Other research groups have explored the potential ofalternative 99mTc ligand combinations. These have beenlargely based on Tc(I), and include isonitnles (10), arenes(11,12) and phosphites (13). All the Tc(I) complexes basedon phosphorus donor ligands (13) exhibited similar behavior in man to the Tc(I) complex [@mTc(DMPE)3]+ IDMPE= 1,2 bis(dimethylphosphino)ethane@. They clear from the

blood very slowly and show high liver uptake and slowwashout from the heart. The isonitrile complex[99mTc(TBIN)]+(where TBIN represents t-butylisonitrile),however, was shown to be unique amongst the Tc(I)complexes in that it cleared rapidly out of the blood.Subsequent development ofthe isonitrile concept gave riseto a new cation, @mTc@hexakis@methoxyisobutylisonitrile(MIBI) which is being applied for myocardial perfusionimaging (14).

We have explored the possibility that the limitationsencountered with 99mTccomplexes of simple alkyl or aryldiphosphines might be overcome by the introduction ofhetero-atomic functions to modify nontarget uptakes(15, 16). We report here the pre-clinical development ofone of these complexes [99mTc(tetrofosmin)2O2]+, wheretetrofosmin= l,2-bis[bis(2-ethoxyethyl)phosphino]ethane.Note: this ligand has been referred to in earlier publicationsby the code ‘P53'.

MATERIALS AND METhODS

LigandThe structure of the ligand tetrofosmin is shown in Figure 1.

Details of the synthesis and characterization of the ligand havealready been reported (1 7).

Preparationof @“TcComplexesFor the purpose of determining tissue distribution in small

animals and for subsequent gamma camera imaging in pigs andearly volunteer studies in man, the [@mTc(tetrofosmin)@O2)J@

A new cationic complex, [@mTc(tetrofosmin)2O2]@,wheretetrofosmin is the ether functionalized diphosphine ligand 1,2-bis[bis(2-ethoxyethyl)phosphinojethane, has been synthesizedandevaluatedforpotentialuseinmyocardialperfusionimaging. The structure of the complex has been determinedby x-ray crystallography of the @Tcanalog. In comparisonwith previously reported @“Tccomplexes of alkyl-phosphines,the tetrofosminspeciesshowssubstantiallyincreasedclearancefrom nontargettissue,especiallybloodandliver.Afreeze-dried kit formulation has been developed. The kit provides a product of high radiochemical purity up to 8 hr afterreconstitution at room temperature.

J NucIMed 1993,34:222—227

n the past decade, substantial effort has been directedto the identification of 99mTccations for myocardial perfusion imaging. To a significant extent, the body of research has been driven by interest in exploiting the superior

imaging characteristics of 99mTcover 201T1(1).Although the first documented case of a @mTccation

(2) was based on a nitrogen macrocycle, the pioneeringstudies in the potential application of @mTccations toheart imaging were largely based on phosphine complexes(3—7)and, to a lesserextent, on arsines(3,4). These earlyattempts to obtain clinically useful myocardial imagingagents were frustrated by the inadequacy ofanimal modelsto predict behavior oflipophilic cations in man (8,9). ForTc(V) diphosphine cations, the question of interspeciesvariability had not arisen; no Tc(V) cation with promisingheart uptake in animal models had been identified (8).

ReCeived May 11, 1992; revision accepted Sept. 26, 1992.For correspondence or reprints contact: J.D. Kelly, Pharmaceuticals

Research and Development, Amersham International plc, White Lion Road,Amersham, Buckinghamshire HP7 9LL, 1k@itedKingdom.

222 The Journal of Nuclear Medicine•Vol.34 •No. 2 •February 1993

Technetium-99m-Tetrofosmin as a NewRadiopharmaceutical for MyocardialPerfusion ImagingJ. Duncan Kelly, Alan M. Forster, Brian Higley, Cohn M. Archer, Fong S. Booker, Lewis R. Canning,K. Wai Chiu, Barbara Edwards, Harjit K. Gill, Mary McPartlin, Katharine R. Nagle, Ian A. Latham,Roger D. Pickett, Anthony E. Storey and Peter M. Webbon

Pharmaceuticals Research and Development, Amersham Internationalpk, Buckinghamshire, United Kingdom; School ofChemistry, University ofNorth London, London, United Kingdom; Department ofMedicine, Royal Veterinary College,North Mymms, Hatfield, Hertfordshire, United Kingdom

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FIGURE 1. Structureofthephosphineligandtetrofosmin:1,2-bis[bis-(2-ethoxyethyl)phosphino]ethane.

complex was prepared as a liquid formulation. A freeze-driedformulationwassubsequentlydeveloped.

Allmanipulationswerecarriedout usingstandardproceduresto ensure sterile, pyrogen-freepreparations. Unless otherwisestated, oxygen was excluded from vials and solutions by nitrogenfilling and purging, respectively.

LiquidFormulation [@)mTc(tetrofosmin)2O@J@.The tetrofosminligand (2 @d)was added to 10 ml saline containing 0.33 GBq99m@(j4- in a 10-mI vial sealed with a neoprene septum. Thepreparation was left to stand at ambient temperature for a periodof not lessthan 2 hr and not more than 3 hr. The radiochemicalpurity was checked by HPLC or ITLC to ensure that @mTcO4_was less than 5% before filtration through a 0.2-@smAcrodisc(Gelman)filterinto a septum-sealedvial.The filterwasretainedfor microbiological testing. The filtered preparation was stablefor up to 3 hr.

Lyophilized Formulation [@mTc(:etrofosmin)2Of (M@view,code PPNJOJJ). The complex was prepared by the addition of 1GBq @Tcas sodium pertechnetate in 4—8ml of saline to alyophilized kit formulation in a lO-ml vial. Each vial contained0.23 mg tetrofosmin, 30 @gstannous chloride dihydrate, 0.32 mgdisodium sulphosalicylate and 1.0 mg sodium gluconate, pHadjusted before lyophilization and sealed under an atmosphereof nitrogen.The vial was shakento dissolvethe contentsandallowedto standatambienttemperaturefor 15mmbeforeassay.

f99mTc(DMpE)]+ Samples of [@Tc(DMPE)3]@ were prepared by literature methods (7).

Preparation of “Tc-TetrofosmlnThe long-lived @Tc-tefrofosminanalogwaspreparedby mix

ing @TcO4(0.09mmol)and tetrofosmin(0.45 mmol)in aqueousethanol (6 ml). The mixture waspurifiedby ion exchangechromatography(SephadexSPC-25eluted with 0.15 M Li@CF3SO3)and a pink precipitate was isolated after mixing with saturatedaqueous NH.[Cr(SCN)4(NH3)@].The yield based on radioactivitywas65%andproductwascharacterizedbymicroanalysis(found%C 39.75, %H 7.46%, %N 6.98; calculated forC@HuCrN6OioP4S4Tc%C 39.56, %H 7.14, %N 6.92). Diffraction quality crystals were obtained from cold ethanol.

Analytical MethodsHigh-Performance Liquid Chromatography (HPLC). HPLC

was used to analyze the radiochemical purity of @Tcand @Tcpreparations. The HPLC system consisted of a Hamilton PRP-lcolumn (150 x 4.1 mm) eluted at a flow rate of2.0 ml/min witha 17-mmlinear gradient from 100% 10 mM phosphate buffer(pH 7.5) to 100%tetrahydrofuran.The radioactivitydetector(beta or gamma)was fitted to a rate meter and microcomputerprogrammed for peak integration.

Thin-LayerChromatography.Measurementofthe radiochemical purity ofMyoviewm preparations was made using an ITLC/SO strip eluted with a 35:65 acetone:dichloromethane solventmixture. Pertechnetate moves at the solvent front, and reducedhydrolyzedtechnetiumand any hydrophiliccomplexesare retamed at the origin. Radiochemical purity was measured as thepercentage activity between R10.3 and 0.8.

GelElectrophoresis.Electrophoresiswasusedto determinethecharge on cationic complexes. Studies were performed using astationary phase ofagarose A gel in 50 mMphosphate buffer, pH7.0. Movement was determined relative to an anionic marker,bromophthalein blue (movement = - 10.0).

X-ray Crystallography. X-ray diffraction data were collectedon a Philips PW 1100 diffractometer in the 0 range 3—25°usingMo-K,, radiation from a weakly diffracting crystal measuring0.48 x 0.12 x 0.10 mm3. Crystal data are as follows:C@H@CrN6OioP@.S4Tc,M = 1214.22, Triclinic, space groupFl(No. 2), a = 12.635(3) A, b = 12.939(3) A, c = 12.021(3) A, a= l06.95(3)°, fi = 1 13.1 l(3)°, @y 60.83(3)°, U 1566.38 A3,

F(000) = 639, @(Mo-K,)= 0.64 mm', Z = 1, D@= 1.287 g cm3;finalR 0.102(R@0.0932)for 1409data with I/a(I) > 2.5

Biodistributlon of “TcComplex In RatsWistar male and female rats (Interfauna UK, Huntingdon,

Cambs) weighing between 150 and 200 g were injected with 0.1ml of the test material via the lateral tail vein under light etheranesthesia Animals were killed by exsanguination under etheranesthesia and the percentage ofinjected dose in the excreta andorgans and tissues was determined by dissection. Samples ofblood, muscle, bone, skin and fat were collected in pre-weighedcontainers. Other organs were removed intact, as listed in Tables2, 3 and 4. All organs and tissues were assayed for radioactivityin a twin crystal automatic gamma counter. The accumulatedactivity in each organ or tissue was calculated as a percentage ofthe total dose.

Forthe liquidpreparations,threemale ratswerekilledat 2mm and 60 mm postinjection. For the freeze-dried formulation,six rats were killed at 2 mm, 60 mm and 24 hr postinjection. The

RCPofall preparationswascheckedpriorto injection,andatalltimes the purity ofthe @mTccomplex was not less than 90%.

Blodistributlon of WTc Complex in Guinea PigsDunkin-Hartley albino male guinea pigs (Charles River UK,

Margate,Kent)weighingbetween230 and 265 g wereinjectedwith 0.1 ml of the test material via a front paw vein under localanesthesia(xylocaine 1%).Six guinea pigs were injected with eachpreparation, with three each being killed at 2 mm and 60 mmpostinjection. Animals were killed by overdose ofether anesthesiafollowedbyexsanguination.

The percentageof injecteddose in the excretaand organsandtissues was determined by dissection and assay for radioactivityin an automatic gamma counter.

Gamma Camera Imaging In MinipigsGamma camera imaging studies were performed in male mm

ipigs(RoyalVeterinaryCollege,Hatfield,Hertfordshire)weighingbetween 15 and 25 kg. Animals were sedated with azaperone (80mg i.m. followed by 160 mg i.p.) and were then anesthetizedusingmetomidate(75 mg i.v. initially).

EtO@@ /\ OEtP PEtO @.@OEt

Technetium-99m-Tetrofosmin •Kelly et al. 223

0.1 2.5hr Uver and GI 38.7 ±4.1 44.6 ±2.13 4@.U ±b.b ni .@

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One milliliter of the liquid [@mTc(tetrofosmin)2O2]+preparation containing approximately 5 mCi (185 MBq) @mTcwasadministered via a Portex cannula into the jugular vein. Theanesthetized minipig was placed supine on the face ofa large fieldof view gamma camera and images were acquired using theanterior view at 2, 15, 30, 60, 90 mm and 3, 5 and 24 hrpostinjection.

ToxicologyAcute single-dose intravenous toxicity studies were performed

in rats (six male and six female) using the liquid formulation oftetrofosmin. A dose equivalent to 400 times the human dose wasadministered, and animals were observed for 7 days followingadministration.

For the freeze-dried formulation of tetrofosmin (PPN1O11),acute toxicity over a 14-day period was assessed in rats (five maleand five female) and rabbits (three male and three female) at 0,100 and 1,500 times the maximum single human dose. Repeatdose toxicity was assessed in rats (10 male and 10 female) andrabbits (5 male and 5 female) at 0, 10, 100 and 1,000 times themaximum human dose daily for 14 days.

MutagenicftyThe mutagenic potential oftetrofosmin was evaluated in three

in vitro tests (Ames, mouse lymphoma and human lymphocyte)according to standard procedures and in one in vivo test (mousemicronucleus) modified to encompass two administrations of testarticle within 24 hr as a response to the rapid biological clearanceoftetrofosmin.

RESULTS

ChemistryThe route ofsynthesis of [@mTc(tetrofosmin)2O2]+ using

the liquid fprmulation was directly analogous to themethod already established for the preparation of[99mTc(DMPE)O]+ (8). Gel electrophoresis confirmed

that the species formed was cationic; the 99mTc complexshowed movement towards the cathode of +4.4 unitsrelative to bromophthalein blue (—10 units) as a standardcontrol. It was routinely possible to obtain preparationshaving radiochemical purity (RCP) greater than 90% byboth HPLC and TLC with the liquid or freeze-dried formulations. A typical HPLC trace is shown in Figure 2.The [99mTc(tetrofosmjn)O]+ species has a retention timeof8.3 mm.

Confirmation of the structure of the [99Tc(tetrofosmin)2O2]@ cation has been established by x-ray single

crystal analysis of the @Tcanalog in combination withestablished HPLC procedures to demonstrate equivalenceof @“Tcand @Tcspecies.

A perspective view of the cation is shown in Figure 3.The structure shows the expected linear trans-oxo core,with the four phosphorus atoms of the two bidentatediphosphine ligands forming an exactly planar array. Themain deviation from idealized octahedral geometry arisesfrom the steric requirements of the five-membered ringformed by the diphosphine ligand resulting in P(1)-TcP(2) angles of 8 1.4(2)°.

The rate of formation of the [99mTc(tetrofosmin)2O2]+cation in the liquid formulation, which contains onlytetrofosmin ligand and @TcO4, is dependent upon theconcentration of ligand (Table 1). At a concentration of0.05 mg/ml, for example, reaction was only 50% completeafter 6 hr standing at room temperature. The rate ofreaction can be increased by increasing the concentrationofligand, by heating the preparation, or by a combinationofboth ofthese. At 120°C,and a tetrofosmin concentrationof 0.05 mg/ml, the time taken to reach 50% conversionof 99m@fj4- to [99mTc(tetrofosmin)O]+ is reduced to lessthan 15 mm. In comparison, the Myoview―kit formulation enables the complex to be formed rapidly at roomtemperature with a ligand concentration as low as 0.03mg/mI (Table 1). The kit preparation is stable for at least8hrafterreconstitution.

II) 16

FIGURE 2. HPLC analysis of[@“Tc(tetrofosmin)@O2]@.

224 The Journal of Nuclear Medicine •Vol. 34 •No. 2 •February 1993

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Timepostinjection[@Tc(tetrofosmmn)@O2J@[@“Tc(DMPE)s1@2mm60 mm2 mm60 mm

Distribution

TimepostinjectionTABLE

3of [@‘Tc(tetrofosmin)@O2]@

in Guinea Pigs

[@Tc(tetrofosmin)@O2}@and

[@‘TC(DMPE)@J@

[@“TC(DMPE)@J@

2 mm 60mm'2mm 60 mm

TABLEIDependenceof Rate of Formationof[@“Tc(tetrofosmin)@O2]@onConcentration of TetrofosminLigandTime

requiredforcompleteLigand

reaction(noconcentrationdetectable(mg/mI)

99mTc04)Liquid

formulation 0.05 >6hr0.12.5hr0.2

2hr1.0>1hr3.0>0.5hr6.0

0.5hrKit

formulation 0.03—0.06 <15 mm

TABLE2Distributionof [@“Tc(tetrofosmin)@O2]@and[@“TC(DMPE)@]@

inRats@- @.1

Heart1.58±0.091.53±0.131.32±0.011.18±0.13Blood2.99±0.340.54 ±0.075.05 ±0.380.58 ±0.13Muscle30.8±4.231 .3 ±7.927.4 ±3.925.5 ±9.1Lung1

.51±0.350.59 ±0.192.34 ±0.061 .31±0.09Liver13.5±3.02.99 ±0.5121.8 ±0.911.8 ±0.8Liver

andGI34.5 ±1.542.2 ±2.237.2 ±0.744.6 ±4.7Kidneyand12.1 ±1.513.3 ±1.91 2.3±0.61 5.1±0.7

()

I\/ 06(1@

\

urine

Mean±s.d of threeanimals%lDin wholeorganor tissue.

hr postinjection. The data are in good agreement withresults obtained with earlier liquid formulations (Table 2).

In acute toxicity studies in the rat, there was no evidenceof toxicity of the “wet―formulation at a dose equivalent,on a body weight basis, to 400 times a single human dose.

The toxicology and mutagenicity of the freeze-driedformulation of tetrofosmin (PPN1O1 1) has also been investigated. No mortalities occurred in any study. No toxicologically significant findings were made on single-doseadministration of 1,500 times the maximum equivalenthuman dose, or on 14-day repeat dose studies at a level of100 times the maximum human dose. Some changesindicative of liver effects (a slight reduction in organweight) were noted on 14-day repeat dose studies at 1,000times the maximum human dose in rabbits. Urinalysisand hematology were unremarkable in every case.

No significant mutagenic potential was seen in any ofthe test systems used.

DISCUSSION

In developing this complex, we sought to harness themyocardial affinity of 99mTc@diphosphine complexes and,

FIGURE 3. A perspectiveview of the [Tc(tetrofosmin)@O2]@cationiccomplexinthesolidstateshowingthetransoctahedralarrangementofthedonoratoms.Selectedbondlengths(A):TcP(1)2.476(8),Tc-P(2)2.470(6),Tc-O 1.738(17).

Biodistributionand Safety StudiesThe biodistribution of [99mTc(tetrofosmin)2O2]+ in rats

and guinea pigs is shown in Tables 2 and 3, respectively.The complex shows good heart uptake with rapid clearancefrom blood and liver, and there is no significant uptake inlung tissue. Compared with the prototypical phosphinecomplex, [99mTc(DMPE)3]+, liver clearance, in particular,is greatly improved.

Figure 4 shows an anterior image taken 90 mm postinjection in the pig. The complex is excreted primarilythrough the hepatobiliary system and, to a lesser extent,by the urinary route. Clinical studies in volunteers havesince confirmed parallel behavior in man (15).

The detailed biodistribution in the rat of[99mTc(tetrofosmjn)O]+ prepared from freeze-dried kits(MyoviewTM) is set out in Table 4 for timepoints up to 24

Heart1.33 ±0.140.99 ±0.120.53 ±0.080.38Blood3.11 ±0.800.41 ±0.0728.6 ±3.72.45Muscle30.0

±4.443.4 ±28.41 1.0 ±0.711.1Lung1.14±0.190.47 ±0.032.28 ±0.420.66Liver11.6±2.52.13 ±0.5638.0 ±3.236.8Liver

andGI38.7 ±4.144.6 ±2.848.0 ±5.561.5Kidneyand16.7 ±1.216.1 ±1.411.1 ±0.315.7

urine

* n = 2.

Mean±s.d.of threeanimals,%IDinwholeorganor tissue.

225Technetium-99m-Tetrofosmin•Kellyetal.

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TimepostinjectionFemaleMale2mm60 mm24 hr2 mm60 mm24hrHeart1.75

±0.071.39 ±0.090.11 ±0.031.75 ±0.091.49 ±0.190.11 ±0.02Blood1.68±0.160.12 ±0.030.02 ±0.012.01 ±0.170.22 ±0.070.03 ±0.01Muscle34.0±11.026.3 ±6.716.0 ±2.024.0 ±7.530.5 ±11.017.1 ±2.8Lung1

.43±0.190.37 ±0.050.03 ±0.011 .68±0.260.50 ±0.200.04 ±0.01Liver12.1±3.11.66 ±0.430.21 ±0.0215.0 ±2.72.06 ±0.580.26 ±0.03Small

intestine8.50 ±2.173.67 ±1.210.30 ±0.127.41 ±1.674.15 ±1.040.35 ±0.08Smallintestinecontents6.88 ±1.8138.0 ±2.81 .08 ±0.518.16 ±2.6031 .2 ±6.61 .10 ±0.26Largeintestine2.36 ±0.651 .47 ±0.160.35 ±0.112.82 ±0.681 .72 ±0.190.36 ±0.05Largeintestinecontents1 .65 ±0.334.1 0 ±0.513.20 ±1.061 .81 ±0.684.00 ±0.612.52 ±1.05Feces0.00

±0.000.01 ±0.0163.0 ±3.30.00 ±0.000.00 ±0.0060.3 ±3.5Kidneys12.8 ±1.42.57 ±0.300.23 ±0.0212.8 ±2.52.73 ±0.710.25 ±0.04Total

urine0.13 ±0.0810.3 ±0.813.2 ±2.70.15 ±0.069.52 ±1.7314.7 ±2.0Thyroid0.19±0.020.10 ±0.020.03 ±0.010.16 ±0.070.12 ±0.020.04 ±0.01Brain0.05±0.010.01 ±0.010.00 ±0.000.05 ±0.010.02 ±0.010.00 ±0.00Fat1

.78±0.621 .02 ±0.390.08 ±0.021 .99 ±1.051 .70±0.970.53 ±0.72Mean

±s.d.of six animals;%IDin whole organor tissue.

analogous to those previously used for preparation of[Tc(diphosphine)2O2]@ complexes (8). The structure assigned to the tetrofosmin complex has been confirmed byx-ray crystal structure analysis and shows the expectedtrans-dioxo configuration.

The [99mTc(tetrofosmin)O]+ species is the first exampleofa @mTc@dioxoentity to have shown substantial myocardial uptake and retention, in combination with fast nontarget clearance, across a range ofanimal species, includingman (15). In a review published in 1989, it was stated thatno Tc(V) cation has been shown to accumulate in themyocardium ofany species (8). The authors proposed thatthe polarity of the Tc = 0 linkages prevented myocardialuptake. This hypothesis may well explain the absence ofheart uptake for Tc(V) cations based on simple alkyl oraryiphosphines, but it is clear that it does not provide abasis for understanding the biological behavior of etherfunctionalized phosphine complexes of technetium.

The freeze-dried formulation (Myoviewe) addresses theinherent limitations of the reaction between 99mTc04_ anddiphosphines. At low ligand levels, the rate of reactionbetween 99mTc04_ and diphosphines alone is relativelyslow, as we have found using the simple wet formulationswhich contain only diphosphine ligand plus 99mTcO4_ insaline solution (see Table 1). The rate of reaction can beaccelerated by increasing the ligand concentration or byheating. Because ofthe recognized thermodynamic labilityof the Tc(V) dioxo diphosphine complexes (8), however, these approaches are likely to give rise to[99mTc(tetrofosmin)]+ Using the MyoviewTM formulation,the desired dioxo complex is formed rapidly in high radiochemical purity at ligand concentrations (at the highestvolume of reconstitution) lower than 30 @g/ml.There isno formation of [@mTc(tetrofosmin)3]+ over the 8-hr lifeof the reconstituted kit.

FIGURE4. Anteriorviewin thepigimagedat 90 mmafterinjectionof [@“Tc(tetrofosmin)@O21@.The positionof the heart isindicatedby an arrow.

at the same time, to eliminate the problems of poorbackground clearance. By the use of ether functionalgroups, we have managed to overcome the problems ofretention in blood and slow hepatobiliary clearance whichhave generally been observed in studies in man of alkylphosphine complexes of technetium.

By use ofa “wet―formulation, the 99mTc@dioxo complexof the ether functionalized phosphine, tetrofosmin, can beprepared in high radiochemical purity by reactions directly

TABLE4Biodistnbutionof [@“Tc(tetrofosmin)@O2]@Preparedfrom Myoview@Kitsin Femaleand Male Wistar Rats

226 The Journal of Nuclear Medicine •Vol. 34 •No. 2 •February 1993

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Med 1981;22:897—907.5. Deutsch E, Bushong W, Glavan KA, et al. Heart imaging with cationic

complexes oftechnetium. Science 198 l;2l4:85—86.6. GersonMC, DeutschEA, NishiyamaH, et al. Myocardialperfusion

imaging with @mTc@DMPEin man. Eur JNuclMed 1983;8:371-374.7. GersonMC,DeutschEA,LibsonK, etal.Myocardialscintigraphywith

‘@“Tc-ths-DMPEin man. EurJNucl Med 1984;9:403-407.8. Deutsch E, Ketring AR, Libson K, Vanderheyden J-L, Hirth WJ. The

Noah's ark experiment: species dependent biodistributions of cationic99mTc complexes. mt JRadAppllnstrum [B] l989;l6:l9l—232.

9. GerundiniP,SaviA,GilardiMC,etal.Evaluationin dogsandhumansofthree potential technetium-99m myocardial perfusion agents. J Nuci Medl986;27:409—416.

10. Holman LB, Jones AG, Lister-James J, et al. A new Tc-99m-labeledmyocardial imaging agent, hexakis(t-butylisonitrile)technetium-(I)[Tc99m-TBI]: initial experience in the human. J Nuci Med l984;25:1350—1355.

11. Dean RT, Wester DW, Nosco DL, et al. Progress in the design, evaluationanddevelopmentofTc-99m radiopharmaceuticals. In: Nicolini M, BandoliG, MazziU, eds. Technetiumin chemistryand nuclearmedicine.NewYork: Raven Press; 1986:147—154.

12. Wester DW, Nosco DL, Coveney JR. et al. New Tc-99m myocardial agentwith low plasma binding and fast blood clearance [Abstract]. J Nucl Med1986;27:894.

13. Wester DW, White DH, Miller FW, Dean RT. Synthesis and characterization of a technetium-phosphite complex: hexakis(trimethyl-phosphite)technetium(I)tetraphenylborate. Inorg Chem 1984;23:lSOl—l502.

14. Wackers FJT, Berman DS, Maddahi J, et al. Technetium-99m hexakis 2-methoxyisobutyl isonitrile: human biodistribution, dosimetry, safety, andpreliminary comparison to thallium-20l myocardial perfusion imaging. INuclMed 1989;30:30l—3l1.

15. Lahiri A, Higley B, Smith T, et al. Myocardial perfusion imaging in manusing new @mTcla@ll@Jdiphosphine complexes [Abstract]. Nucl MedCommun1989;lO:245.

16. Kelly JD, Higley B, Archer CM, et al. New functionalised diphosphinecomplexes ofTc-99m for myocardial perfusion imaging [Abstract]. I NuclMed l989;30:773.

17. U S Patent 5,045,302.

227Technetium-99m-Tetrofosmin •Kelly et al.

CONCLUSIONBased on the results of the experiments reported here,

we have concluded that the structure of the technetiumtetrofosmin complex is the trans-dioxo-bis(diphosphine)technetium (V) cation [Tc(tetrofosmin)2)O2]@. We havedeveloped this complex of tetrofosmin for clinical use onthe basis that it provides excellent myocardial uptake andretention with rapid background clearance. In addition,the lyophilized kit provides the convenience of room temperature reconstitution with 8-hr stability. Clinical trialsare being conducted and will be reported in due course.

ACKNOWLEDGMENTSThe authors thank the numerous technical staff at Amersham

International whose cooperation has been essential to this work,and Mrs. Chris Matthews for her help in the preparation of themanuscript.

REFERENCESI. Strauss HW, Pitt B. Thallium-20l as a myocardial imaging agent. Semin

NuciMed 1977;7:49—58.2. Simon J, Ketring A, Troutner DE, Volkert WA, Holmes RA. Labelling of

a macrocyclic tetraaza ligand with technetium-99m. Radiochem Radioana!Let!l979;38:133—l41.

3. Deutsch E, Glavan KA, Ferguson DL, Lukes Si, Nishiyama H, Sodd VJ.Development of a Tc-99m myocardial imaging agent to replace Tl-20l[Abstracti.JNuclMed 1980;21:56.

4. Deutsch E, Glavan KA, Sodd VJ, Nishiyama H, Ferguson DL, Lukes 5J.Cationic Tc-99m complexes as potential myocardial imaging agents. JNucl

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1993;34:222-227.J Nucl Med.   M. WebbonEdwards, Harjit K. Gill, Mary McPartlin, Katharine R. Nagle, Ian A. Latham, Roger D. Pickett, Anthony E. Storey and Peter J. Duncan Kelly, Alan M. Forster, Brian Higley, Colin M. Archer, Fong S. Booker, Lewis R. Canning, K. Wai Chiu, Barbara  ImagingTechnetium-99m-Tetrofosmin as a New Radiopharmaceutical for Myocardial Perfusion

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