tions. Ofthe radioiodines, 1231,1251and ‘@‘Ihave been mostcommonly used in medicine. The former two decay byelectron capture followed by internal conversion and, as aconsequence, emit numerous low-energy Auger electrons

(1). These low-energy (@-.-2O—5O0eV) electrons have rangesof subcellular dimensions and therefore impart their energy locally (1). The favorable organ dosimetry for theseradionucides has led to their use predominantly in diagnosis. Although the low-energy nature of the photonsemitted by 1251has limited its utility as an in vivo diagnosticagent, it is the radionucide of choice for radioirnrnunoassay. Because of its desirable physical properties andfavorable dosimetry, 1231is routinely used for thyroid uptake and imaging studies. Other promising radiopharmaceuticals such as the brain imaging agents H'23IPDM(N,N,N'-trimethyl-N'-(2-hydroxyl-3-methyl-5-iodobenzyl)-1,3-propanediamine)(2) and ‘23I-Spectamine®('231MP:N-isopropyl-p-iodoamphetamine) (3,4) are also finding aplace in nuclear medicine. In contrast to the above radioiodines, the physical properties of ‘@‘Ifavor therapeuticapplications (5).

It is widely believed that the lethality ofbeta emitters oflow linear energy transfer (LET) are reasonably independent ofthe subcellular distribution. Conversely, however, itis now well recognized that the radiotoxicity of Augerelectron emitters depends strongly on their distributionwithin the cell (6-9). The most severe effects have beenobserved when the Auger emitter is localized in the cellnucleus and bound to DNA, while effects akin to betaemitters are observed when situated in the cytoplasm (6,8,10). For DNA-boundAugeremittersin vivo and invitro, the values of relative biological effectiveness (RBE)have been as high as those observed for high-LET alphaparticles (9,11). Since the biological effects of Auger-emitting radiochemicals can not be predicted a priori, it ispresently necessary to ascertain the biological effects ofeach radiocompound individually. Accordingly, in thiswork the well established mouse testis model is employedto investigatethe lethality of the brain imagingagent‘231MP,as well as three additional radioiodinated products

In this work, spermhead survivalin mouse testis was used toinvestigate the radiotoxicity of several intratesticularly localized radioiodinated pharmaceuticals. Radioiodines that decayby electron capture and/or internal conversion (1231,1251)aswell as by@ decay (1311)were coupled to pharmaceuticalsthat selectivelylocalizein differentcell compartments.Doseresponse curves yield D37values of 62 cGy, 75 cGy, 61 cGyand 7.7 cGy for 1231MP(N-isopropyl-p-iodoamphetamine),131IdU(iododeoxyuridine),H131IPDM(N,N,N'-tnmethyl-N'-(2-hydroxyl-3-methyl-5-iodobenzyl)-1,3-propanediamine) and125IdC(iododeoxycytidine),respectively.At 37% survival,therelativebiologicaleffectiveness(ABE)of these radiochemicals, when compared to the pure gamma-emithng radiochemical 7Be-chlonde(D37= 65 cGy), are 1.0, 0.89, 1.1 and 8.4,respectively. Intratesticular @Be,with an effective half-lifeof430 hr in the organ, was used as the source of referenceradiationtodeterminetheRBEvaluesbecauseitsolelyemits477 keV gamma rays, and the dose to the testis is deliveredchronically, as in the case of the other radiocompounds.Subcellulardistributionstudiesshow that all of the cellularactivity is localized in the cytoplasm in the cases of 123IMPand H131IPDM,while virtuallyall of 131ldUand 125IdCwerebound to DNA in the cell nucleus.In agreementwith ourearlier in vivo studies, these data show that subcellular distilbution plays a key role in the radiotoxicity of Auger electronemitters such as 1231and 1251,and has no role for beta emitterssuch as 1311These findings may have implications in thedesign of radiopharmaceuticals for both diagnosis (localizeAugeremitterincytoplasmof cell)andtherapy(localizeAugeremitter in cell nucleus).

J NucIMed 1992;33:2196-2201

dioiodinated pharmaceuticals are widely used innuclear medicine for diagnostic and therapeutic applica

ReceivedApr.17, 1992;revIsionaccepted Jun. 29, 1991.For rep,ints contact: Dandamudi V. Rao, PhD, Department of RadiOlOgy,

MSB F-451, UMDNJ-NewJerseyMediCalSchool,185 S. OrangeAve.,Newark,NJ 07103.

2196 TheJournalof NuclearMedicine•Vol.33 •No. 12 •December1992

Radiotoxicity of Some Iodine-123, Iodine-125and Iodine- 131-Labeled Compounds inMouse Testes: Implications forRadiopharmaceutical DesignVenkat R. Narra, Roger W. Howell, Raw S. Harapanhalli, Kandula S. R. Sastry and Dandamudi V. Rao

Department ofRadiology, University ofMedicine & Dentistry ofNew Jersey, New Jersey Medical School, New Jersey andDepartment ofPhysics andAstronomy, University ofMassachusetts, Amherst, Massachusetts

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including H'31IPDM, ‘25lododeoxycytidine(‘25IdC)and‘31lododeoxyuridine (‘31IdU).Subcellular distribution ofthese radiochemicals is determined and correlated with thebiological effects. These results, in conjunction with earlierstudies (7,8,12), suggest that the design ofdiagnostic radiopharmaceuticals involving Auger emitters should take intoaccount subcellular distribution in order to minimize risk.For the therapeutic use ofAuger emitters, it is desirable tomaximize the biological effect by directing the radiochemical to the tumor cell nucleus. Finally, the results confirmthat in general subcellular distribution is not a determinantin the design ofbeta-emitting radiopharmaceuticals. However, it should be noted that there may be instances wheresubcellular distribution plays a role (13).

MATERIALSANDMEThODSSpermatogenesisin mousetestiswasused as the experimental

model with spermhead survival serving as the biologicalendpoint. This model has been used extensively to investigate theradiotoxicityof a variety of radiochemicals(7,8,11,14,15).Therationale for this model stems from the differential radiosensitivity ofthe various cells in the testis. The primary spermatogonialcells(typesA3-A@,In, B) are the most radiosensitivewith LDse@—4OcOy, while the remaining cell types (spermatocytes, etc.)have substantiallyhigher LDsevaluesrangingfrom 200-60,000cOy (16,17). Therefore, irradiation of the testis with low dosesresultsin a reducedspermheadcount about 29 days postirradiation, the time required for the spermatogonia to become sonication resistant spermatids ofStages 12—16(16,17). Further detailsregarding the model may be found elsewhere (7,8,15).

Anesthetized male Swiss Webster mice (8-9 wk) weighingabout 30 g were intratesticularlyinjectedwith 3 @tlof a solutioncontaining the radiochemical. In order to facilitate a reasonablyuniform distribution of the radiochemical in the testis, a lineinjection was performed wherebythe needle was continuouslywithdrawn during the injection (7,8,11,12). This mode of administration is preferred over intravenous and intraperitoneal injections because the radiobiologicaleffect of particulate radiation(alpha,beta, Auger)can be ascertainedwithout the interferenceofpenetrating radiationemanatingfrom the wholebody.

RadiochemicalsRadioiodinatedHIPDM waspreparedand assayedaccording

to the procedures of Lui et al. (18) using @I(New EnglandNuclear, N. Billerica, MA). Spectamine®(‘231MP)and 7Be-chloride were obtained from Medi-Physics(South Plainfield, NJ). The‘231MP,alsoprovided,had a 4.8%(byactivityat time ofuse) 124!contaminant which contributed about 16% ofthe total testicularabsorbed dose. The radiochemical ‘25IdCwas obtained from ICN

Radiochemicals (Irvine, CA). Finally, ‘3tIdUwas prepared by anadaptation of the syntheses of Hadi et al. (19) and Bakker andKaspersen (20). Briefly, a solution of chloramine T (400 @gin200 @lofphosphatebuffer(PB), 0.1M, pH 6.95)2'-deoxyuridine(400 @gin 400 @lof PB) was stirred at 105°Cin an oil bath. Onemillicurie of Na'311 (New England Nuclear, Billerica, MA), spe

cific activity 770 Ci/mmol, was added and the heating continuedfor 25 mm. Upon cooling to 25°C,K2S2O5(400 @gin 40 @lPB)wasadded,the mixturepassedthrougha 0.4 smfilterand purifiedby HPLC. The HPLC system consisted of an Ultremex®C18

column (150 x 4.6 mm, 5 @m,Phenomenex, Torrence, CA)equilibrated with 8% methanol in water at a flow rate of 1 ml/mm. Pure radiolabeled ‘31IdUwas eluted after 12 mm. One totwo additional passes through the HPLC column afforded >98%

radiochemical purity, 55% radiochemical yield, and specific ac

tivity 300 Ci/mmol.

Biological Clearance from the TestisThe right testis of mice were intratesticularlyinjected with

small quantities ofthe radiochemicals. The mice then were killed

under ether in groups of four at various times postinjection. Thetestes were removed and the radioactivity contained within eachtestis was determined with a Nal well counter. The fraction ofactivity retained in the testis was the ratio of aveçage activity in

the testes to that in the injection standard.

Subcellular DistributionSubcellular distribution ofthe radiochemicals in the testicular

cellswasdeterminedaccordingto proceduresdescribedelsewhere(14). Briefly, one day following intratesticular injection of theradiochemical, the animals were killed and the testes removed.The testicular cells were isolated and the cytoplasmic and nuclearfractionsseparated.Aliquotsof these fractionswere counted forradioactivity and the fraction of total cellular activity found inthe two compartments was obtained. The nuclei were furtherprocessed to obtain the fraction of nuclear activity bound toDNA.

Optimal Day to Perform Spermhead Survival AssayBecause irradiation ofthe testis with low doses primarily affects

only the spermatogonia, the minimum testicular spermheadcount is not observable until the time required for spermatogoniato become sonication-resistant spermatids (Stages 12—16).Hence,the optimal day to perform the spermhead survival assay (minimum spermhead count) was ascertained. Forty mice were intra..testicularly injected with a fixed quantity of radiochemical. Onvarious days postinjection, the animals were killed, the testis

removed and placed in 1 ml deionized water, homogenized,sonicated, and the spermhead count determined according toprocedures reported earlier (15). Using these data, the optimalday was delineated.

Spermhead Survival AssaySpermhead survival as a function of testicular absorbed dose

was obtained as follows. Various amounts of the radiochemicals

were injected into the right testes ofthe animals (groups of four).On the optimal day postinjectionas determined above, the animals in each group were killed,the spermheadcounts obtainedand the surviving fraction compared to controls (injected withnormal saline or the nonradioactive compound) were determined.

RESULTS

Biological Clearance and Radiation DoseFigure 1 shows the biological clearance of the radi

ochemicals from the testis following intratesticular administration. Similar elimination patterns have been consistently observed for all radiochemicals studied in this model(7,8,11,12). The biological clearance data were leastsquares fitted to a two-component exponential expression:

f = ( 1 —a) e@693t@'@@ a e°693t@'@'@, Eq. 1

Toxicity of Radioiodinated Compounds •Narra et al 2197

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RadiochemicalaT1 (hr)T2(hr)131ldU0.044

±0.00470.16 ±0.068108 ±40125ldC0.0030±0.000430.1 8 ±0.0051 72 ±391231MP0.42±0.0560.34 ±0.0442.3 ±0.317Be-chloride0.20±0.0290.27 ±0.033648 ±102

1.0z0

0z

z0

0

00.1

0 20 40 60 80 100

TESTIS DOSE (cGy)15050 100

TIME (h)

FIGURE1. Biologicalclearanceof the radiochemicalsfrommouse testis followingintratesticular injection. The data for 131ldU,‘23IMPand 125ldCare representedby t@,0 and •,respectively.Clearancepatternswerenotaffectedby theamountof radioactivity injectedover the rangeused in these studies. Representative standarddeviationsare indicatedby the error bars.

where f is the fraction of injected activity remaining in thetestis at time t (in hours) postinjection. The biological halflives of the two components are given by T3 and T2. Thefitted parameters a, T1, and T2, are given for the variousradiochemicals in Table 1. The biological clearance for

H131IPDMwas the same as that for H'25IPDM and maybe found elsewhere (8).

The absorbed dose D to the testis was calculated usingconventional MIRD techniques (21) where D = (A@,r/m)

@ The values of A (mean energy emitted per transition) for the radionuclides were taken from Weber et al.(22). Assuming uniform distribution ofthe radiochemical

in the testis, the absorbed dose per unit cumulated activitywas calculated (23). Finally, residence times r were obtamed by integrating the expressions for f (the biologicalhalf-lives being substituted with the appropriate effectivehalf-lives) over seven days, the time over which the dosewas delivered to the spermatogonia, that subsequentlybecome spermatids 29 days later (7,8,14,15).

Spermhead Survival as a Function of TesticularAbsorbed Dose

The optimal day to perform the spermhead survivalassaywas determined to be the 29th day postinjection forall of the radiochemicals studied in the present work (data

TABLE 1Parametersfor LeastSquaresFit of Testicular

Clearance Data

FIGURE2. Dependenceof spermheadsurvivalon the testicularlyabsorbed dose delivered by photons. The survival followingselectiveacute irradiationof the testis with external 60 kVp (0)and 120 kVp x-rays (S) (7) are shown. Similarly, the survivalfollowingintratesticularinjectionof the pure gammaemitter @Bechloride(0) is presented.Error bars are representativestandarddeviations.

not shown). Figure 2 shows the spermhead survival as afunction of the testicular absorbed dose from acute external x-ray irradiation and from chronic internal gammairradiation with 7Be-chloride. Similarly, Figure 3 shows

the spermhead survival on the 29th day postinjection as afunction of the testicular dose for ‘23IMP,‘25IdC,‘31IdUand H'31IPDM. The survival data were least squares fittedto a two-component exponential expression

S = (1 — a) e_@1 + a e_D@@2, Eq. 2

where S is the survival fraction, D is the absorbed dose incOy and D1 and D2 are the slopes ofthe two components.

FIGURE3. Spermheadsurvivalas a functionof absorbeddoseto the testisfromintratesticularlyinjectedradiochemicals.1@lMP(0),125ldC(•),131ldU(@)andH131IPDM(). Representativestandarddeviationsare shown.

z0

0

0 25 50 75 100TESTIS DOSE (cGy)

2198 The Journal of Nuclear Medicine •Vol. 33 •No. 12 •December 1992

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RadiochemicalaD1 (cOy)D2(cOy)131ldU0.80

±0.0350.73 ±0.6697 ±14H131IPDM0.78±0.0220.67 ±0.2682 ±7.8125ldC0.55±0.0230.56 ±0.07319 ±2.11231MP0.88±0.0100.68 ±0.2271 ±2.77Be-chlonde0.88±0.0370.70 ±1.176 ±11

SubcellularABEcomparedAadiochemicaldistribution D37(cGy) toacutex-ray& Reference

131ldU100% N, 100% D75 ±120.89 ±0.150.87 ±0.19thisworkH131IPDM100%Cy61 ±6.31.1 ±0.121.1 ±0.20thiswork125ldU100%N, 100% D8.5 ±2.17.9 ±2.07.6 ±2.211125ldC1

00% N, 100% D7.7 ±1.28.7 ±1.48.4 ±1.8thisworkH125IPDM100%Cy68 ±61.0 ±0.100.96 ±0.1781@lMP1

00% Cy62 ±31 .1 ±0.071 .0 ±0.16thiswork7Be-chloride54%N, 46% Cy65 ±I 01 .0 ±0.16—7 and thiswork.

External 60 kVp or 120 kVp x-rays where 037is 67 ±3 cOy (7).N = nucleus, Cy =cytoplasm and0 = DNA.

TABLE 2Parametersfor LeastSquaresFit of Spermhead

Survival Data

(a few microcuries) and is a highly suitable in vivo modelto ascertain the biological effects ofradionuclides that emitparticulate radiation. The reasons for this are twofold.First, there is no testicular irradiation by low-LET photonsemanating from the whole body. Both intraperitoneal andintravenous modes of administration, which involve administration of large amounts of activity, result in a significant nontarget (whole body) to target (testis) dose frompenetrating radiation. Second, most of the absorbed dosedelivered to the testis from intratesticularly injected activity is from the particulate radiation. Due to their smallabsorbed fractions, photons contribute only minimally tothe total absorbed dose. For example, for 125!,our absorbeddose calculations indicate that photons deposit only 10.5%of the total testicular dose. Even smaller contributionswere found for 123!,1241and ‘@‘Iwhere the photon component was only about 7%, 7.2% and 1.4%, respectively.These small fractions indicate that the survival curveslargely reflect the radiotoxicity ofthe electrons emitted bythe radioiodines and support the notion (7,11,14,15) thatthis model is well suited to studying the dependence of thelethal effects of Auger electron emitters on the subcellulardistribution of the radiochemicals.

The possibility exists that the intratesticular line injection may lead to a highly nonuniform activity distributionand a correspondingly nonuniform energy deposition,thereby causing distortions in the survival curves. Ourmacroscopic distribution data (7,8,14,15) show that thereis a reasonably uniform distribution ofactivity in the testis(within 10%—l5%).The present data for 7Be-chloride,‘231MP,‘31IdU,and H'31IPDM, in conjunction with ourearlier data for H'25IPDM (8), support the presence ofuniform distribution for the following reasons:

1. Uniform irradiation of the testis with acute externalx-rays is as effective as chronic irradiation ofthe testiswith gamma rays from intratesticularly injected @‘Be.

2. All low-LET type electron emitting radiochemicals

(e.g., f@ emitters and cytoplasmically localized Auger

emitters) including ‘231MP,131IdU, H'31IPDM, andH'25IPDM (8) produce survival curves equivalent to

The parameters a, D1 and D2 are given in Table 2 for thevarious radiopharmaceuticals. The two-component natureofthe survival curves, also observed by other authors (24—26), is a characteristic of this model, and it is most likelydue to the differential radiosensitivities of the spermatogonial cells (24,27). The absorbed doses required toachieve 37% survival (D37)are given in Table 3 along withthe RBE value of each radiochemical compared to bothacute external 60 or 120 kVp x-rays and chronic internal7Begamma rays. It should be noted that with the exceptionof ‘231MP,there were no chemotoxic effects observed withthe unlabeled compounds in the amounts used in thesestudies. The chemical IMP was slightly chemotoxic, causing an 8% reduction in the spermhead count when thehighest concentration was injected. Corrections to the doseresponse curve were made accordingly.

Subcellular Distribution of the RadionuclidesThese results are summarized in Table 3. In agreement

with our earlier results for H'25IPDM (8), our subcellulardistribution studies for H'31IPDM indicate that virtuallyall of the radionuclide is localized in the cytoplasm. Thesame distribution was found for ‘231MP.In contrast, as inthe case of ‘25IdU(11), both ‘25IdCand ‘31IdUwere entirelylocalized in the nucleus and bound to DNA.

DISCUSSION

The mouse testis model employed in this work entailsintratesticular injection of small amounts of radioactivity

TABLE3D37Values and SubcellularDistributionfor lodinated Radiochemicals

ABE comparedtochronic7Begammarays

2199ToxicityofRadioiodinatedCompounds•Narraetal

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those obtained by uniformly irradiating the testiswith external x-rays. These consistent results wouldnot be observed if significant inhomogeneities werepresent.

The primary aim ofthis work is to examine the dependence of the toxicity of radioiodinated pharmaceuticals ontheir subcellular distribution in an in vivo experimentalmodel. The survival curves in Figure 3, along with otherdata in the literature (6—8,10,12),point to the strongdependence of the radiotoxicity of Auger emitters on thiskey parameter. In this work, ‘25IdC,which covalently bindsto the DNA in the cell nucleus, produces damage akin tohigh-LET alpha particles (9,11) with an RBE value of

8.7 ±1.4comparedto x-rays.This isin reasonableagreement with our value of 7.9 ±2.0 for ‘25IdU(11), and itcompares favorably with our in vitro data (9). In contrast,the radioiodinated compounds that emit Auger electronsand localize in the cytoplasm, including ‘231MP,H'23IPDM(unpublished data) and H'25IPDM (8), are much less lethalwith RBE values of about 1. Finally, the RBE values forthe ‘@‘icompounds are essentially equal to one, withinexperimental errors. This is in keeping with earlier reports(10,28—30) that the subcellular distribution of 131! plays

no role in determining its lethality. It should be furthernoted that the above conclusions which are based onresults from the mouse testes model, seem to be independent of the nature of the irradiation (i.e., chronic internalversus acute external) as evidenced by the 7Be-chlorideand x-ray data shown in Figure 2.

It has been a common practice to base the risk associatedwith diagnostic nuclear medicine procedures on the average absorbed dose to the organ. Macroscopic nonuniformities in organ activity distribution may result in significantly different local absorbed doses (23,31). Similarly,when specific cells within an organ selectively accumulatethe radiochemical, the absorbed dose to these cells may behigher than the average organ dose (32-34). Accordingly,the risk may be higher than expected (35). Further complicating the issue of risk assessment is the dependence ofthe biological effects of incorporated radionuclides onsubcellular distribution (6—10).This is particularly important for Auger electron emitters (e.g., 1231,201TI).While itis increasingly being recognized, this aspect is not yetfolded into the design of diagnostic radiopharmaceuticals.Our data for a variety ofradioiodinated compounds (Table3) suggestthatthosecompoundsintendedfordiagnosisshould be directed to the cytoplasm of cells in order tominimize the risk. In this context, our recent discussionon the dose equivalent for 1251,which incorporates subcellular distribution (9,27), may be of some value. For therapeutic uses, however, the Auger emitter must be directedto the tumor cell nucleus (preferably DNA) in order toachieve maximal therapeutic efficacy (36). Since mostnuclear medicine radionucides are copious emitters ofAuger electrons (1,37) [e.g., @mTc(4 Auger electrons),I I ‘In (8 Auger electrons), 1231 (1 1 Auger electrons), 201TI

(20 Auger electrons)J, the findings reported. here may beof value for future radiopharmaceutical development.

ACKNOWLEDGMENTSStable HIPDM was kindly providedby Prof. Hank F. Kung

(University of Pennsylvania Hospital, Philadelphia, PA). Thiswork was supported in part by USPHS grant no. CA-32877, NewJersey Cancer Commission grant no. 689-042 and New JerseyCancer Commission Fellowship nos. 690-080 (V.R. Narra) and91-2l33-CCR-00 (R.S. Harapanhalli).

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1992;33:2196-2201.J Nucl Med.   Venkat R. Narra, Roger W. Howell, Ravi S. Harapanhalli, Kandula S. R. Sastry and Dandamudi V. Rao  Mouse Testes: Implications for Radiopharmaceutical DesignRadiotoxicity of Some Iodine-123, Iodine-125 and Iodine-131-Labeled Compounds in

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