Since its introduction by Bonte et al. in 1974 (1),myocardial scintigraphy with the Tc-99m phosphorusbone-seeking agents has become a useful adjunct in thediagnosis of acute myocardial infarction (AM!). The

mechanism of uptake in damaged myocardium remainsthe subject of investigation, but the phenomenon hasbeen shown by Buja and colleagues (2) to be related tothe presence of calcium deposits in the infarct. In thatrespect AM! uptake is quite consistent with the knownproperties of the phosphate skeletal tracers. The predominant view is that bone agents are taken up onbone-mineral surfaces (3) and hence are indicators moreof calcium phosphate surface structure and area, ratherthan of bone mass or calcium content per Se. A contraryand controversial view is that the technetium is actuallytaken up in the collagen moiety of bone (4).

The canine model of acute myocardial infarction, inwhich the left anterior descending (LAD) coronary artery is occluded, has been used by other investigators(1,5,6) to evaluate potential infarct-imaging agents. Inthis study we have used the permanently occluded modelto compare four Tc-99m-labeled phosphate agents; py

Received Sept. I4, 1979; revision accepted May 28, 1980.For reprints contact: Andrew J. Tofe, PhD, Miami Valley Labo

ratories, P.O. Box 39175, Cincinnati, OH 45247.

rophosphate (PPi), methylene diphosphonate (MDP),(1-hydroxyethylidene)diphosphonate(HEDP),andhydroxymethylenediphosphonate (HMDP) (7).

MATERIALS AND METHODS

The administered solutions were prepared either fromcommercially available skeletal-imaging agents or, inthe case of Tc-99m HMDP, commercially equivalentkits (8).

Twenty adult purebred beagle dogs (average weight8.9 ±1.5 kg) were studied. Rather than adjust dose levelsfor body weight in our dogs, we chose to approximateadult human dose levels. This was justified on thegrounds that the Tc-99m-labeled phosphates functionover a wide dose range (8), and that we were thereforeable to compare the various compounds under clinicalconditions of volume, concentration, activity, etc.

Variations in anatomical size and the severity of myocardial infarction were circumvented by use of an internal control. The details of the doses used for imaging

myocardial infarcts in dogs are given in Table 1.All the dogs were anesthetized and the chest opened.

The proximal left anterior descending coronary arterywas dissected free 1 to 2 cm from its origin and ligated.Forty-eight hours after the experimentally induced infarct, each dog received a 1-ml dose (10—15mCi/ml) of

967Volume 21, Number 10

Tc-99m HMDP(HydroxymethyleneDiphosphonate):A Radiopharmaceuticalfor

Skeletal and Acute Myocardial Infarct Imaging. II. Comparison of Tc@99m

Hydroxymethylene Diphosphonate (HMDP)with Other Technetium-Labeled

Bone—ImagingAgents in a Canine Model

John A. Bevan, AndrewJ. Tote, James J. Benedict, MarionD. Francis, and BobbyL. Barnett

Miami Valley Laboratories, TheProcter & Gamble Company, Cincinnati, Ohio

Technetlum-99mhydroxymethylenediphosphonate(Tc-HMDP) was comparedwith the two otherdlphosphonates(Tc-MDP andTc-HEDP) andTc-99m pyrophosphate (Tc-PPI) in a canIne model of acute myocardlal Infarction.The TC-HMDPshowedhigheruptakein Infarctedmyocardiumthanthe othertwo dlphosphonates,and uptakeequivalentto that of Tc-PPI.

J NucIMed21: 967—970,1980

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TABLE 1.DOSEDETAILSINCOMPARISONSTUDYCompound

Type of formulationDosevol.

(ml)Amountof active

(mg)Tc-99m (mCi)

BEVAN, TOFE, BENEDICT, FRANCIS, AND BARNETT

HMDP Lyophilized kit' 1.0 0.5 10—15MDP Commercial kitt 1.0 0.5 10—15

Dry@mixt 1.0 1.1HEDP Commercialkit11 1.0 1.2 10—15Ppl Commercialkit@ 1.0 3.1 10—15

. Experimental formulation (see Ref 8).

t Osteolite, New England Nuclear Corp, Boston, MA.

* MDP substituted for HEDP in Osteoscan formulation: 5 mg MDP, 0.16 mg SnCl2, 0.56 mg sodium ascorbate.II Osteoscan, Procter & Gamble, Cincinnati, OH.

§Technescan PYP, Mallinckrodt Nuclear.

have some method of normalizing the distribution datato allow for the variation. Buja et al. (2) have reporteda high correlation between the Tc-99m pyrophosphateagent and H-3-labeled HEDP localization in two dogs.We have adopted this approach by administering astandard dose of C-14-labeled HEDP as an internalcontrol 15 mm after the dose with the Tc-99m-labeledagent. This procedure assumes that the 15-mm intervalprecludes interference with the uptake of the Tc-99mtracer and that the C-14 HEDP uptake is a valid indexof “calcification.―The physiological dose of HEDP,calculated as usual in terms of the disodium salt, was 1mg, approximately equal to the amount usually injectedin a single dose of Tc-HEDP. This is not considered to

be a pharmacologically significant dose (JO).The value of the internal standard is immediately

apparent when one compares the Tc-99m data with theTc-99m/C-14 concentration ratios in Table 2. The rangeof the ratios is considerably less than for Tc-99m alone,confirming that there is substantial animal-to-animalvariation in these studies, even though purebred beaglesfrom the same supplier were used. The raw Tc-99m datado not account for this variation, which tends to obscurethe true nature of the agent-to-agent differences. Thenormalization procedure of taking the Tc-99m/C-14ratio permits a more reliable comparison. For example,the superiority of the Tc-HMDP for osseous uptake isevident in the Tc-99m results and is made particularly

clear in the Tc-99m/C-14 concentration ratios. Infarctedmyocardium uptake of the agents is variable, but whennormalized to the C-14 content, the Tc-PPi is shown to

be superior to the HEDP and MDP agents (p < 0.01),in agreement with clinical experience (11,12). At thesame time, the uptake ratio of the HMDP agent is notsignificantly different from that of PPi for infarct uptake.Recent clinical data (13) slightly favored PPi overHMDP for infarct imaging.

Although normalization is achieved by calculating theTc-99m/C-14 ratios for bone and infarcted heart, it

one of the Tc-99m-labeled test agents by bolus injectioninto the cephalic vein. To provide an internal control(v.i.), I 5 mm later each dog received 1 ml of C-l4 HEDP

(1 mg/ml; 37 @tCi/ml)by bolus injection into the contralateral cephalic vein. Ninety minutes after the initialdose, each dog was anesthetized with pentobarbital disodium, and scintiphotos were made with an Angercamera. A blood sample was obtained, and the animalwas then killed with a lethal dose of pentobarbital.Scintiphotos of cross sections of the excised heart weretaken to help differentiate infarcted from normal myocardium. Representative tissue samples included rib,femur, normal heart, infarcted heart, and femoralmuscle. Both Tc-99m and C- 14 were assayed in eachtissue sample: Tc-99m in a gamma spectrometer andC-l4 as previously described (9). The results were expressed as percent administered dose (Tc-99m or C-14)per gram tissue.

The data were analyzed using the experimental agent(Tc-HMDP) as the control in an analysis of variance.This reversal of normal practice was adopted for convenience, since we wished to compare each of the current

agents against the new one. Differences between groupmean values were tested for significance by Student'st-test and in a nonparametric analysis by the Wilcoxonsigned rank sum test.

RESULTS AND DISCUSSION

Technetium-99m assay data for rib, femur, infarct,normal myocardium, femoral muscle, and blood aresummarized in Table 2. Beneath these results are listedthe ratios (Tc-99m agent)/(C-14 internal control) forrib, femur, and myocardial infarct.

A major problem with the AM! dog model is the largevariation in size and severity of the infarct from animalto animal. Because of temporal effects upon the degreeof necrosis, it is rarely feasible to study more than oneagent in each dog. Therefore, it is highly desirable to

968 THE JOURNAL OF NUCLEAR MEDICINE

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Rib Femur Musc)e Blood Normal InfarctedMyocardium M@ocardium

Tc-99m HMDPTc-99mcontent (and range) in

Tc-99m MDP%dose/g in tissue X iO@

Tc-99m HEDPTc-99mPPiTissue(n8)(n3)(n4)(n5)

BASIC SCIENCESRADIOCHEMISTRY AND RADIOPHARMACEUTICALS

TABLE2. DISTRIBUTIONOF Tc-99m SKELETAL/MYOCARDIALIMAGINGAGENTSINMYOCARDIAL INFARCT MODEL)

DOGS(ACUTE

Rib 5.37(3.15—7.36)

1.76(1.34—2.58)

5.05(1.03—11.6)

0.15(0.09—0.26)

0.07(0.04—0.10)

0.49

(0.31—0.82)

4.32(2.71—5.64)

1.30(0.46—1.94)

3.20(2.40—4.95)

0.21(0.18—0.23)

0.109(0.08—0.14)

0.74

(0.60—0.95)

2.27(1.76@2.96)'

0.42(0.38@0.46)'

0.97(0.72—1.53)

0.15(0.11—0.20)

0.07(0.05—0.11)

0.58(0.37—1.01)

4.95(3.07—8.29)

1.30

(0.61—2.51)

4.44(0.03—8.20)

0.31(0.13—0.62)

0.14(0.09—0.200)'

0.78(0.63_O.84)t

Femur

Infarctedmyocardium

Normalmyocardium

Femoralmuscle

BlOOd

Tc-99m/C-14 concentration ratiosRib 1.00 0.69 0.78 0.84

(O.59_l.Ol)t0.81

(0.57—0.91)'1.27

(0.94—i .52)

(0.92—1.10)1.09

(0.64—0.74)' (0.58—1.0 1)'Femur 0.64 0.56

(0.43—0.65)'(0.91—1.15) (0.55—0.72)'Infarcted

myocardium1.18

(0.98—1.56)0.53 0.65

(0.50—0.57)' (0.57—0.73)'

Significance of difference compared with Tc-99m HMDPvalue, ‘:p < 0.01; t: p < 0.05.

serves little purpose when applied to the tissues in whichuptake of both tracers is low; the concentration ratio is

then the ratio of two small numbers. In an attempt to

normalize the biodistribution data in such a way as topreserve the contrast between calcified and noncalcifiedtissues, we have done the following. The average C-14HEDP values (% dose/g) were calculated for each tissue,the average being calculated over all the animals in thestudy (= [Cl4]avg). Then the Tc-99m value in eachtissue was adjusted according to the formula.

C,)0

C

2

FIG. 1.ComparativedistributionsofTc-99mphosphateagentsincanine model of acute myocardial infarction.

. [C14]av@[C-14]

Where [Tc] is the measured Tc-99m concentration and[C-14] is the measured C- 14 concentration.

The results, which better indicate the scintigraphicproperties of the various agents as predicted by this an

imal model, areshown inFig.I.

The Tc-HMDP shows significantly higher uptakethan the other three agents in rib and femur, significantlyhigher uptake in myocardial infarcts than Tc-MDP and

Tc-HEDP, and approximate equality with Tc-PPi. This,coupled with the previous finding (8) that the bloodclearance of Tc-HMDP is equal to or slightly faster than

that of Tc-MDP, indicates that the former should provide excellent imaging of both skeletal disease and acute

myocardial infarction.

REFERENCES

I. BONTE FJ, PARKEY RW, GRAHAM KD, et al: A newmethod for radionuclide imaging of myocardial infarcts.Radiology110:473-474,1974

2. BUJA LM, TOFE AJ, KULKARNI PV, et al: Sites andmechanisms of localization of technetium-99m phosphorusradiopharmaceuticals in acute myocardial infarcts and othertissues. I C/in Invest 60:724-740, 1977

3. JONESAG, FRANCISMD, DAVIS MA: Bone scanning:radionuclide reaction mechanisms. Semin Nuci Med 6:3-18,1976

[TCladj [Tc]

NormalizedBiodistñbut@nof Tc-99m Phosphorus Agents(Average Tc—99m eve4s normakzed 10 average C—14HEDP Ieve4s ‘neach tissue)

. . .. Denotes average C14 evel

U0 HEDP

@MDP

0@•Der@otessignificant dfference from

Tc-99m HMDP @veIspcOO5@

Volume 21, Number 10 969

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BEVAN, TOFE, BENEDICT, FRANCIS, AND BARNETF

4. ROSENTHALL L, KAYE M: Observations on the mechanismof @‘°Tc-labeledphosphatecomplexuptakein metabolicbonedisease. Semin Nucl Med 6:59-67, 1976

5. ZWEIMAN FG, HOLMAN BL, O'KEEFE A, et al: Selectiveuptake of 99mTccomplexes and 67Ga in acutely infarctedmyocardium. I Nucl Med 16: 975-979, 1975

6. POLINERLR,BUJALM, PARKEYRW,etal:Comparisonof different noninvasivemethodsof infarct sizingduringcxperimental myocardial infarction. I Nucl Med 18:517—523,I977

7. BEVAN JA, T0FE AJ, FRANCIS MD, Ct al: Tc-99m hydroxymethylene-diphosphonate (HMDP): A new skeletalimaging agent. Radiopharmaceuticals II. New York, Societyof Nuclear Medicine, I979, pp 645—654

8. BEVAN JA, TOFEAJ, BENEDICTJJ, et al: Tc-99m HMDP(hydroxymethylene diphosphonate): A radiopharmaceuticalforskeletalandacutemyocardialinfarctimaging.I.Synthesisand Distribution in animals. I NucI Med 21:961-966, 1980

9. TOFEAJ,FRANCISMD:Optimizationof theratioofstan@ nous tin: ethane-1-hydroxy-1,1-diphosphonate for bone

scanning with 99mTc.pertechnetate. I Nucl Med 15:69-74,1974

10. TOFE AJ, FRANCIS MD: Toxicity of 99mTcSn.EHDP. INucl Med 16:444—445,1975 (Letter to the Editor)

11. KELLEY Ri, CHILTON HM, HACKSHAW BT, et a1: Comparison of Tc-99m pyrophosphate and Tc-99m methylenediphosphonate in acute myocardial infarction: Concise cornmunication. I Nucl Med 20:402-406, 1979

12. MAKLER PT, LEDERMAN S, CHARKES ND, et al: Myocardial infarct imaging with @mTc@pyrophosphateand99mTc..methylene diphosphonate: lack of correlation. ClinNucl Med 4:89-91, 1979

13. WAKAT MA, CHILTON HM, HACKSHAW BT, et al: Comparison of Tc-99m pyrophosphate and Tc-99m hydroxymethylene diphosphonate in acute myocardial infarction:Concise communication. I Nucl Med 21:203-206, 1980

TheScientificProgramCommitteeof the SouthwesternChapterof theSocietyof NuclearMedicineinvitessubmilled abstracts of original work in nuclear medicine from members and nonmembers of the Society of Nuclear Madicine to be considered for the 26th Annual Meeting to be held March 27-29, 1981 at the Fairmont Hotel in New Orleans, LA.

Theprogramwill includesubmittedscientificpapers,invitedspeakers,andteachingsessionscoveringareasofcurrent interest in nuclear medicine. The program will be approved for credit toward the AMA Physicians RecognitionAward under Continuing Medical Education Category 1 through the Society of Nuclear Medicine.

Scientificexhibitsalsoaresolicitedfor thismeeting.Usetheabstractsubmissionguidelineslistedbelow.Exhibitswill be judged on scientific content in the technologist and professional level categories and awards presented.

TheSouthwesternChapterannualNuclearMedicinerefreshercoursewill beheldMarch26,1981at theFairmontHotel. The course will Include reviews of basic science, instrumentation, radiopharmaceuticals, and in vitro and diagnostic imaging techniques. Nuclear medicine scientists, technologists, and physicians interested in a state of theart review are invited to attend.

Submitted abstracts should contain a statement of the purpose, the methods and materials used, results, and conclusions. The title.authors,and institutional affiliations should be includedat the top of theabstractpage.The nameof the author presenting the paper must be underlined. If needed supporting data should be limited to no more thantwoseparatepagesoffiguresandtablesandshouldbeincludedwiththeabstract.Accepted abstracts will be published and should not exceed 300 words.

OrIginal abstracts and four copies should be sent to the Program Chairman:

Lynn A. Witherspoon, M.D.Dept.of Nuclear Medicine

Ochsner Medical Institutions1514 Jefferson HighwayNew Orleans, LA. 70121

For further information regarding the program, write or telephone (504) 834-7070, Ext. 2216.

ABSTRACTDEADLINE:DECEMBER15,1980POSTMARK

970 THE JOURNAL OF NUCLEAR MEDICINE

SOUTHWESTERN CHAPTER

SOCIETY OF NUCLEAR MEDICINE

26thANNUALMEETINGMarch 26-29, 1981 Fairmont Hotel New Orleans, Louisiana

ANNOUNCEMENT AND CALL FOR ABSTRACTS

ABSTRACT GUIDELINES

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1980;21:967-970.J Nucl Med.   John A. Bevan, Andrew J. Tofe, James J. Benedict, Marion D. Francis and Bobby L. Barnett  Canine ModelDiphosphonate (HMDP) with Other Technetium-Labeled Bone-Imaging Agents in aand Acute Myocardial Infarct Imaging. II. Comparison of Tc-99m Hydroxymethylene Tc-99m HMDP (Hydroxymethylene Diphosphonate): A Radiopharmaceutical for Skeletal

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