CLINICALSCIENCES

Meta- [I- 131]iodobenzylguanidine (I- I31 MIBG) isa radiolabeled analog of the adrenergic blocking agentguanethidine (1). Its affinity for the adrenal medulla hasmade it useful in the detection of pheochromocytomasand adrenal medullary hyperplasia (2,3). In the canineadrenal medulla 1-131 MIBG is sequestered mainly inthe chromaffin storage granules (4). In addition it appears that a major component of MIBG retained inmyocardium is that sequestered within the norepinephrine storage vesicles of the adrenergic nerves of thecanine heart (5). 1-131 MIBG is thus believed to shareuptake and storage mechanisms similar to those of norepinephrine.

We have frequently observed prominent visualizationof the salivary glands on the 1-131 MIBG head-chestimages routinely obtained to detect extraadrenal andmetastatic pheochromocytomas (6). Accumulation of1-131 MIBG in the salivary gland may be related tosympathetic innervation as this organ which, like theheart, is richly supplied by sympathetic nerves (7,8).This study was undertaken to elucidate the uptake and

Received Jan. 31, 1983; revision accepted July 21, 1983.For reprints contact: Dr. B.Shapiro, Div.of Nuci. Med., University

of Michigan Hospitals, Ann Arbor, MI 48109.

excretion mechanism of 1-131 MIBG accumulation inthe salivary glands.

MATERIALS AND METHODS

Because the salivary glands are known to concentrateI-I 31 ions, it was first necessary to exclude the possibilitythat the observed salivary images were merely due to theuptake of free radioiodide present in the radiopharmaceutical or liberated from it in vivo. To do so, the following experiments were performed.

Studies in man. I . As the salivary glands, thyroid, andstomach are all known to concentrate iodide (9) thefrequency of visualization of these organs was evaluatedin the images of I51 patients referred for the location ofpossible pheochromocytomas (67 male; 84 female, ages6—73yr).

2. The influenceof thedoseof iodideadministeredwas noted on the frequency of visualization of salivaryglands, thyroid, and stomach. Seventy-five patients hadreceived three drops of saturated solution of potassiumiodide per day (SSKI, I20 mg of iodide), 61had receivedLugol's solution six drops per day (40 mg of iodide) toblock thyroidal uptake of I- I3 1. Administration of iodides was begun on the day before tracer injection and

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DIAGNOS11C NUCLEAR MEDICINE

SalivaryGlandAccumulationofMeta-[13'l]lodobenzylguanidine

M.Nakajo,B.Shapiro,J.C.Sisson,D.P.Swanson,andW.H.Beierwaltes

Universityof Michigan,AnnArbor,Michigan

intenseuptakeof m-[1311]iodobenzylguanidine(1-131MIBG) hasbeenobservedin the salivaryglandsof patientsundergoingscintigraphyfor the locationof suspectedpheochromocytomas.Thisuptakeof radioactivitywas notdueto free 1-131derived from the 1-131MIBG but rather to uptake of 1-131MIBG by sympatheticneuronalelementsin the salivaryglands.Inkeepingwith this,administrationof tncyclic antidepnessantsreversiblyblockedsalivaryuptake of 1-131MIBG.Furthermore, 1-131 MIBG uptake was markedly diminishedby the ipsilaterai salivaryglandsin a patientwith Homer'ssyndrome,andwas bilaterallydiminishedina patient withsevere idiopathicsympatheticautonomicneuropathy.The salivaryglanduptake of 1-131MIBGmay providea meansfor the studyof sympatheticinnervation of these organs,and thusfor the studyof generalizeddisordersof autonomicinnervation.

J NucI Med 25: 2—6,1984

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Thyroid blocking agents (dose/day)Lugol'ssolutionsS

Organs 4 hrKI(120mgof I)(40 mgof I)Omitted

48 hr 4 hr 24 hr 48hr24hr48 hr4 hr24 hr

CLINICAL SCIENCESDIAGNOSTIC NUCLEAR MEDICINE

continued for at least 4 days afterwards. The remaining15 patientsreceivednoiodides,eitherinadvertentlyorbecause of previous thyroidectomy. The images wereobtained at 4 hr in some cases and at 24 and/or 48 hrafter the intravenous injection 0.5 mCi of I- I31 MIBGper I .7 m2 (2). Visualization of the salivary glands(parotid) and thyroid were evaluated on the posteriorhead/chest images. In selected cases, additional anteriorand lateral images of the head and neck were obtainedfor detailed delineation of all the salivary glands. Theregion of the stomach was examined on anterior andposterior abdominal images.

Studies in the dog. As the dog parotid gland is able toconcentrate iodides and the submandibular gland is not(10,1 1), this animal provides an opportunity to determine whether salivary gland activity is due to the uptakeof free 1-131 ions by acinar tissue or 1-131 MIBG byneuronal elements. To do this, tissue distribution studieswere performed on three female mongrel dogs (2 1—27kg) that were injected with 200 @Ciof I- 131 MIBG intravenously. No iodides were administered and animalswere killed by intravenous sodium pentobarbital 2 hrafter tracer injection. Duplicate tissue samples of submandibular and parotid gland were weighed and countedin an auto-gamma counter, with corrections for radioactive decay, background, and counter efficiency. Thetissue concentration was expressed as % kg dose/g.

To further elucidate the mechanism of 1-131 MIBGuptake, a detailed retrospective examination was madeof the group of patients (seven) in whom the salivaryglands were not visualized. This included four patientstaking tricyclic antidepressant medications, one withprofound sympathetic autonomic neuropathy, and onecase of unilateral decreased I-i 31 MIBG uptake in theipsilateral salivary glands of a woman with Homer'ssyndrome.

Additional studies were performed to determinewhether the radioactivity visualized in the salivary glandsat scintigraphy was excreted in the saliva and, if so, inwhat chemical form.

Salivary gland concentration. The subjects were ninepatients with no evidence of salivary gland disorders whowere referred for I- 131 MIBG imaging (three male, sixfemale, ages 26—66yr). All subjects received SSKI asdescribed above. After obtaining informed consent, bloodsamples and unstimulated mixed saliva were collectedat 15 mm, and at 1, 4, 24, and 48 hr following the injection of the diagnostic dose of I- 131 M IBG. Plasma andsaliva samples were counted in an auto-gamma counter,with corrections for radioactive decay, background, andcounter efficiency. Saliva-to-plasma I- I31 ratios werecalculated.

Chemical forms of the radioactivity in saliva. Thesubject was a 61-yr-old white man with metastaticpheochromocytoma, who was referred for I- I31 MIBGtherapy to his malignant lesions (12). The unstimulatedmixed saliva was collected I hr after completion of an i.v.infusion (over 90 mm) of 100 mCi I-I 3 1 MIBG. Aftercollection of the unstimulated saliva, a collection was alsomade following stimulation of the salivary glands bysugarless chewing gum. The chemical form of the radioactivity in the both unstimulated and stimulated saliva was determined using thin-layer chromatography(silica gel G support, acetate/ethanol ( 1:I) Rf I- 131MIBG = 0. 1, Rf I- 13 1 iodide = 0.6) following the dilution of the saliva samples.

RESULTS

Table 1 shows the frequency of visualization of thesalivary glands, thyroid, and stomach observed on 1-131MIBG scintigrams. The salivary glands are visualizedin 92% to 100%of patients, whereas gastric uptake wasnever observed despite the fact that both organs sharesimilar mechanisms for the uptake of iodide. The thyroidgland was seen in all instances where iodide treatmentwas omitted, and in no more than 7% where iodides wereadministered. The presence or absence of pheochromocytoma did not appear to affect visualization of any ofthese organs. Figure 1 shows the salivary glands in thepresence of SSKI administration.

TABLE1. VISUALIZATIONRATE(PERCENT)OF ThE SALIVARYGLANDS,ThYROIDS,AND STOMACHon 1-131MIBGIMAGES

SalivaryglandThyroidStomach

Numberof patients

100 100 92 — 100 1000 0 1 — 3 7

— 100 92

— 100' 100'

013(1)

0 01(1)t 34(5)

0 0 0 0 0 076(9) 5(2) 36(12) 44(15) 1 9

4 Percent in the patients with thyroids (n 3 at 24 hr. 4 at 48 hr).

t ( ) = number harboring pheochromocytomas.

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NAKAJO. SHAPIRO, SISSON. SWANSON, BEIERWALTES

gland images were obtained (Fig. 2). There was in addition a fourth patient who had taken doxepin hydrochloride 600 mg/day up to the time of I- 131 MIBG injection. This drug is a tricyclic antidepressant with actionsimilar to imipramine hydrochloride; it had a similareffect on the salivary glands, reducing visualization toa bare minimum.

One patient had evidence for severe autonomic neuropathy. His plasma catecholamine concentrations wereextremely unusual in that on several occasions theydemonstrated very low recumbent norepinephrine (NE)associated with normal epinephrine (E): NE 39, 24, and15 pg/mI; E 80, 86, 50 pg/mI. There was no significantincrease in norepinephrine on standing. These valuessuggested a severe adrenergic autonomic neuropathy.Figure 3 shows the posterior head-chest image of thispatient, in whom no radioactivity was seen in any salivarygland.

In the remaining three patients, the causes of nonvisualization of the salivary glands could not be identifled. The salivary glands were seen faintly on the 24-hrimages that were available in two of them.

Examination of the salivary gland intensity between24-hr and 48-hr images was possible in 64 patients. Theintensity appeared to decrease between 24 hr and 48 hrin 53% of the cases, with no change in the rest.

The final case was that of a 72-yr-old white womanwith a Homer's syndrome on the right side. She hadepisodes of headache, palpitations, and hypertension. Shegave a history of thyroidectomy for goiter at age 40, withinadvertent sympathectomy leading to a completeright-sided Homer's syndrome. She was referred forI- I3 1 MIBG imaging because of a suspicion of pheochromocytoma. Anterior and lateral head images withI-I 3 1 MIBG were added to the routine images. Afterobtaining the informed consent, salivary gland imaging

@@-•t

r.

FIG. 1. Posterior head-chest image of patient taking SSKI,at 24hr after -131 MIBG.Salivaryglandsshowclearly,butnotthyroid.

The tissue distribution studies in dogs showed that theconcentrations in the submandibular glands (which donot concentrate iodide) were 0.502% kg dose/g ±0.059(mean :1:s.c.m., n six glands) while those in the parotidglands (which do concentrate iodide) were 0.475 ±0.124(n six glands).

Thus it appears that the activity observed in the salivary glands is not due to the concentration of free iodide.

Seven patients showed no salivary gland visualizationat 48 hr after tracer injection. Of these, four were receiving tricyclic antidepressant therapy. Three of thesetook imipramine hydrochloride, a tricyclic antidepressant known to inhibit the neuronal uptake of norepinephrine and guanethidine (13). Two patients weretaking the drug at a dose of 75 mg/day at the time of I-131 MIBG injection, while the third had been taking 40mg/day until 7 days before 1-131 MIBG injection. Intwo of the patients 1-131 MIBG scintigraphy was repeated at 3 and 3½wk following withdrawal of imipramine hydrochloride, and this time clear salivary

F.'.-@

•@@‘:@‘-

.

A B

0

.@.

S@ ,@S.

. .,

*

FIG.2. (A)Salivaryglandsareseenon48-hrposteriorhead-chest1-131MIBOimage, 3 wk after discontinuation of imipramine hydrochloride administration. (B) They had failed to show on 48-hrposterior head-chest1-131MIBGimagetakenduringadministrationof drug(75 mg/day).

FIG.3. Posteriorhead-chestimageat 24 hr after 1-131MIBO,frompatient with idiopathic autonomic neuropathy.No radioactivity appears in salivaryglands;thyroidaccumulationis due to inadvertentomission of iodide administration. Four radioactive surface markersare onshouldertipsandaxillae.

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Time after 1-131MIBGinjection15mm1 hr 4hr 24hr 48hr

CLINICAL SCIENCESDIAGNOSTIC NUCLEAR MEDICINE

:‘@ @..

....@

FIG. 4. Anteriorimagesof patientwithright-sided Homer's syndrome. Discrepancyinrightsalivaryglandvisualizationisobviousbetween24-hr 1-131MIBG(A)and20-mm 99@'TcO4 (B) images.

was performed 20 mm after intravenous injection of 5mCi of Na 99m1c04, and the two sides were compared.The concentration mechanism for pertechnetate in thesalivary glands is similar to that of iodide (14—16),andthus this experiment permitted the examination of theuptake of 1-131 MIBG in neuronal elements and Tc-99mby glandular acini.

Figure 4 contrasts the findings in the salivary glandsbetween I- I31 MIBG (A) and 99mTcO4—(B) imagingin this patient with right-sided Homer's syndrome. Thedifference in the salivary gland images is striking in thetwo studies. The right-sided glands are not seen withMIBG, whereas they are a bit darker, ifanything, withpertechnetate, especially the parotid.

Excretion mechanisms. Table 2 shows radioactivityfrom I- I31 MIBG in plasma and saliva, and the salivato-plasma ratio with time. The mean radioactivity washighest at 15 mm, then declined in both plasma and saliva. The saliva-to-plasma ratio was greater than 1.0 atall times. The greatest mean ratio was observed at 4 hr.Chemical forms of the radioactivity were 98% free I-I 31and 2% 1-131 MIBG in the unstimulated saliva, and 93%and 7%, respectively, in the saliva stimulated withchewing gum. The activity excreted in the saliva represented only a minute fraction of that in the salivarygland.

DISCUSSION

The data summarized in Table I show that themechanism of salivary gland uptake of 1-131 MIBG is

not simple concentration of radioiodide. Although thedosage of iodide (40-130 mg/day) was sufficient toblock iodide uptake by the thyroid, such doses may notfully inhibit uptake by the salivary glands and stomach(16—19).However, only the salivary glands were visualized, and never the stomach despite the fact that bothorgans can concentrate I-131 ions (or 99mTcO4—)by thesame mechanism and with similar affinity (9,20).This discrepancy between salivary gland and gastricvisualization precludes a simple concentration of I- I31ion, and suggests a specific uptake of 1-131 MIBG. Thetissue studies in dogs likewise show that I- 131 M IBG isequally concentrated in the submandibular and parotidglands, both being sympathetically innervated (/0,11),although only the parotid is able to concentrate iodide.

The neuronal nature of the 1-131 MIBG uptake isfurther suggested by:

I . The inhibition of such uptake by tricyclic antidepressants. 1-131 MIBG is a derivative of guanethidine,and shows structural similarities to norepinephrine (1,2).High concentrations of radioactivity from C-14 guanethidine have been found in the salivary glands of miceon whole-body autoradiography (21 ). Antagonism ofguanethidine by tricyclic antidepressants has been welldocumented (22—24).It inhibits the norepinephrineuptake mechanism in the peripheral adrenergic neuronin man and thereby prevents uptake of guanethidine atits site ofaction (13).

2. The lackof 1-131 MIBG uptakeby thesalivary

TABLE2. RADiOACTIVITY(1O@X cpm/l,mean±s.e.m.)FROM1-131MIBGINPLASMAANDSALIVA,ANDSALIVA-TO-PLASMARATIO

PlasmaSalivaSaliva/Plasma ratio

. ( ) = No. of patients.

11.9± 1.3(9)'72.4 ±10.5(9)6.9± 1.3(9)

6.5±0.8(9)55.2 ±7.0(9)9.6±1.6(9)

4.4±0.6(9)53.3 ±8.2(9)13.1 ±2.1(9)

2.5±0.5(7)20.8 ±2.7(9)10.8 ±2.7(7)

1.8 ±0.3(8)10.8 ±2.9(8)5.9±1.6(8)

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NAKAJO. SHAPIRO, SISSON, SWANSON, BEIERWALTES

glands of a patient suffering from severe autonomicneuropathy.

3. The ipsilateral decrease in I- 13 1 MIBG uptake bythe salivary glands of a patient with specific adrenergicsympathetic denervation of these glands due to surgicallyinduced Homer's syndrome.

Although the secretion of saliva is primarily governedby parasympathetic innervation of the salivary glands,these organs receive a rich sympathetic innervation andare sites of norepinephrine uptake (25). The sympatheticnervous system serves to modulate the composition ofsaliva secreted (26). The clearance of I-131 MIBG fromthe plasma was very rapid and the saliva-to-plasma ratioof radioactivity was always greater than 1.0 from 15 mmto 48 hr after 1-131 MIBG injection. The majority ofradioactivity in the saliva was in the form of free I-i 31ion. Stimulation by chewing caused a slight increase inI- 13 1 MIBG in the saliva. This excretion of radioactivityrepresents only a small fraction of that in the gland.

The source of both the free I- 131and I- 131 MIBG isprobably the sympathetic neurons of the salivary glands,although some direct concentration of the radiopharmaceutical by acinar cells may occur. However, the1-131 MIBG seen in images of the salivary glands appears to be principally the neuronal component.

Salivary gland imaging with radioiodinated MIBGmay be useful in assessing disorders of the gland's sympathetic innervation, and thus may be a “diagnosticmirror―of a generalized adrenergic neuropathy such asthat of diabetes.

ACKNOWLEDGMENTS

We thank Dr. T. Mangner and Holly Anderson-Davis for themanufacture of I- 131 MIBG the Phoenix Memorial Laboratory forthe use of their radiochemistry facilities, and Ms. Joanne Boldt forpreparation of the manuscript.

This work was supported by the followinggrants: DHEW #3M01RR00042-22 Sl CLR, NIH #R01 AM 21477, NIAMDD #5P60AM 20575, NCI #09015, and the Nuclear MedicineResearchFund.B.S. is the recipientof an NIH Clinical AssociatePhysicianAward(DHEW #3M01 RR00042-22S1CLR)

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3. VALK TW, FRAGER MS. GROSS MD, et al: Spectrum ofpheochromocytoma in multiple endocrine neoplasia. A scmtigraphic portrayal using ‘311-metaiodobenzylguanidine.AnnIntern Med 94:762—767,1981

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5. WIELAND DM, BROWN LE, ROGERS WL, et al: Myocardial imaging with a radioiodinated norepinephrine storage

analog. J Nuci Med 22:22-3 1, I9816. NAKAJOM, SHAPIROB,Co@@J,etal: Thenormaland

abnormal distribution of the adrenomedullary imagingagent‘31l-metaiodobenzylguanidine (‘311-MIBG)in man: Evaluation by scintigraphy. J. Nucl Med 24:672-682, 1983

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11. COHEN B, MYANT NB: Concentration of salivary iodide:A comparative study. J Physiol 145:595—610,1959

12. SISs0N JC, SHAPIRO B, BEIERWALTES WH, et al:Treatment of malignant pheochromocytomas with a new radiopharmaceutical. C/in Res 31:547A, 1983 (abst)

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14. ALEXANDER WD, HORDEN RM, MASON DK, et al:Comparison ofthe concentrating ability of the human salivaryglands for bromine, iodine and technetium. Archs Oral Biol11:1205—1207,1966

15. HARDEN RMCG, HILDITCH TE, KENNEDY I, Ct al: Uptake and scanning of the salivary glands in man using pertechnetate@99mTc.C/in Sci 32:49—55,1967

16. HARDEN RMcG, ALEXANDER WD, SHIMMINS J, et al:Quantitative aspects of the inhibitory effect ofthe iodide ionon parotid salivary iodide and pertechnetate secretion in man.J Lab ClinMed 71:92-100,1968

17. FERGUSON MH, NAIMARK A, HILDES JA: The interrelationshipbetweenthe parotidsecretionofthiocyanate, iodide,andchloride.Can J BiochemPhysiol35:333—337,1957

18. BROWN-GRANT K: Extrathyroidal iodide concentratingmechanisms. Phys Rev 41 :189—213, 1961

19. TAPLIN GV, JOHNSON DE, DORE EK, et al: Suspensionsofradioalbumin aggregates for photoscanning the liver, spleen,lung and other organs. J Nuci Med 5:259-275, 1964

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21. FURST CJ: Studies on the distribution and excretion of ametabolite of guanethidine in the rat. Br J Pharmacol Chemother32:57-64,1968

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23. MICHELL JR. ARIAS L, OATES JA: Antagonism of theantihypertensive action ofguanethidine sulfate by desipraminehydrochloride. JAMA 202:973-976, 1967

24. MEYER JF, MCALLISTER CK, GOLDBERG LI: Insidiousand prolongedantagonism ofguanethidine by amitriptyline.JAMA 213:1487-1488,1970

25. LEE C-M, JAVITCH JA, SNYDER SH: Recognition sites fornorepinephrine uptake: Regulation by neurotransmitter.Science 220:626-629, 1983

26. ABE K, YONEDA K, FUJITA R, et al: The effects of epinephrine, norepinephrine and phenylephrine on the types ofproteins secreted by rat salivary glands. J Dent Res 59:1627-1634,1980

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1984;25:2-6.J Nucl Med.   M. Nakajo, B. Shapiro, J. C. Sisson, D. P. Swanson and W. H. Beierwaltes 

I]Iodobenzylguanidine131Salivary Gland Accumulation of Meta-[

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