (8).Sestamibi is retained in the myocardium for a long periodof time; this property, combined with the moderately energetic gamma emission of@ makes feasible SPEC!',which has been demonstrated to be more effective thanplanar imaging in clinical applications (9—11).However,liver accumulation of sestamibi can interfere with the correct evaluation of heart images, and also imposes a timedelay between injection and acquisition. More recently

@“@Tc-teboroxime,an MPIA characterized by veiy rapidwashout from the myocardium has been proposed (12,13).With this agent, planar imaging is possible only within afew minutes after injection, and tomographic images arepossible only with multiple-headed gamma camera systems. Again, liver accumulationof this agent is very highand interferes with heart images, particularly in planarviews. Tetrofosmin is a newer @“TcMPIA which exhibitsmore rapidhepatobiiary clearance, and in turn allows foran earlieracquisitiontime (14,15). Tetrofosmin also undergoes myocardial washout, although at a much slower ratethan is observed for teboroxime.

We have been developing a new class of @“@TcMPIASthat is designed to clear rapidly and extensively from theliver. This new class of @TcMPIAS is based upon acationic @9'c(IH)center which has been configured sothat it cannot suffer in vivo reductionto a neutral @‘@TC(II)form which has been shown to wash out of the heart(16,17).This resistance to in vivo reduction means thatthese agents can be designed to be retained in the myocardium for long periods of time, similar to the myocardialretentionobservedforsestamibi.The prototypicalmemberof this class has been designated @9'c-Q3,and in bothanimal and human studies this prototype has shown goodclinical potential (18—20).Most importantly, @‘@Tc-Q3cxhibits rapid and extensive clearance from the liver, andgood myocardial images can be obtained at rest within 15min after injection (21). We now report on an improved

Technetium(III)-99m-O1 2, trans-(1 ,2-bis(dihydro-2,2,5,5-tetrameth@1- 3(2H)furanone- 4 - methy1eneimino)ethane)b@(ths(3-methoxy-1-propyl)-phosphine)technetium(IIl)-99m,is a nonreduable complex of Tc(III)wh@h is herein evaluated as a myocardial perhi@onima@ngagent Mthode: The @Od@thbU@Onanddosimetryof @°“@Tc-Q12wereassessedin 10 normalvolunteers,while fts p@entialdin@aIuse was eValUatedin 70 patients. Results: Safetyparameters measured up to 24 hr posth_on demonstrateno dinicalty significantdrug-relatedadversereactions. Technelium(III)-99m-012exhibitsgood heart uptake(2.2%Injecteddoseat 1 hr postinjectionunderrestingconditions)and no detectable myocard@washout or redistributionupto 5 hr posbnjec@on.The t@OdiStdbUtIOnis characte&ed byveryrapidhepatobiliarydearancewt*h allowseffectivemyocard@imagingat timesas shortas 15 mmpostinjection.Bloodandplasma clearances and myocardialuptake are rapkl,whilelunguptake is minimal.The heart-to-lungand heart-to-liverratiosarehigher at stress than at rest, independentof the time elapsedbetween injectionand image acquisition,and independent ofwhether the @entis fasted or fed after tracer adminlatration.Apreliminarycorrelationshowsthat 46/47 pa@entaw@ianglographicallydemonstratedCAD also have perfusiondefectsdemonstrated by °@ro-Q12.Conclusions: On the basla ofthestudies reported herein, @Tc-O12appears to be a promisingmyocard@perfusionimagrngagent

Key Words: myocardium; technetium-99m-012; myocardial-on

J NuciMed1994;35:1571-1580

he presence andextent ofmyocardial perfusionimpairment is currently assessed by scintigraphyusing appropriate myocardial perfusion imaging agents (MPIAs) (1—4).Thallium-201 is the principle MPIA, and it has been inwidespread clinical use for over two decades (5). In orderto overcome the limitationsof @°‘Tlwhich result from the

ReceivedNov.18,1993;revisionaxeptedMay5, 1994.Forcorrespondenceorreprintscor*@Ferrua@loFazio,MD,Dipailmentoc@

MedicineNucleare,I@ltutoScientifi@H.S.Raffaele,ViaOlgettina,60,20132Milano,Italy.

I 571Technebum-99m-012 Human B@distñbu@on•Rossetti et al.

Human Biodistribution, Dosimetry and ClinicalUse of Technetium(III)-99m-Q12Claudio Rossetti, Giovanna Vanoli, Giovanni Paganeffi, Marek Kwiatkowski, Felicia Zito, Fabio Colombo,Chiara Bonino, Assunta Carpinelli, Rosangela Casati, Karen Deutsch, Mary Marmion, Steven R. Woulfe,Fabio Lunghi, Edward Deutsch and Ferruccio Fazio

Institute H.S. Raffaele, Milano, INB-CNR, University ofMilano, Sorin Biomedica, S.p.A., Sa1u@ia, Ita@yandMallinckrodtMedica4 Inc., St. Louis, M&@sowi

determined by Atlantic Microlab, Inc., (Norcross, GA). TLCanalyses of organic compounds were carried out with Analtechglass-backed250-n silica gel GF plates. TLC analysis for reducedhydrolyzedtechnetiumin @“@Tc-Ql2was carried out on paperstrips using 80% acetone, 20% saline as solvent.

The tetradentate ligand 1,2-bis[dihydro-2,2,5,5-tetramethyl3(2H)-furanone4.methyleneamino]ethane(SWL) was preparedvia the Schiff base condensationof ethylenediaminewith theappropriatedicarbonylcompound.A solutionof dihydro-2,2,5,5-tetramethyl-3(2H)furanone (32.1 g, 226 mmole) in 50 ml of diethylether was added dropwise to a stirredsuspension of sodium hydride (18.1 g 60%, 453 mmole) in 400 ml of ethyl ether containingtwo dropsof ethanoland 36.5ml (453mmole)of ethylformateat0°C.After stirring overnight at room temperature,the reactionmixture was taken up into water, washed with additional ethylether, acidifiedwith 6N HO and extractedwith ethyl ether. Thecombined ether layers were washed with water and brine, driedover magnesium sulfate, decolorized with charcoal, filteredthrough celite and evaporated. The residue was recrystallizedfrom ethyl ether-hexanes to afford 30.4 g (79%)of 4-hydroxymethylene@ihydro-2,2,5,5-tetramethyl-3(2H)furanone as an offwhite solid. Freshly distilled ethylenediamine (1.15 ml, 17.4mmole) was added to a solution of 4-hydroxymethylene-dihydro2,2,5,5-tetramethyl-3(2H)furanone (5.9 g, 34.7 mmole) in 40 ml oftetrahydrofuran.After refluxingthis solutionfor 1hr, the solventswere removed by evaporation. The residue was trituratedwithice-cold ether (50 ml) and the solid was collected by ifitration.Recrystallization from tetrahydrofuran (50 ml) followed by dryingat 70°Cunder high vacuum (1 mm Hg) afforded5.3 g (76%)of1,2-bis[dihydro-2,2,5,5-tetramethyl-3(2H)furanone-4-methyleneaminojethane (SWL) as a white solid ‘H-NMR(300 MHz, 1/1CD3OD/D20+ 1drop1%KOD)8 1.25(s, 12H),1.40(s, 1211),3.55 (s, 4H), 7.17 (s, 2H); ‘3C-NMR(75 MHz, CD3NO2) 8 27.00,32.64, 50.90, 80.02, 82.05, 109.39, 150.17, 204.13; IR (KBr) 1670,1590, 1470, 1440 @fl_1@TIC (silica, EtOAc (5% TEA)) R@= 0.56;FAB mass spectrum m/z = 365 (M + H); Anal. Calculated forC,@H32N2O4C, 65.93;H, 8.79;N, 7.69.FoundC, 65.68;H, 8.90;N, 7.65.

Tris(3-methoxy-1-propyl)phosphine (TMPP) was prepared byslowlyaddinga solutionof 1-chloro-3-methoxypropane(20.0g,184 mmole) in 50 ml of tetrahydrofuran to magnesiummetal(4.48g, 184mmole)inorder to maintaina gentlereflux.Refluxingwas continuedfor 2 hr postadditionto afford a solutionof theGrignard reagent, 3-methoxy-1-propyl magnesium chloride. Thesolution was filtered to remove traces of magnesium metal, thencooled to —78°Cin a dry ice-acetone bath under argon. Dichloroethoxyphosphonite(3.50 ml, 30.7 mmole) in 10 ml of tetrahydrofuran was added dropwise to the Grignard reagent over 1 hr.The solution was warmed to room temperaturegradually, thenheated to reflux for 2 hr. The reaction was quenched by theaddition of deaerated water (20 ml). The tetrahydrofuran solutionwas driedover sodium sulfate, cannula transferredto a dry flaskand distilled (bp = 154 —155°C@ 2.4 mmHg) to afford3.80 g(49%)ofTMPP as a colorlessoil: ‘H-NMR(benzene-d@)S3.29(t,J = 6.5 Hz, 6H), 3.21 (s, 9H), 1.51 —1.64(m, 611),1.28 —1.36(m,6H); ‘3C-NMR(benzene-d6)8 73.3 (J@ = 12.1Hz), 58.2, 25.6 (J@= 13 Hz), 23.0 (J,@ = 12.5 Hz); 31P-NMR (benzene-d@) S — 32.9;

El mass spectrum m/z = 251 (M + 1).

Radlochemical PreparationOne synthesisof @‘9'c-Q12was based on the two-stepproce

dure used in the preparation of@―Tc-Q2and @“Fc-Q3(1820). In

SWL

— +

acac2en

Q12

FiGURE1. StructuresoftheSchiffbaseligandsacec@enandSWLand structureof the Tc(lll)-012 cation.

member of this class, designated @@Fc-Q12:trans-(1,2-bis(dihydro - 2,2,5,5 - tetramethyl - 3(2H)furanone - 4 - methyleneimino)ethane)bis(tris(3- methoxy - 1- propyl)phosphine)technetium(III)-99m (Fig. 1) (1,22—25).

Initial in vitro experiments with @Tc-Q12demonstrated that this agent is chemically veiy stable and that itcan be prepared with high radiochemical purity. Studies inanimal models showed no signs of toxicity (acute or subacute), as well as the expected high and stable myocardialuptake (26). More recent studies in dogs have shown agood correlation between blood flow and @9'c-Q12 myocardial uptake (24).

The aim of the present study was to characterize thebehavior of @Tc-Q12in humans. To this end we firstassessed the biodistribution,dosimetryand safety of

@‘@‘Fc-Q12after intravenous injection at rest or during cxercise in normal volunteers. We then evaluated the clinicaluse of this tracer by assessing organ uptake ratios underfasting or feeding conditions, at different acquisition timesafter injection, both at rest and following exercise. Theresults of these initial human studies are reported herein.

MATERiALS AND METHODS

ChemIstryThe metastable isotope @Tc,as sodium pertechnetate in

aqueous NaCl (0.15 Al) was obtained from a commercial generator (Sorin Biomedica, Italy or DuPont de Nemours, Germany)eluted with saline that was provided by the manufacturer. Protonand ‘3C-NMRspectrawere obtainedon a VarianGemini-300FTNMR spectrometer. Phosphorous-31-NMR spectra were obtainedon a JEOL FX900 spectrometer. Infraredspectrawere recordedon a Perkin-Elmer283B spectrophotometer.Fast atom bombardment (FAB) and electron impact(El) mass spectrawere obtainedon a FinniganTSQ 700 spectrometer while inductively coupledplasma (ICP) mass spectroscopic measurements were made usinga Sciex Elan Model 250 instrument. Elemental analyses were

1572 The Journal of Nuclear Medicine •Vol. 35 •No. 10 •October 1994

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M&uFIGURE 2. Fast atom bombardmentmass spectrum(FAB-MS)of @Tc-O12.

the first step, @“@TCO@(20—200mCi, 0.74—7.4GBq, 1 ml) wasaddedto a vial containing15mg of SWL in 0.1 ml of ethanol. Thesolutionwas deaeratedfor 15minwith a vigorous streamof argon;15 @gof Sna2 (in degassed ethanol) and 0.03 ml of 1 M NaOHwere then addedto this solutionofSWL and @“Tc-pertechnetate.The preparationwas then incubatedfor5 mmat 100°Cto yield the[@Tc―(O)(SWL)]@intermediate. Radiochemical purity was determined by reversed-phase HPLC to be >95% (PRP-1 column:150 x 4.1 mm, 10 @;45%acetonitrile/O.1M NH4OAc, 2.0 mi/mm,tr = 3.0 mm).

In the second step, 0.1 ml of a TMPP . Ha solution (1 gTMPP . Ha in 10 ml ethanol) was added to the[@‘Tc―(O)(SWL)j'preparation and the solution heated for 15min at 100°Cto yield the desired [@Tc― (SWL)(TMPP)2J@(@Tc-Q12) complex. Separation of the radiolabeledcomplexfromreagentswas performedby dilutingthe preparationto 20mlwithwater, loadingit onto a prewetC18Sep-Pakandwashingtheloaded Sep-Pak with water (20 ml) and ethanolwater (80:20, 4ml); the product was then eluted in ca. 60%yield with 2 ml of80:20 ethanol:saline. Quality control effected by reverse-phase}IPLC (same conditions as above, ç= 3.5 —4.0 mm) showed>95% radiochemical purity. This eluate was diluted with normalsaline to generate an ethanol concentration <5%, and the dilutedeluate was then passed through a sterile 0.2-u Flow Pore D-26filterto provide a preparationsuitablefor humanuse. The apyrogenicity of this preparation was evaluated by standard LymulusAmebociteLysate testingon decayedsamples.

The Sep-Pak purifiedproduct is obtained in 30%-50%overallyield (based on @“Tc-pertechnetate).The final radiopharmaceutm@iformulation(5%ethanolin saline) is stable forat least 8 hr;noloss in radiochemical purity is observed over this time period.Inductively coupled plasma mass spectroscopy (ICP-MS) experiments were performed on decayed radiopharmaceutical preparations to ensure that the Sep-Pak purification removed all detectable TMPP. In all cases, the purifiedpreparationscontainedlessphosphorus than can be detected by this technique (ca. 1 ppmtotal phosphorus). Phosphorus contents were calculated from acalibrationcurve wherein the 31Pintensity signal from a series ofstandard solutions was plotted as a function of known 31Pconcentration. In addition, for each experiment, the solvent matrix ofthe samplewas also subject to ICP-MSanalysis so that any signal

due to the solvent matrixcould be distinguishedfrom the samplesignal.

The majority of patient studies were conducted with @“Tc012 preparedfroma one-step “instantkit―suitableforhumanuse(24).Thechemistryof thisone-stepformulationwillbe describedin a subsequentpublication.All @Tc-Q12prepared in this manncr was of >95% radiochemicalpurity, as assessed by reversephase HPLC (same conditions as above).

Chemical Characterization of Technetlum-99m-Q12The 012 complex was chemically characterizedby fast atom

bombardmentmass spectroscopy (FAB-MS) after adding“earner― @Tcto the @“Tcpreparation.In this experiment, the @‘Tc012 complex was preparedwith generator eluate that had beenspiked with 2.5 mg of Na@M'cO4.The “carrier-added―preparation was purifiedby reverse-phase HPLC, and the collected 012preparationanalyzed by positive ion FAB-mass spectrometry.The FAB-MS spectrum shows a parent peak at m/z = 962 amuwhich is consistent with the 012 cation, [Tc(SWL)(TMPP),J(calculated average mass is 962.1 amu). Fragment ions comesponding to losses of the phosphine ligands and phosphine Rgroups are also observed. The predominant peak in the FAB massspectrumof 012 occurs at m/z = 712 amu, which corresponds tothe loss of one TMPP ligand. The FAR mass spectrum of 012 isshown in Figure 2.

ProtocolsAllprotocolsinvolvinghumanswere approvedby the Institute

H. S. Raffaele Ethics Commiftee. Each subject or volunteersignedan informedconsent statement; the attendingcardiologistagreed to the pmotocoland consent form, according to the EthicCommittee guidelines.

The clinical safety of @“Fc-Q12was evaluated in normalvolunteers by monitoring vital signs, as well as blood and urinechemistries, immediately before and 24 hr after tracer administration; the details of these evaluations are providedbelow. Also, inallhumanstudies an attendingphysicianmonitoredthe subjectforpossible adverse reactions, and the presence or absence of suchadversereactionswas recorded.

I 573Technebum-99m-012 Human BiodiSbibUtiOn•Rosseth at al.

Kinetics, Bkxflstrlbutlon and DosimetryTen normalvolunteers, nine males andone female (age22 to 42

yr) were studied to assess dosimetry by acquiringradiobiodistribution data. Seven subjects were studied at rest and three werestudied by injecting the tracer under exercise conditions. Eachvolunteerwas enrolledaftera generalclinicalevaluationincludingblood pressure, heart rate, blood chemistry (hemoglobin, hematocrit, complete blood count, sodium, potassium, urea, calcium,creatinine,chloride,SGOT,SGTP)and urine chemistry;the female volunteer also had a test to establish that she was notpregnant at the time of the study. Blood and urine chemistry,blood pressure and heart rate were also monitored up to 24 hrpostinjection. Data were acquiredwith a 40-cm circulargammacamera system (7500 Orbiter-Siemens; equipped with a generalpurpose, parallel-hole collimator) using a 64 x 64 matrix size andZoom 1.

Before tracer administration, either at rest or under exercise,whole-body transmission images were recorded to determine thefraction of attenuated activity for each organ. In this procedure ahomogeneous flood source (a circular flood phantom; diameter 50cm, thickness 1 cm) filled with ca. 10 mCi of @Fcaqueoussolution was used as an external source. First, 4,000 Kcountswere acquiredfrom the flood source and the elapsed time registered. Using this time, four sequentialplanarviews (head, chest,upper abdomen and lower abdomen)were then acquiredby positioningthevolunteerequidistantbetween the flood phantomandthe gamma camera. In order to ensure the same body positionduring the biodistribution imaging, each view was registeredthroughthe use of reference markers.

For rest studies, a volunteerwho had fasted for over 12hrwaspositionedsupineon the gammacamerabed. A plasticcatheter(20gauge)was insertedin the left antecubitalvein for intravenousadministration of the tracer and a catheter of the same size wasinserted in the contralateralvein for collection of blood samples.

After the transmissionscans, approximately12mCiof @Tc012, in a volume of 1—5ml for the purifiedpreparationand < 1 mlfor the kit formulation, were injected as a bolus through theindwelling catheter. Radiochemical puritywas assessed by HPLCanalysis before the injection, and the syringe residual was similarly analyzed; in all cases, both analyses showed a radiochemicalpurity of greater than 95%.A dynamicacquisitionof the upperbody (chest andupperabdomen)was startedsimultaneouslywiththe injection and was continued for 60 mm (0.5 sec/frame for atotal of 1 mm and then 1 mis/framefor 59 mm). Planar views(LAO 45°,anterior, LAO 70°)were subsequently acquired. Approximately 1 hr after injection, subjects were repositioned withthe use of the reference markersnoted above (fromthe transmission study), and whole-body anterior and posterior projectionswere recorded in a preset time mode of 2 min. This same biodistributionacquisitionprotocolwas repeatedat 3 hr and5 hr postinjection.

For the stress studies, after completion of the transmissionacquisitions, catheters were inserted as for the rest studies. Thesubjects were then exercised on a treadmill (Marquette Case 12)followingthe Bruce protocol and a twelve-leadECG was constantly recorded. The tracer was injected when the normal volunteersapproachedmaximumfatigue;theywere thenencouragedtocontinue the exercise for 1 mm longer in order to allow for cornplete tracercirculation.After the end of the exercise protocol, thesubjectswere monitoredby ECG duringthe recoveryperiod;thedurationof recovery, heartrate and systolic blood pressurewerealso assessed. The subjects were then positioned supine on the

gamma camera bed. The rest of the protocol was the same asdescribed above for the rest studies.

Blood and Urine ClearancesTo determinethe blood clearanceprofileof @“Tc-Q12,venous

samples were drawn from the arm contralateral to the injectionsite. Duringthe restingstudies, the firstsamplewas drawnimmediately after the bolus injection, and about 20 samples were takenwithin the first 10 mis. During the stress studies, sampling wasstarted5 mis aftertracerinjection. For both rest and stress studies, subsequent samples were collected at 30 mm, 1 hr, 1.5 hr,3 hr, 5 hr and 24 hr after injection. A portion (0.5 ml) of eachwhole-bloodsamplewas assayedfor @‘“Tccontent; resultswerecorrected for physical decay of the isotope, normalized for thecirculating blood volume and expressed as percentage of injecteddose/mi. The rest of each whole-blood sample was centrifuged toseparate plasma from RBCs; 0.5 ml of each plasma sample wasthen assayed as above to estimate the plasma clearance whichreflects the extravascular clearance.

The urine clearance profflewas obtained by collecting urineover the following periods:0—1,1—3,3—5and 5—24hr after injection; after volume measurements, 0.5 ml from each sample wasassayed for @“Tccontent; these data were corrected for physicaldecay of the isotope, normalized to the volume of urine collectedandthe resultingvalues expressed as percentageof injecteddose.

Patient StudlesSeventy patients with suspected or proven coronary artery

disease were studied with @“@Tc-Q12in order to evaluate theoptimal time to wait between injection and imaging, as well as theinfluence of fasting conditions. All patients were previously studied with echocardiography,rest and exercise ECO. A detailedclinical history was collected from every subject, paying particular attentionto the risk factors for coronary diseases; blood andurine chemistries were also evaluated. Subjects with evidence ofliveror kidneydisfunctionwere excluded.Allpatientsdiscontinued cardioactive medications and maintainedfasting conditionsfor the 12 hr preceding tracer injection. Blood pressure valueswere keptundercontrolwith diureticsand/orACE inhibitors.Thesubjects were then randomly classified into four different groupsaccording to protocols based on varying elapsed times betweeninjection and image acquisition. These elapsed times were chosenin light of.the organ and blood clearances observed in normalvolunteers; for practical reasons, 60 mm postinjectionwas thelongest elapsed time studied. The groupswere designated as follows: Group A had acquisition at 15 mm postinjection, Group Bhadacquisitionat30 mmpostinjection,GroupC hadacquisitionat45 mm postinjection, and Group D had acquisition at 60 minpostinjection. Within groups B, C and D, ten subjects were studied under fasting conditions and ten subjects were studied afterconsuming a fatty meal subsequent to tracer administration. ForGroupA, the short elapsed time between injection and the firstimaging (15 mm postinjection) made it impractical for patients toeat before the first imagingprocedure, and thus this group contains only the ten fasted patients.

Every subject was studied under the same conditions at restand 48 hr later after treadmill exercise. During exercise, threeECG leads were continuously monitored and, at each minuteduring exercise and recovery, a twelve-leadECG was also recorded. The endpointswere definedas anginaof a least moderateseverity, 2 mm ST segment depression, hypotension, frequentventricular premature beats or ventricular tachycardia, excessivefatigue, shortness of breath or weakness. The exercise ECOS

1574 TheJournalofNuclearMediane•Vol.35•No.10•October1994

were interpretedas positive if therewas >1 mm ST depressionofthe flator downslopingvariety, or ifthere was a 1.5-mmupslopingST segment depression. The exercise ECGs were interpretedasnegative if there were no changes during exercise provided thatthe patient achieved >85% of maximalpredicted heart rate. Tomographic studies over 360°(64 x 64 matrix, 64 views beginningfrom anteroposterior, 30 sec/view) were performed using the samegamma camera system specified above in the biodistribution studies. The tomographicstudies were started at the indicated timeafter intervenousinjectionof 20—25mCiof @‘Tc-Q12.

DataAnalysis: KineticsTime-activity curves were constructed for the period 10 to

60 mm postinjectionby positioningregionsof interest(ROIs)overthe entire liver, gallbladder,lungsandleftventricle ofthe heartasvisualized in the anteroposterior dynamic images. The averagecountsper pixelof the relativeROlswere correctedfordecayandnormalized to the initial myocardial count density at 5 mm postinjection. Organ activities were then plotted versus time after injection.

DataAnalysis: BIOdIStrIbUtIOnand DosimetryOrganuptakeswere calculatedfromthe whole-bodybiodistri

bution studies using the simplifiedmethod describedby Myres Ctal. (27) within the following formalism:

A = F'I(Na X N@x exp (@l))@VA@,

where A is the organ activity expressed as percentage of theinjected dose, F' is the cross-calibration factor (pCi/counts/mm)obtainedby positioninga sourceof knownactivityat 10cm fromthe gammacameraandcollecting counts for 2 min, Na andN@arethe counts obtainedfromthe emission scan in the anteroposteriorand posteroanteriorviews respectively, exp(pi) is the body attenuation correction factor measured directly from transmissionscans, and A0 is the injected dose. The parameter exp(.d) isdirectlyobtained fromthe ratio NF/NT where N'Frepresentsthecountswithinthe ROIsdrawn aroundthe organon the transmission image and NF represents the correspondingROl countsobtained on the flood source image. For emissionscans, ROIswere drawn around each organ and then counts and numberofpixels within the ROI were recorded. When organs overlapped,the organactivitywas determinedby normalizingto fullorgansizethe counts/pixel values obtained from nonoverlappedsites. Thismethodwas used for liver in the presence of gallbladderand rightkidney, and for left kidney in the presence of activity within theintestine. For kidneys, twice the activity in the left kidney wasused. Values obtainedby applicationof formula1were correctedfor the physical decay of @Tcin order to determinethe percentof injected dose (%ID)versus time for different organs (heart,lungs liver, gallbladder, kidneys and bladder). The bladder %IDwas determined by summing the %ID estimated from imagingdata (via Eq. 1) with the %IDexcreted in the urine.

The mean absorbed dose D(r@)in a targetorgan rkwas calculated applyingthe standardMIRD formulation:

D(r@J@@ i = @: A@S(rk@—rh),

where Ah is the source organ accumulatedactivity, S(rk @—rh)isthe mean dose to target organ ri,, and n is the numberof sourceorgans. In this study, bone marrow, heart, lungs, liver, galibladder, kidneys and bladderwere identified as source organs. Absorbed dose normalized to injected dose and expressed as mRad/mCi was assessed for the following target organs: bone marrow;

kidneys, bladder wall and testes or ovaries. Source organ accumulated activity was directly calculated as the integral of theestimatedbestfitfunctionsappliedto the%IDversustimecurve.Bone marrowaccumulatedactivitywas estimatedas 25%of theblood accumulated activity (28). Bladder accumulated activitywas integratedover the interval0 to 5 hrassumingnovoided urineuntil 5 hr postinjection. All absorbed dose calculations includedthe physical decay of @9'c.

DataAnalysis: Patient Organ Uptake RatiosFrom the anteroposteriorview (i.e., the first of the 64 steps

taken during the tomographic studies), average counts/pixel values were calculated for liver, lungs and heart; for the normalheart, the ROl was at least 16pixels away from the pathologicallyaffected area. The resulting values were corrected for backgroundactivity by subtracting the average counts/pixelvalue obtained byplacing an ROl next to the organ being considered. Heart-to-liverandheart-to-lungsratioswere thencalculated.The values of theseratios obtainedunder differentconditions(rest/stress,fasting/fedand time postinjection)for Groups B, C and D were then statistically analyzed. To determine if the varying conditions generatedstatistically significant differences, an ANOVA was applied withtwo grouping factors (fasting/fed and time) and one within factor(rest/stress);this is also known as a SPUT-PLOT design (29).Student's t-testwas used to compareGroupA (whichwas studied

Eq 1 at 15minpostinjectiononly underfastingconditions) to the groupstudied at 30 mm postinjectionunderthe same conditions.

Image QualityFor the 70 patient studies, rest/stress tomograpic images oh

tamed between 15 miii and 60 mm postinjection as describedabove, were analyzed by three independentobservers experienced in nuclear cardiology. Observers were asked to assesswhether or not the images had adequatediagnosticvalue.

RESULTS

ChemistryThe radiochemical purity of @Tc-Q12,as assessed by

HPLC, is always above 95%, both before injection andimmediately after injection (as measured in the syringeresidual). All radioactive impurities elute before @“@‘Fc-Q12in the reversed-phase HPLC system, and thus appear to bemore hydrophilic than @‘@Tc-Q12.Moreover, these radioactive impurities appear to be rapidly excreted through therenal system and do not add to the heart or liver uptakes.The Sep-Pak purification procedure provides 30%-50%overall yield of a radiopharmaceutical with low phosphoruscontent (< 1 ppm by ICP-MS) in a sterile and apyrogenicform suitable for intravenous administration to humans.

Blood and urine chemistries were normal in the 10 volunteers for 24 hr after injection of @9'c-Q12. None of the

Eq 2 70 patients studied reported any subjective adverse reactions within 48 hr of tracer administration. Three normalvolunteers and eight patients reported a transient metallic

taste immediately after injection of @9'c-Q12.

KineticsFor the resting studies, time-activity curves generated

from ROIs over the entire heart, lungs, liver and galiblad

1575Technetium-99m-012 Human Biodisthbution •Rossetti at al.

I hrpostinjection3 hrpostinjection5 hrpostinjectionHeart2.20±0.401.87±0.501.72±0.70Lungs3.98

±0.423.07 ±0.483.10 ±0.50Liver6.30±2.984.60 ±2.513.82 ±I.80Gallbladder7.31±3.108.01 ±3.396.80 ±2.50Bladder14.59±4.118.6±3.8020.7±5.06Kidney3.8

±1.022.7 ±0.822.4 ±0.35Muscle(16 pixels)0.17 ±0.040.092 ±0.0030.085 ±0.005

3.1% in the gallbladder.The %ID in the heart is 22% ±0.4% while the two lungs accumulate 3.9% ±0.4% ID. Alimited ROl (16 pixel) over the quadricipitis, taken as background, shows 0.17% ±0.04% of ID (Table 1).

From 1 to 3 to 5 hr postinjection, the heart activityremains substantially stable; the uptakes measured at thesetimes, 2.2% ±0.4%, 1.9% ±0.5% and 1.7% ±0.7%respectively, are not statistically different (p@ 0.05, pairedt-test with 12 degrees of freedom). Figure 4 shows thewhole-body biodistribution images obtained for one volunteemat 1, 3 and 5 hr postinjection.

After injection of @“@‘Fc-Q12under stress conditions, thebiodistribution pattern is quite similar to that observed atrest; the average heart uptake is higher under stress conditions, although the difference observed in these studies isnot statistically significant(Table 2).

The results of the dosimetriccalculationsbased on thesedata are given in Table 3.

Blood and Urine ClearancesIn both the rest and stress exercise studies in normal

volunteers, clearance of activity from the blood can adequately be described by a dual exponential function. Atrest, the maximum observed whole-blood pool activity is40% ID at about 2 mm postinjection, this then decreases to10% ID within 10 miii postinjection and to <5% ID at 20min postinjection. The blood pool activity remainsnegligible from 20 mm postinjection to the end of the Study(24 hrpostinjection). In the exercise studies, the first blood samplc was collected at 5 mm postinjection. The blood-poolactivity had already decreased to the same level observedin the rest studies at approximately 10 min postinjection(i.e., to 10%).

The plasmaclearances at rest and stress follow the sameprofiles observed for the respective blood clearances.However, the peak activity observed in plasma is lowerthan that observed in whole blood (20%versus 40% ID).

The amount of activity excreted in the urine at 1 hrpostinjectionis somewhat higherin the restingstudies thanin the studies conducted under stress (Fig. 5): 14.6% ±4.1% versus 10.2% ±2.4%. Similarly, at 24 hr postinjection the excreted amountsare 26%±4%at rest and 23%±5% at stress.

II

TIME P.L (

FIGURE3. Tune-ar@tMtyctavesforvariousorgans.Technetium99m-012Injectedat restInnormalvolunteers(meanof n = 5; errorbars Indicate±1s.d.).Thedata are nOrmalizedto cardiacactMtyat5 mm postinjection.

der from 10 to 60 mm postinjection show the highest concentration of activity in the gallbladder. The activity in the

gallbladder peaks at 35 min postinjection (Fig. 3) and thendecreases, although the activity in the gallbladder alwaysremains higher than the activity in the other organs. Theinitial liver activity is 160% that of the heart; at 60 minpostinjection the liver activity drops 44% and becomesonly 90% that of the heart. The heart activity generated by

@Tc-Q12remains substantially constant at all times after5 mm postinjection, with no evidence for washout or redistribution. The lungs exhibit intravascular activity in thefirst 2 min postinjection; after this intravascular activitywashes out, the lung activity remains stable and relativelylow. Once the contributions from activity in the gallbladderand major biliaiy ducts are subtracted, the liver activity isseen to decline steadily from 10 miii postinjection, the firsttime at which meaningful measurements could be made.

BlodlstrlbutlonandDosimetryIn normalvolunteers, when @‘@Tc-Q12is injected at rest

at 1 hr postinjection, the highest observed @‘9'caccumulations (expressed as percent of injected dose after application of decay and attenuation correction) are 14.6% ±

4.1% in the bladder, 6.3% ±3.0% in the liver and 7.3% ±

TABLE ITechnetium-99m-012 BiOdiStribUtiOnat Rest (%ID, mean ±s.d., n =7)

1576 The Journalof NudearMedicine•Vol.35 •No. 10 •October1994

1 1wpo1Ir@on3 tEpoArØ@on5 hrpoetinjectionHeart2.39±0.42.11±0.51.87±0.23Lungs4.1

±0.64.0 ±0.433.8 ±0.43L@Iver5.33±0.34.23±0.73.2±0.5GallbI&lder7.56±0.3211.2±4.59.64±3.5Bladder10.2±2@415.15±1.920.59±2.5Kidney5.6±0.93.2±1.012.1±0.46Muscle

(16 pIxels)0.13 ±0.047O.O@ ±0.010.09 ±0.026

O@ne Doss@

Soumeorgans:head, QaOb@dder,Over,lungs, @dney,red marrowandb@dder.

TAII.I 2TechnetIum-9@mQ12Blodlstrlbutlonat S@sss(%1D,mean ±s.d., n —3)

PetleM Organ U@c. RatiosAverage heart-to-lung and heart-to-liver ratios in pa

tients are given in Table 4. An ANOVA shows that theadministration of a fatty meal did not significantly improvethe heart-to-liverratio.However,significantly(p S 0.05)better heart-to-liver ratios were observed at stress relativetothoseobservedatrest;thispresumablyresultsfromthehigher blood-flow rates encountered during exercise. Asexpected, lengthening the time elapsed between tracer ad.ministration and image acquisition significantly (p S 0.05)improves the heart-to-liver ratio since longer elapsed timesallow for more extensive clearance of the tracer throughthehepatobiiaiysystem.

The heart-to-lungratiois positiveat 15 miiipostinjection, allowing facile visualization ofthe myocardial uptake.

—The three independentobserversconsideredthe rest/

stressimagesinall70patientstudiestobeofgoodquality,providing adequate diagnostic value independent of acqul.sition time (even for the 15 mm postinjection studies) andfasting conditions.

Thechemistryof the “0series―of @@1Tccomplexesisnow well established (16,1$,19). The octahedral coordina

t@n sphere of these cationic, nonreducible Tc(III) corn@N1$com@d of a tetradentate Schiff base ligand

(IA) and two monodentate phosphine ligands which aresituated trans to one another. Both @Tc-Q3and @FcQ12containthesamephosphineligand(TMPP),buttheydiffer in the identity of the IA Schiff base. Figure 1 showsthe structures of the LA ligands used to prepare @Fc-Q3(I@4—acac@en)and @‘@‘Fc-Q12(IA = SWL) (2430). Thecyclic ether moieties of SWL make this LAligand easier tolabelwith99•'Tc.ThegreaterrigidityofSWLalsoappearsto impart greater chemical Stability to @Fc-Q12(relativeto 99@Tc.Q3),and this may account for the more extensivehspatobiliaiy clearance of @Tc-Q12.

Given the well-documented chemistiy of the “0-seflea,―the chemical identity of @‘Fc-Q12is easily established by MB mass spectroscopy conducted in the catKmic@ (Fig.2).Theobservedparentpeakat962amuis consistent with the proposed formulation and cationiccharge ofQl2. In addition, the predominant peak observedat 712 smu corresponds to loss of one TMPP ligand fromthe Q12 complex; this fragmentation pattern is characteristic @rthe“Qseries―ofmixedligandTc(III)complexes,and is consistent with the known trans labilizing effect of

— _8mc two-steplabelingprocedureusedtoprepare@Tc.Q12involves initial stannous reduction of @‘9'CO

to generate the Tc(V) intermediate [@Fc―(O)(SWL)]@,and then subsequent application of TMPP in a substitutkioh@eductkin reactkm to form the productE99@ITcW(SWLX@1@MPP)a]+,@9c-Q12.Thisprocedurehasbeen desi@ to generate an agent which contains >95%99mTc-Q12sad <5% of radiolabeled Impurities, all of whichexhibit rsvsrs.d.@e }IPLC retention times less than thatof991'rc.012.ThismeansthattheradiOlabeledimpuritiesareall mete hydrophilic than is @Fc-Q1Zand thus these ün_iss@ not accumulate in the liver. Rather, these unpurit@ @psarto be rapidly cleared through the renal systemsad do not dsgade the heart to nontarget organ ratios. Theone.stsp kltprepsration also provides >95% radiochemicallypure 9@Tc-Q12with the same ensemble of hydrophilic im

A simpleC18Sep-Pakpurificationwas developedtoremove the excess ligands (SWL, TMPP) from the finalformulation. The efficiency ofthis purification was checkedby determining the amount of total phosphorus, which is a

TABLE 3Technetlum-99m-012:EstimatedRadlaton Absoitsd Doss

(rest, 5 hr postinjectlon)

I.8251

280.037.621.613.65.93.4

97.13.2

HeertwalGaNb@derwaN

LW&

Ova@esTestes

Redmarrow

Technetium-99m-012 Human Biod@rIbsAIon•Rosssthat 1577

30mm45mm60mm15mm30 mmpostirijection45 mmpostmnjection60mmpostinjectionpostinjectionpostinjectionwfth

fatty mealpostinjectionwfth fatty mealpostmnjectionwfth fattymealtasting(n= 10)fasting(n= 10)(n = 10)fasting (n= 10)(n = 10)fastIng (n= 10)(n =10)Heart-to-lungRest1.33±0.251.54±0.161.59±0.161.81

±0.201.75±0.251.57±0.461.90±0.36StressI.46±0.201 .70 ±0.191 .59 ±0.121 .84 ±0.121 .83 ±0.221 .73 ±0.292.08 ±0.16Heart-to-lungRest0.63±0.050.60±0.290.61

±0.160.94±0.151.01±0.371.40±0.461.50±0.35Stress0.67±0.110.78±0.460.69±0.201.07±0.141.43±0.311.65±0.331.55±0.35

TABLE 3Technetium-99m-012 Organ Ratios in Patients (AverageCounts, n = 70 mean ±s.d.)

measure of TMPP concentration, in the purified preparation. Inductively coupled plasma mass spectroscopy wasused to measure these very low concentrations of phosphorus. This very sensitive technique shows that theamount of phosphorus in the final formulation is always <1ppm, which is the level of trace phosphate in the normalsaline used to preparethe final formulation.Thus, the C18Sep-Pak procedure removes more than 99.9% of the TMPPused in the original reaction.

The C18 Sep-Pak purification procedure provides a30%—50%overall yield of @“Fc-Q12in a matrix of normalsaline which contains no more than 5% ethanol. Afterfiltration, this solution is apyrogenic and sterile. Thus, thedescribed procedure generates a radiopharmaceutical ofhigh radiochemical purity (>95%) and high chemical purity(total phosphorus content < 1 ppm) in a form suitable forintravenous administration to humans. However, becauseof the necessity of diluting the ethanol content to less than5%,thevolumeofinjectateiscorrespondinglylarger(1to5 ml) than normal, and thus this Sep-Pak purified formulation is not useful for first-pass radioangiography whichcurrently requires < 1 ml injected volume.

Human StudiesThe studies reportedhereinestablish thatthe injectionof@Tc-Q12into ten normal volunteers generates no subjec

tive or objective adverse reactions under the describedexperimental conditions. No substantive subjective reactions were reported by any of the 70 patients during the48 hr after tracer administration.

Technetium-99m-Q12 exhibits rapid whole-blood andplasma clearances as well as rapid heart uptake, similar towhat is observed for other @‘@Tcbased MPIAS(8@13,14).The dosimetry results presented in Table 3 indicatethatthecritical nontarget organ for @“@Tc-Q12is the gallbladder; atrest, an injected dose of 20 mCi @“@Tc-Q12would deliverabout 6 rad to the wall of the gallbladder. The doses dclivered to the sex organs and bone marrowat rest are in therange of those delivered by the other @‘@TcMPIAS(8,13,14). During exercise, the dose delivered to most organs is markedly reduced because of the generally morerapid clearance of the agent. Moreover, @“Tc-Q12undergoes renal, as well as hepatobiiary clearance; this rapidinitial renal clearance, comparable to that observed for

tetrofosmin (14), reduces the overall dose absorbed by thepatient. There is very little lung or thyroid uptake of @“Tc012, althoughthe salivaryglandsexhibit significantuptake(Fig. 4).

Technetium-99m-Q12 generates favorable heart/liver ratios at short times postinjection. A comparison of the dataobtained herein for @“@Tc-Q12to literature data for @‘@Tcsestamibi and @@Fc-tetrofosmin,shows that at 60 minpostinjection, at rest under fasting conditions, the heart-toliver ratio is 0.6 ±0.1 for sestamibi (8), 1.2 ±0.8 fortetrofosmin(14) and 1.4 ±0.5 for 012. The peak of activityin the gallbladderis reached at 36 min postinjectionfor 012(Fig. 4) versus >60 min postinjection for sestamibi (8)(both values at rest under fasting conditions), further indicating the lower hepatobiliary activity of 012 relative tosestamibi at early times postinjection. This faster hepatobiiaiy clearance of @‘@‘Fc-Q12from the principle nontargetorgan system translates directly into earlier image acquisition times.

The myocardial uptake of @Tc-Q12is significantlyhigher than that reported for @‘@Tc-tetrofosmin(14):2.2% ±0.4% versus 1.2% ±0.4% (% injected dose at rest,1 hr postinjection). Moreover, the myocardial uptake of

@‘Fc-Q12remains constant with time, whereas @‘@Tctetrofosminwashes out of the heartwith time (14). Thus,

@Tc-Q12combines the relatively high myocardial uptakeand prolonged myocardial retention of @@Fc-sestamibiwith the relatively rapid hepatobiiary clearance of @Tctetrofosmin.

The data in Table 4 show that heart-to-lungand heartto-liver ratios observed for @‘@Tc-Q12are consistentlyhigherat stress than at rest, and that this result is independent of image acquisitiontime and independentof whetherthe patient is fasted or fed aftertraceradministration.Thisresult is compatible with the higher blood flows encountered under exercise conditions, and with previously reported animal studies which demonstrate that the myocardial uptake of@Tc-Q12 is proportional to blood flow (24).

The optimal time for imagingwith a MPIA results froma balance between the need to have good target to nontarget contrast (and most specifically, good heart-to-livercontrast), and the need to have sufficient heart activity(assuming that the heart uptake remains constant through

1578 The Journal of Nudear Medicine•Vol.35 •No. 10 •October 1994

30.

20.

I0@

0.

—0——RESTSTUDIES

—4—-—SflFSS S1IIDIES

o@ 10 15

TIME P.I.(ho.r.)

20 25

FiGURE 4. Mteroposterior whole-body Images at I (A), 3 (B)and5 (C)hrafterinjectionof @Tc-012atrestina normalvoluntear.

the end of the acquisition). For @Tc-Q12,good imagequality is achievable as early as 15 min postinjection(Fig. 6A, 6B) although a longer delay would be recommended for patients with compromised biliary function;between 15 min postinjection and 60 min postinjection, the

time elapsed before imageacquisitiondoes not affect imageinterpretation or diagnosis. With such an early acquisitiontime it may be feasible to develop a one-day rest/stressimaging protocol for @‘@Tc-Q12.

While evaluation of diagnostic accuracy using @‘9'c-012 was not within the scope of this work, the imagequality obtained during our SPECT studies allowed delincation of both rest and stress perfusion defects. A preliminary correlation between the grade of coronary stenosisand the presence of perfusional defects as assessed by

@‘@Tc-Q12was performed for the 47 patients in whom sucha correlation was feasible (31); these included the fivepatients studied at 15 min postinjection. In this preliminarystudy, readingsby three independentobservers established

FiGURE 6. Technetlum-99m-012m@card@ISPECT lm@esobtained15mmpostinjectlonat restandduringexerciseIna patientwithsignificantcoronaryarterydisease.Theperfusionimagesalongthe short (A@and horizontal long (B) axes demonstrate lschemiainvoMngante@ate@segments.

that46/47patientswith angiographicallydemonstratedCADhadperfusionaldefects demonstratedby @Fc-Q12imaging.

Finally, it should be noted that the advent of @9'c-Q12in an “instantkit―formulation(25) would allow for injection of this tracer in a small volume (< 1 ml) suitable forassessment of rightand left ventricularejection fractionbyfirst-pass radionuclide angiography. Further studies areclearly warranted in order to establish the clinical efficacyof this new agent.

SUMMARY

Technetium-99m-Q12 is a radiotracer developed formyocardial perfusion imaging. It shares the same advantages as do the other myocardial perfusion imaging agents(MPIAs) based on @‘Tc;the most important being the141-keV photon, which is optimal for gamma camera imaging, the relatively low dosimetry and the ready availability of the isotope. The in vivo kinetics of @“Tc-Q12werestudied in ten normal volunteers. To assess the potentialclinical use ofthis agent, 70 patients were evaluated. Safetyparametersmeasured in this populationup to 24 hr postin

I

.3

FiGURE 5. Cumulativeuhnatyclearance of @Fc-Q12afterinjectionat rest (meanof n = 5) andduringexercise(meanof n = 3).Errorbarsindicate±1s.d.

1579Technetium-99m-Q12Human Biodistribution•Rossettiat al.

12. Leppo JA, DePucy EG, Johnson LL. A review of cardiac imaging withsestamil,iandteboroxime.JNUCJMed199132:2012—2022.

13.StewartRE,SchwajgerM, HutchinsGD,etaLMyocardialclearancekineticsof technetium-99m-S030217:a markerof regionalmyocardialbloodflow.JNUC1Me41990@,31:1183-1190.

14. Highley B, Smith FW, Smith I, Ct aL Iechnetiuin-99m-1,2-bis[bis(2-ethyoxyethyl)pboapkino@-ethane:humanbiodistribution,dosimetryandsafetyof a newmyocardialperfusionimagingagent.INuciMed 1993;34:30-38.

15.Kelly3D,ForsterAM,HigleyB,etaLTechnetiom-99m-tetrofosminasanew radiopharmaceutical for myocardial perfusion imaging. I Nuci Med1993;34:222-227.

16.JurissonSS,DanceyK, McParthnM, laskerPA,DeutschE. Synthesis,characterizationandelectrochemicalpropertiesof technetiumcomplexescontainingboth tetradentateSchiffbaseandmonodentatetertiaryphosphine ligands:single-crystalstructure of#N,N'-ethylenebis-(acetylacetoneiminato))bis(triphenylphosphine)- techaetium(Ill)hexafluorophosphate. Jnorg Chem 1984;23:4743—4749.

17. VanderheydenJ-L, Heeg MJ, DeutschE. Comparisonofthe chemical andbiologicalpro@es ofbw&c-fFc(DMPE)@Q@andnwsr-[Re(DMPE)@a,J@,whereDMPE= 1,2-bis(dimethylphosphino)ethane.Single-crystalstructuralanalysisofbwtc4Re(DMPE@i@JPF6.Iwxg Client198524:1666-1673.

18.DeutschE,VanderheydenJ-L,GerundiniP,CtaLDevelopmentofnonreducibletechnetium-99m(llI)cations as myocardialperfusionimagingagents:initial experiencein humans.JNuclMed 1987;28:1870-1880.

19.Lal,sonK, MesasC, KWiatkOWSkiM, CtaL Developmentof newmyocardialperfusionimagingagentsIn: NicoliniM, Bandoli0, MazriU,Eds. Technetiumand ,*eniwn in chemistryand nuckar medicine3.Verona: Cortina International; 1990;365-.368.

20. RossettiC, BestI, Paganelli0, Ctal. A new,nonreducil,teIc-99m(ffl)myocardialperfusiontracer:humanbiodistributionandinitialclinicalexperience[Ahstractj.JNuclMed 199030:834.

21.GersonMC,LukesJ,DeutschE,etaLComparisonoftechnetium-99m-Q3and thallium-201for detection ofcoronaiy artery disease in humans.JNuclMed 199435:580-586.

22. ColomboF, MarmionM, DeutschK, Ctal.A new@Ic radiotracernamed0-12:amyocardialperfusionagentwithoptimizedimagingproperties[Abstractj.JNucl Bid Med199236:114.

23. MarmionM, DeutschK, Grummon0, et al. Thedevelopmentof nonreducil,ie @Fcmyocardialperfusionagentswithoptimizedimagingcharacteristics[Abstractj.JMid BIOIMed199236:157.

24.GersonM@MillardRW,RoszellNJ,etaLKineticpropertiesof―@c-Q12in caninemyocardium.Caniiology1994;89:1291.

25. DeRoschMA, BrOdack3W,GrummonGD,etal. Kit developmentfor theIc-99m myocardial imaging agent IechneCard'@ [Abstract]. I Nud Med199233:850.

26.WoulfeSR,DunnIJ, MarmionME, MacDonaldJR.RogicMM, DeutschE. Thesynthesisof analogousN202,N2OSandN2S2Schiffbaseugandaforuseinradiopharmaceuticalimagingagents[Abstract].JNuclMed1991;32:1101.

27. MyresMJ,LavenderJP,DeOlIVeiraJB,MaseraA.Asimplifiedmethodofquantifyingorganuptakeusingagammacamera.BrJRadiol 198154:1062-.1067.

28. SnyderWS, Ford MR.,WarnerGC, et aL “5―absorbeddoseper unitcumulatedactivity for selectedradionuclidesand organs.MIRDpWnpIS1etno. 11. New York: Society of Nuclear Medicine, 1975.

29. SnodecorGW.Statirticdmethodr.Ames,1A IowaStateUniversityPress;1967.

30. MarmionM, KWIatkOWSkIM, NoscoD, CtaLChemistryofa newclassof99m-Ic myocardial perfusion agents with optimized imasin@properties[Abstractl.INuciMed 1991;32:925.

31.RossettiC,VanoliG,CarpinelliA,etal.Identificationofmyocardialperfusion defects using @9@c012 [Abstractl. EUrINUCIMed 1993;20:860.

1580

jection demonstrated no clinically significant, drug-relatedadverse reactions. Technetium-99m-Q12 exhibits goodheart uptake (2.2% ID at 1 hr postinjection under restingconditions) with no significantmyocardialwashout or redistribution up to 5 hr postinjection. The tracer clears rapidly from blood and from the liver via the hepatobiliarysystem. This rapid hepatobiliary clearance minimizes themajordisadvantageencounteredwith @‘Fc-sestamibiand

@Tc-teboroximeand allows effective myocardial imagingat times as short as 15 mm postinjection.

On the basis of the studies reported herein, @“@Tc-Q12appears to be a promising MPIA. Further studies will berequired in order to establish the clinical efficacy of thisagent.

ACKNOWLEDGMENTS

The authorsthankDr. L Gallifor her assistancewith thestatistical analysis and Dr. F. Bonetti for his support and cornrnents. This work was supported by a National Research Councilrant.

REFERENCES

1. RossettiC, Pagancili0, Vanoli0, et al. BIOdIStrI1MItIOSin humansandprdliminaiyclinicalevaluationofa newtracerwithoptimizedpropertiesformyocardialperfusionimaging:[@FcJQ12[E@@tendedAbstract].JNuclBio1Med 199236(Suppl):29-31.

2. Rossetti C, Vanoli G, PaganeHi0, Ct al. Biodistribution and preliininaiyclinicalevaluationofakitfonnulationforthenewmyocardialimagingagent99@@rc012[Abstractl.EuriNuciMed199219@.5%.

3. RossettiC, Vanoli 0, Paganelli0, et aL Biodistnbution in humansofa newtracerformyocardialperfusionimaging: @Tc-Q12[Abstractj.JNucIBioIMed 199236:194.

4. ShaWGB,GoRI, MaclntyreWJ.Radiopharmaceuticalsforcardiovascularimaging.NuclMedBioI 199219:1-20.

5. StraussHW, Pitt B. Thallium-@1as a myocardialimagingagent SeminNuciMed 1977;7:3—7.

6. BelierGA,WatsonDD.Physiologicalbasisofmyocardialperfusionimas@with the tethnetium-99m agents.SeminNUC1Me41991;21:173—181.

7. Botvinick EH. The promise of tCChnCtiUm-99m-baSedperfusion imagingagents.Cfrr@uIation199082:22fl-2280.

8. Wackers FiTh, Berman DS, Maddahi J, et al. Iechnetium-99m hexakis2-methoxyisobutyl isonitrile: human biodistribution, dosimetry, safety andprehininaiycompatiscato thallium-201formyocardialperfusionimaging.JNuciMed 198930:301—311.

9. KahnJK, McGhiCI, AkersMS,Ctal. Quantitativerotationaltomographywith @‘11and “Ic-methoxy-isthutyl-isonitrile: a direct comparison innormalindividualsandpatientswith ceronaiyarterydisease.Circulation1989;79:1282-1293.

10.KiatH, MaddahiJ,RoyLI, CtaLComparisonoftechnetiuni-99mmethoxyisobuylisonitrileandthathum-201for evaluationof coronazyarterydiseaseby planarandtomographicmethods.AmHeaiii 1989;117:1-11.

11. IskandrianAS,HeoJ,KongB,LyonsE,MarschS.Useof technetium-99misonitrile(RP-30A)inassessingleftventricularperfusionandfunctionatrestand duringexercise in coronaryartery diseaseand comparisonwith coronaryarteriographyandexercisethallium-201SPECIlmaging.AmlCwdiol1989;64:270—fl5.

The Journal of Nudear Medicine•Vol.35 •No. 10 •October 1994