carcinoids, islet cell tumors of the pancreas, paragangliomas and small-cell carcinomas ofthe lungs (1—4).Ourexperience points to several drawbacks of ‘231-Tyr-3-octreotide in its use for in vivo scintigraphy. First, the labelingof Tyr-3-octreotide with 123!is cumbersome and requiresspecial skills. Second, Na'23! of high specific activity (5,6)is expensive and hardly available worldwide. Third, themoment of the labeling and scanning procedures is dependent on the logistics of the production and delivery ofNa'23!. Finally, substantial accumulation of radioactivityis seen in the intestines, since a major part of ‘231-Tyr-3-octreotide is rapidly cleared via the liver and biliary system.This makes the interpretation of planar and single-photonemission computed tomographic (SPECT) images of theupper abdomen difficult.

Part of these problems can be solved by replacing 1231with ‘‘‘In,which also improves scintigraphy 24—48hr afterapplication by virtue ofits longer half-life. Binding “Into the somatostatin analog octreotide has been carriedout by complexing with a diethylenetriaminepentaaceticacid (DTPA) group coupled to the aNH2-group of theN-terminal D-Phe residue (7). In rats, it appeared thatI I ‘In-DTPA-D-Phe-l-octreotide: (1) is excreted via the

kidneys, (2) shows only minor accumulation in theliver and (3) has an initial plasma half-life in the orderof minutes (8).

In this study, we report data concerning the metabolismof intravenously administered ‘‘‘In-DTPA-D-Phe-l-octreotide in man, as well as estimates of its radiation dosein principal organs and the effective dose equivalent. Also,scintigraphic images of various somatostatin receptor-positive tumors have been compared using both ‘23I-Tyr-3-octreotide and ‘‘‘In-DTPA-D-Phe-l-octreotide as radiopharmaceuticals in the same patients.

MATERIALS AND METhODS

Sdn@graphy with @l-Tyr-3-octreotidehas several majordrawbacks as regards its metabolic behavior, its cumbersomepreparationandtheshortphysicalhalf-lifeof theradionuclide.The use of another radiolabeledanalog of somatostatin, 111lnDTPA-D-Phe-1-octreotide, has consequently been proposed.DTPA-D-Phe-1-octreotidecan be radiolabeled with 1111nin aneasy single-step procedure. DTPA-D-Phe-1-octreotide iscleared predominanfly via the kidneys. Fecal excretion ofradioactivity amounts to only a few percent of the administered radioactivity.For the radiationdose to normaltissues,the most important organs are the kidneys, the spleen, theurinary bladder, the liver and the remainder of the body. Thecalculated effective dose equivalent is 0.08 mSv/MBq. Optimal ‘111n-DTPA-D-Phe-1-octreotidescintigraphicimagingofvarioussomatostatinreceptor-positivetumorswas obtained24 hr after injection.In the six patientsstudied,tumor localizationwith 1231-Tyr-3-octreotideand with 1111n-DTPA-D-Phe1-octreotidewere found to be similar.However,the normalpituitary is more frequently visualized with the latter radiopharmaceutical. Inconclusion, 1111n-DTPA-D-Phe-1-octreotideappears to be a sensitive somatostatin receptor-positive tissue-seeking radiopharmaceuticaJ with some remarkable advantages: easy preparation, general availability, appropriatehalf-life and absence of major interference in the upper abdominal region, because of its renal clearance. Therefore,‘11ln-DTPA-D-Phe-1-octreotidemay be suitable for use inSPECT of the abdomen,whichis importantin the localizationof small endocrine czastroenterooancreatic tumors.

J NucI Med 1992; 33:652—658

e recently introduced the somatostatin analog Tyr3-octreotide labeled with 1231for the localization of primaryand metastatic somatostatin receptor-rich tumors, such as

Received Jul. 23, 1991; revision accepted Dec. 4, 1991.For reprintscontact: E. P. Krenning,MD,PhD,Professor of NuclearMedi

e@ine,University Hospital Dijkzigt, Department of Nudear Medicine, Dr Molewaterplein 40, 3015 GD Rotterdam, The Nethetlands.

Thesomatostatin derivatives DTPA-D-Phe-l-octreotide (SDZ2 15-811) and Tyr-3-octreotide (SDZ 204-090) were prepared by

652 The Journal of Nuclear Medicine •Vol. 33 •No. 5 •May 1992

Somatostatin Receptor Scintigraphy with Indium111-DTPA-D-Phe-1-OctreotideinMan:Metabolism, Dosimetry and Comparison withIodine- 123-Tyr-3-OctreotideE.P. Krenning, W.H. Bakker, P.P.M. Kooij, W.A.P. Breeman, H.Y. Oei, M. de Jong, J.C. Reubi, T.J. Visser,C. Bruns, D.J. Kwekkeboom, A.E.M. Reijs, P.M. van Hagen, J.W. Koper, and S.W.J. Lamberts

Departments ofNuclear Medicine and Internal Medicine III, University Hospital Dijkzigt, Rotterdam, The Netherlands;Sandoz Research Institute, Berne and Department ofEndocrinology, Sandoz Pharma AG, Base!, Switzerland

Sandoz (Basel, Switzerland). Indium-i 11-chloride (“ultra-pure―)and Na'231 were obtained from Mallinckrodt Diagnostica (Petten,The Netherlands) and Medgenix (Fleurus, Belgium), respectively.Indium-l 11-chloride contained ‘I4mInto a limited extent (0.5kBq ‘‘41n/MBq‘‘‘Inat calibration time). RadiolabelingofDTPAD-Phe-l-octreotide with ‘‘‘Inand of Tyr-3-octreotide with 1231and quality control of the products were performed as describedbefore (5—8).Depending on the interval between injection andscintigraphy,and whetherSPED' wasrequired,the administeredradioactivity of ‘‘‘In-DTPA-D-Phe-l-octreotideand of ‘23I-Tyr3-octreotide ranged from 185 to 259 MBq and from 370 to 555MBq, respectively, given as an intravenous bolus. The administered dose ofthe somatostatin analogs varied from 7 to 20 @tgperinjection.

ImagingPlanar and SPECT images were obtained with a large field of

view gamma camera (Counterbalance 3700 and ROTA II, Siemens, Hoffman Estates, IL), equipped with a medium-energyparallel-hole collimator. The pulse-height analyzer windows werecentered over both ‘‘‘Inphoton peaks (172 keY and 245 keY)with a window width of 20%. Data from both windows wereadded to the acquisition frames. The camera was connected to adedicated PDP 11/73 computer (Digital Equipment Corp., Maynard, MA) using the Gamma 11 and SPETS V 6.1 software(Nuclear Diagnostics, Stockholm, Sweden). The acquisition parameters for planar images were: ( I) 128 x 128 word matrix,(2) imagesof head/neck:300,000presetcounts (or max. 15mm)at 24 hr and 15 mm preset time (@200,000counts) at 48 hr afterinjection and (3) images of the rest of the body: 500,000 counts(or max. 15 mm); for SPECT: (1) 60 projections, (2) 64 x 64word matrix and (3) 60-sec acquisition time per projection.SPECT analysis was performed with a Wiener filter on originaldata. The filtereddata were reconstructedwith a ramp filter. Ifindicated, SPECT studies were performed 4 hr (head and neck)or 24 hr (remainder ofthe body) after injection ofthe radiopharmaceutical. Planar studies were carried out both after 24 hr and48 hr (videsupra),and in a fewcasesalsoafter0.5 hr and4 hrwith the same protocol used in the 24-hr studies. Total-bodyscintigraphy(scintigraphyof extremities only if indicated) ofevery patient was performed at least once, usually 24 hr afterinjection.

Measurement of 1111nRadioactivfty in Blood, Urine andFeces

Radioactivity in blood, urine and feces was measured with anLKB-l282-Compugamma system or a GeLi-detector equippedwith a multi-channel analyser (Series 40, Canberra).

Bloodsampleswerecollecteddirectlybefore injectionand 2,5, 10, 20 and 40 mm and 1, 4, 20 and 48 hr after injection. Urinewas collected from the time ofinjection in two 3-hr intervals andthereafter in intervals of6 hr until 48 hr after injection. If feasible,feces was collected until 72 hr after injection. The chemical statusofthe radionuclide in blood and urine was analyzed as a functionof time by using the SEP-PAK C18, HPLC and gel filtrationtechniques as described previously (5). The nature of peptidebound radioactivity in blood and urine was tested by investigationof specific binding to somatostatin receptors on rat brain cortexcell membranes as described previously (9).

PatientsThe data describedin this paper were derived from patients

who had been referredfor a varietyof potentiallysomatostatinreceptor-positive tumors. All patients gave informed consent toparticipate in the study, which had been approved by the ethicscommittee of our hospital. Kinetic studies with ‘‘‘In-DTPA-DPhe-i-octreotide by means of gamma camera scintigraphy wereperformed in 26 patients. Additionally, plasma, urine and fecessampleswere obtained from 9, 10,and 4 patients, respectively.In another six patients we were able to perform somatostatinanalog scintigraphy with ‘23I-Tyr-3-octreotideas well as withI I In-DTPA-D-Phe-l-octreotide with a maximum interval of 3

mo.

DosimetryFor the estimation of the radiation dose, the MIRDOSE ver

sion 2 program (10) and ICRP publication 53 (11) were used.The uptakes in the most important source organs, the kidneys,the spleen, the liver, the urinary bladder and the remainder ofthe body, were determined as a function of time. Radioactivityin the kidneys, liver and spleen was calculated as described before(6). Radioactivityin theurinarybladderwascalculatedusingthemeasured radioactivityexcreted in the urine and assuming abladder voiding interval of 3.5 hr (11). Radioactivity in theremainder of the body (expressed as percentage of the administered radioactivity) as a function oftime was determined as 100%minus the % uptake in kidneys, liver, spleen, urinary bladder andexcreted radioactivity in urine and feces.

In eight patients, the uptake in the kidneys,spleen and liverwas measured with the gamma camera 0.5, 4, 24 and 48 hr afterinjection of―‘In-DTPA-D-Phe-l-octreotide.The results obtainedin two patients could not be used because ofan extensive overlapof the right kidney and the liver. In the six remaining patients,the excreted radioactivity in the urine (until 48 hr after “InDTPA-D-Phe-l-octreotide injection) was measured as well. Infour patients, the fecal excretion was also determined until72 hr after injection. The calculation ofthe radiation dose in thegastrointestinal tract was performed using the mean radioactivitydetected in the feces ofthese four patients. The dose estimates ofthe various organs and the effective dose equivalent were calculated for each ofthe six patients individually.

In order to perform dosimetry when only gamma camerameasurements were available 24 and 48 hr after ‘‘‘In-DTPA-DPhe-l-octreotide injection, a model was developed. In this modelthe residence times for the kidneys, spleen and liver were calculated for each individual patient on the basis ofthe organ uptakesafter 24 and 48 hr. For the urinary bladder contents and theremainderofthe bodymeasurements,mean residencetimeswereused. With this model, it was possible to calculate the doseestimates and the effective dose equivalent in another 18patients.Apart from the organsmentioned above, radioactivitywas seenin both the thyroid and pituitary glands in most patients.

RESULTSMetabolism

The average plasma radioactivity decreased rapidly afterinjection of ‘‘‘In-DTPA-D-Phe-l-octreotide in nine patients. Assuming a plasma volume of 3 liters, the meanradioactivity in the blood circulation was calculated todecrease within 10 mm to 33% ±7% (s.d.) ofthe injected

653SomatostatinReceptorScintigraphy•Krenninget al

amount. In five patients, the chemical status of the radionuclide in the plasma was investigated as a function oftime. In Figure 1, the time course of total and peptidebound radioactivity in the plasma of these five patientsare presented up to 20 hr after injection of ‘‘‘In-DTPAD-Phe-i-octreotide. During the first 4 hr, plasma radioactivity was mainly peptide-bound in the form of intactâ€â€â€˜In-DTPA-D-Phe-l-octreotide as demonstrated by

HPLC. Only the last two points of the observation periodshowed proportionally increasing amounts of non-peptidebound radioactivity, eluting in the void volume.

Urinary excretion of radioactivity was measured in tenpatients. In five of these patients, the chemical status ofthe radionuclide in the urine was also investigated.Figure 2 shows the rapid excretion of the administeredradioactivity via the urine from about 25% after 3 hr, 50%after 6 hr. 85% after 24 hr to over 90% after 48 hr for thisgroup offive patients. Figure 2 also shows that the excretedradioactivity was mainly peptide-bound in these patients.SEP-PAK and HPLC analyses of urine and plasma samples as functions oftime after injection demonstrated thatpeptide-bound radioactivity predominantly consisted of1@ ‘In-DTPA-D-Phe-l-octreotide during the first hours after

injection. Twenty-four hours after injection, in additionto ‘‘‘In-D-Phe-l-octreotideand peptide-bound degradation products, a major part of urinary radioactivity elutedfrom the HPLC in the void volume (Fig. 3). Feces, collected until 72 hr after injection of ‘‘‘In-DTPA-D-Phe-loctreotide from four patients with normal intestinal function, contained less than 2% of the administered radioactivity. The SEP-PAK C 18 and HPLC-punfied radiolabeledpeptide component in plasma and urine showed the samebiological activity as the radiopharmaceutical itself, as

3

FIGURE1. Totalplasma(.)andpeptide-bound(0)radioactivity after administrationof 1111n-DTPA-D-Phe-1-octreotidein fivepatients.Resultsarecomparedwithtotalplasma(A)radioactivityafter administration of 1@l-Tyr-3-octreotidein seven patientstaken from reference 6. Data are expressed as mean ±s.d.percentage of the administered radioactivity. Note the logarithmicscale of values in the ordinate of the inset.

C)

cc 1000.@

ccI-

@05)c- 605)

In

cc

0

120

80

40

20

0 10 20 30 40 50

hours after injection

FIGURE2. Cumulativetotal(.) andpeptide-bound(0) “1lnurinaryexcretion (n = 5) and mean urinary bladder radioactivityvoiding (—)(n = 5) after intravenousinjectionof 1111n-DTPA-D-Phe-1-octreotide.Dataareexpressedas mean±s.d. percentageof theadministeredradioactivity.

indicated by its specific binding to somatostatin receptorson rat brain cortex cell membranes (data not shown).

DosimetryThe uptake of radioactivity in the liver, spleen and

kidneys was measured with the gamma camera in sixpatients. Ifeither the thyroid or the pituitary, or both, wereclearly distinguishable from the surrounding tissue, theuptake in these organs was measured as well. Other organs(e.g., the intestines) showed low accumulation of radioactivity and were, therefore, disregarded in the gamma cam

FIGURE3. TypicalHPLC-elUtiOnprofileof humanurine,collected 24 hr after intravenous injection of “1ln-DTPA-D-Phe-1-octreotide. At a retention volume of about 4 ml, non-peptidebound1111n,such as 1111n-DTPA,is elUtedat 12—18ml 111Incontainingdegradationproducts and at about 19 ml the originalrad@igand.

C)cc0

@0ccI.

.@

5)I-5)

.;@ 20

@0 10

cc

00

50

40

30

radioactivity In urine (S of maxImum)

100

80

60

40

20

0--0 5 10 15 20 25

elutionvolume(ml)

0 1 2 4

hours after injection

654 The Journalof NuclearMedicine•Vol. 33 •No. 5 •May 1992

TABLE2DoseEstimatesAfter IntravenousAdministrationof 111ln

DTPA-D-Phe-1-Octreotidein Man on the BasisofGammaCameraMeasurements (n = 24), UrinaryExcretionMeasurements

(n = 10) and Fecal ExcretionMeasurements(n=4).Absorbed

doseRangeTargetorgan (mGy/MBq) (mGy/MBq)

RadioactivityTime%UptakeRemainder

of(hr)nLiver Spleen Kidneysthe body

aTheradioactivityintheremainderofthebodyistheadministeredradioactivity(100%)minusthe%radioactivityin liver,spleen,kidneys,urinarybladder,urineandfeces.

era measurements. The time courses of radioactivity inthe liver, spleen and kidneys showed close similaritiesbetween individual patients (data not shown). The resultsof the uptake measurements are given in Table 1. Fivethyroid and two pituitaries in the group of six patientscould be completely distinguished from the surroundingbackground (vide infra). The radioactivity in the thyroid(maximal 0.03%) and the pituitary (maximal 0.003%)varied strongly between individual patients. Frequently,these organs were only visible on the 24-hr images. Therefore, the residence time was calculated assuming that theeffective half-life equals the physical half-life. The absorbeddoses for the thyroid and the pituitary (12,13), corresponding to the maximum uptake measured in the group of sixpatients, are given in Table 2. Radioactivity excreted inthe urine was used for calculation of the residence time ofthe urinary bladder contents for all patients and showedthe same course as the mean depicted in Figure 2. For allpatients, the radioactivity in the feces was taken to be themean of the radioactivity measured in the four patients(0.5% and 1.7% after 24 and 48 hr, respectively). Evenassuming that these maximum values occurred in the samepatient, the contribution of the thyroid, the pituitary andthe feces to the effective dose equivalent was less than 5%and could therefore be neglected. The dose estimates ofthe various organs and the effective dose equivalent werecalculated for these six patients (data not shown).

The contribution to the absorbed dose caused by theâ€L4mIn contamination was calculated on the basis of the

information obtained from the manufacturer and wasfound to be less than 0.5% of the dose from ‘‘‘In.Inpractice, the radionuclide was administered before thecalibration time, thus lowering even more the contributionof ‘I4mInto the radiation dose.

0.45―°0.07M0

0.32MD

0.019'@°0.020―°0.18MN

O.O3―@'@0•04MNt

0.04Mx

0.11MX

0.19—0.800.04—0.150.10—0.66

0.015—0.0260.016—0.026

a

n.a.n.a.

Range(mSv/MBq)0.05—0.12

KidneysLiverSpleenGonadsRedmarrowUrinarybladderwallGltract

SmallintestinalwallULIwallLLIwall

ThyroidglandPituitary

The inputto the smallintestinesis taken to be the same as thefecalexcretionduring72 hr (n= 4),viz 1.7%.Forthe thyroidandthepituitary(n = 6), the radiationdose COrreSpOndSto the maximumorganuptakemeasuredin thesepatients.

MD denotes median.

MN denotes mean.

MX denotes calculations for maximum uptake.

a Not applicable due to the model.

@lCRP30Glmodelused.

On the basis of the data obtained in the six patients, itappears that more than 70% of the effective dose equivalent results from radioactivity accumulated in the kidneys,spleen and liver. The uptake of radioactivity in theseorgans showed much greater individual variation in thesesix patients than the radioactivity excreted in the urineand the calculated uptake in the remainder of the body.Therefore, in the model employed, the uptake of radioactivity in the liver, kidneys and spleen is based on individualgamma camera measurements. Table 1 shows that in thegroup of six patients, radioactivity in the spleen increasesslightly from 0.5 to 24 hr and decreases afterwards in allpatients. In the liver, the radioactivity decreases rapidlyduring the first hour, thereafter an increase is measureduntil 24 hr, followed by a decrease. For the calculation ofthe residence time in the model, the radioactivity in theliver and the spleen was assumed to remain constant from0 to 24 hr and to decreaseafter 24 hr monoexponentiallywith time. Radioactivity in the kidneys shows a steadydecrease (Table 1) starting shortly after the injection of theradiopharmaceutical. For this reason, the calculation ofthe kidney residence time was based on a monoexponential curve. The initial uptake in the kidneys was calculatedby extrapolating the uptakes at 24 and 48 hr to t = 0.

The periodic accumulation and discharge of radioactivity in the urinary bladder was calculated from the mean

Medianeffectivedoseequivalent(mSv/MBq)

0.08

TABLE 1Radioactivity in Selected Organs and Remainder of the

Body (mean ±s.d.) as a Function of Time After IntravenousAdministration of ‘11ln-DTPA-D-Phel-Octreotide in Man on

the Basisof GammaCameraMeasurementsandCalculationsExpressedas Percentageof the Administered

0.562.8±1.22.0±0.96.8±1.384.2±7.7461.9±0.42.4 ±0.97.2 ±1.846.7 ±17.92462.2±0.62.6±1.16.3±2.18.7±9.74861

.8 ±0.41 .8±0.65.0 ±2.07.2 ±8.824183.0

±1.32.9 ±1.64.8 ±1.748182.5±1.02.1 ±1.23.5 ±1.3

655SomatostatinReceptorScintigraphy•Krenninget al

.Patientno.SexAgeTumor typeInterval betweenscansAbnormal

sitesof radioactiveaccumulation‘@I-octreotide‘11ln-octreotide1F66Small-cell

lungcancer5 wkRight lung,lowerlobeRight lung,lowerlobe2M65Gastnnoma7wkGallbladder regionGallbladder region(seetext)3F59Insulinoma1wkNone (SPECTnot done)None (SPECTpositive,Fig.4)4F50Carcinoid1

0 wkLeft supraclavicularlymphnode,liverLeft+nght

supraclavicularlymph node, abdomen,chest,liver5F64Carcinoid5

wk3 caudalabdominalsites,1cranialabdominalsite3

caudalabdominalsites,liver(gallbladderremoved;see

text)6F28Pheochromocytoma4wkLower left abdomenLower left abdomen

collected urinary radioactivity in 10 patients. There is nosignificant difference in the cumulative urinary radioactivity between these 10 patients and the 5 patients presentedin Figure 2. The radioactivity in the remainder ofthe bodywas calculated by subtraction of the mean uptakes in thekidneys (n = 6), spleen (n = 6), liver (n = 6), urinarybladder contents (n = 10)and mean excreted radioactivityin urine (n = 10) and feces (n = 4) from the administeredamount. The residence time in the remainder of the bodycould be determined by fitting a monoexponential curveto the radioactivity course after injection. The six patientswere recalculated using the model described. There wereno statistically significant differences in the dose estimatesof the various organs and in the effective dose equivalentin comparison to the direct estimates for each individual(data not shown). Therefore, application of the modelappeared to be valid. In 18 patients, the uptake in thekidneys, spleen and liver was measured after 24 and 48 hr(Table 1). These data did not differ significantly from thevalues obtained at the same time points in the six patients.Consequently, the model was applied to the additional 18patients. The final dosimetric results for the completegroup of 24 patients are shown in Table 2.

lodine-123-Tyr-3-Octreotide and 111In-DTPA-D-Phe-1-Octreotide Scintigraphy: Comparison in LocalizationofTumorTissue

A comparison between scintigraphy with ‘23I-Tyr-3-octreotide and scintigraphy with ‘‘‘In-DTPA-D-Phe-l-octreotide, performed in an interval ofless than 3 mo for thesame patients, is given in Table 3. In four of six patients(Patients 1—3,and 6) the results of the subsequent scintigrams were identical. In Patient 2, ‘23I-Tyr-3-octreotidescintigraphy showed accumulation of radioactivity in theregion of the gallbladder, which is not unusual for thisradiopharmaceutical, considering its extensive biliaryclearance. However, the same was observed with “InDTPA-D-Phe-1-octreotide, which is unusual, since thisradiopharmaceutical is largely excreted by the kidneys.SPECT with ‘‘‘In-DTPA-D-Phe-l-octreotide demonstrated a tumor located ventral to the gallbladder. In

Patient 3, SPECT images after ‘‘‘In-DTPA-D-Phe-i-octreotide injection revealed the localization of the insulinoma, medial and anterior to the spleen and left kidneyrespectively (Fig. 4). However, this localization had notbeen recognized on planar images with both radiophar

maceuticals. In Patient 4, presumed carcinoid depositswere more numerous using ‘‘‘In-DTPA-D-Phe-l-octreotide scintigraphy. Tumor progression in the relatively longinterval between the two scintigrams cannot be excluded,however. In Patient 5, the liver showed an irregular uptakepattern of ‘‘‘In-DTPA-D-Phe-l-octreotide, whereas a homogeneous distribution was seen with ‘23I-Tyr@-3-octreotide scintigraphy. The cranial abdominal site of radionuclide accumulation observed with ‘23I-Tyr-3-octreotidewas not seen on the subsequent ‘‘‘In-DTPA-D-Phe-ioctreotide scintigram. This site very likely representedabnormal uptake in the gallbladder and the hepatoduodenal ligament, which had been surgically removed between the two scintigrams and were proven to be massivelyinfiltrated by a carcinoid tumor.

Apart from the marked differences in hepatic and renalclearances (Fig. 5), tissue accumulation ofboth radiopharmaceuticals was similar except for the pituitary, which wasnearly always visible with ‘‘‘In-DTPA-D-Phe-l-octreotidein contrast to ‘23I-Tyr-3-octreotidescintigraphy. However,discrimination between accumulation of ‘‘‘In-DTPA-DPhe-l-octreotide in the pituitary and in the surroundingtissues is often impossible, especially caudally. Consequently, only the contour ofthe cranial part ofthe pituitarycan be distinguished since in the region of the brain the(background) radioactivity is relatively very low becauseofthe blood-brain barrier. For both radiopharmaceuticals,radioactivity was always observed in the thyroid, liver,spleen and kidneys, the urinary bladder and in the intestinal tract, although in the last organ ‘‘‘In-DTPA-D-Phe1-octreotide was much less visible.

DISCUSSIONIn spite of a lower affinity of ‘‘‘In-DTPA-D-Phe-l

octreotide for the rat brain somatostatin receptor com

TABLE 3PatientDataandResultsof Somatostatin-ReceptorScintigraphywith 123l-Tyr-3-Octreotideand

111In-DTPA-D-Phe-1-Octreotide

656 TheJournalof NuclearMedicine•Vol.33 •No.5 •May 1992

S

(t,12= 2.8 days for “Inversus 13.2 hr for 1231)results in alonger residence time of the radiopharmaceutical in thetissues. The presence of a lower radioactivity in the remainder of the body 24 hr after injection of ‘‘‘In-DTPAD-Phe-1-octreotide leads to a lower background radioactivity (Fig. 1) (6). The higher background radioactivitywith ‘23I-Tyr-3-octreotideis due to its much higher circulating levels of degradation products than is the case withâ€I ‘In-DTPA-D-Phe-i-octreotide. Therefore, â€â€â€˜In-DTPA

D-Phe-l-octreotide is a more suitable radioligand to localize somatostatin receptor-rich tissues (vide infra). Furthermore, using ‘‘‘In-DTPA-D-Phe-l-octreotide, interpretation ofscintigrams ofthe abdominal region is less affectedby intestinal background radioactivity. This contrasts remarkably with ‘23I-Tyr-3-octreotidescintigraphy, becausethe hepatobiliary clearance of this compound results in ahigh hepatic and intestinal accumulation of radioactivity,which is hardly overcome with laxatives.

Analysis of the chemical status of plasma radioactivityduring the first 4 hr after injection shows mainly peptidebound ‘‘‘Inin the form ofthe original ‘‘‘In-DTPA-D-Phel-octreotide. Similarly, analysis of radioactivity in theurine shows predominantly intact ‘‘‘In-DTPA-D-Phe-loctreotide during the first hours after injection. Furthermore, peptide-bound radioactivity in plasma and urinehas somatostatin receptor-binding properties as demonstrated by specific binding to rat brain cortex cell membranes. Degradation of ‘‘‘In-DTPA-D-Phe-l-octreotidewas observed only in plasma and urine samples obtainedmore than 4 hr after intravenous injection of the radiopharmaceutical, when circulating radioactivity amountedto less than 10% of the administered radioactivity. Ultimately, degradation to ‘‘‘In-labeledproducts such as―‘InDTPA is suggested by the appearance of the peak in thevoid volume of HPLC analysis.

Accumulation ofradioactivity after intravenous administration of' ‘‘In-DTPA-D-Phe-i-octreotide in man is observed in the pituitary and thyroid gland, the spleen, liver,kidneys and the urinary bladder. Imaging ofthe gallbladderis occasionally seen, whereas the presence of intestinalradioactivity (mainly in the colon at 24 hr) depends onthe simultaneous use oflaxatives. The relatively low clearance ofthe radioligand via the hepatobiliary system favorsits use in SPECT of the abdomen, which is stronglyindicated in the localization of small endocrine pancreatictumors. The mechanism of the thyroid gland imaging isstill unclear. With radiolabeled somatostatin analogue autoradiography, we could not find somatostatin receptorsin normal thyroid gland and differentiated thyroid carcinoma (papillary cancer) tissue slices (14,15). However, ahigh percentage ofmalignant parafollicular thyroid tumorsare somatostatin receptor-positive by both autoradiography and scintigraphy (14,15). It is remarkable that in thetwo cases with Graves' hyperthyroidism investigated sofar, accumulation of radioactivity in the thyroid was increased (unpublished data). The presence of lymphocytes

I

‘a'

S

FIGURE 4. Indium-i11-DTPA-D-Phe-1-octreotide 24 hrSPECTimageof Patient3 witha solitaryinsulinomainthetailofthepancreas,whichis shownmedialandanteriorto thespleenand left kidney. The line on the referenceimage (left) indicatesthe positionof the transversalslice(right).K = kidney,S =spleen,T = tumor and L = liver.

pared to that of ‘231-Tyr-3-octreotide(7), the indiumlabeled compound visualized somatostatin receptor-positive animal tumors more efficiently in vivo, probably dueto its different metabolic behavior (8). These metabolicproperties turned out to be similar in man; our studyshows that after intravenous administration ‘‘‘In-DTPAD-Phe-l-octreotide is rapidly cleared from the circulationvia the kidneys. However, its initial disappearance fromthe circulation is considerably slower compared to that of‘23I-Tyr-3-octreotide(Fig. 1) (6). This slower initial clearance, combined with the longer physical half-life of ‘‘‘In

FIGURE 5. Sequentialanteriorabdominalviewsof ‘23I-Tyr-3-octreotidescintigraphy(A)showingrapidhepatobiliaryclearance,and posteriorabdominalviews of 111ln-DTPA-D-Phe-1-octreotidescintigraphy(B) showing rapid renal clearance.Note the rapidlydecreasingblood-poolradioactivityoverthe heartwith both radiopharmaceuticals.The 20-mmimageof the latter scintigramsalsoshowsa low-gradeaccumulationof radioactivityinthelowerpartof the vertebral column due to a chondrosarcoma.

2 5 10 20

657SomatostatinReceptorScintigraphy•Krenninget al

[which can be somatostatin receptor-positive (16)] in thethyroid could explain this observation. Autoradiographyof normal spleen tissue revealed the presence of somatostatin receptors (unpublished); however, the exact celltype bearing the somatostatin receptor has not been iden

tified yet. Patients on octreotide treatment show a diminished accumulation of radioligand in the spleen (unpublished), compatible with occupancy ofspleen somatostatinreceptors by the unlabeled octreotide.

The rapid appearance of intact ‘‘‘In-DTPA-D-Phe-loctreotide in the urine indicates an effective renal clearanceofthis radiopharmaceutical. By contrast, ‘231-Tyr-3-octreotide is rapidly cleared by the liver and little of it is excretedintact into the urine. The different metabolism of “InDTPA-D-Phe-i-octreotide compared with ‘23I-Tyr-3-octreotide indicates that the modification of octreotide withthe ‘‘‘In-DTPAgroup inhibits hepatic clearance and/orfacilitates renal clearance. Rat liver perfusion studies haveindeed shown that ‘‘‘In-DTPA-D-Phe-l-octreotide iscleared much more slowly by the liver than ‘23I-Tyr-3-octreotide (unpublished data). It is unknown whether theeffect of the ‘‘‘In-DTPAgroup on the metabolic routingof peptides is a general phenomenon. The relatively longresidence time of ‘‘‘In-DTPA-D-Phe-l-octreotide in thekidneys suggests that following glomerular filtration partofthe label is reabsorbed in the tubules (8).

The higher sensitivity of ‘‘‘In-DTPA-D-Phe-l-octreotide compared to ‘23I-Tyr-3-octreotide in localizing thepituitary is remarkable, since in vitro studies have showna higher affinity of the radioiodinated ligand for somatostatin receptors in rat brain ( 7). However, its actualaffinity for somatostatin receptors on the pituitary is atpresent unknown.

For several somatostatin receptor-positive tumors, “InDTPA-D-Phe-l-octreotide shares with ‘23I-Tyr-3-octreotide the advantage of providing a more sensitive imagingtechnique when compared to currently available diagnosticprocedures, e.g., CT, ultrasound and MRI. Furthermore,the future availability of both DTPA-D-Phe-l-octreotideand pure ‘‘‘InCl3,will make an easy single-step labelingprocedure possible and, hence, scintigraphy of somatostatin receptor-positive tumors generally available.The effective dose equivalent, although higher than thatof ‘23I-Tyr-3-octreotide,is comparable with values forother ‘‘‘In-labeledradiopharmaceuticals (11) and is acceptable in view of the clinical indications.

658 TheJournalof NuclearMedicine•Vol.33 •No.5 •May 1992

ACKNOWLEDGMENTSThe authors thank ma Loeve, Marianne Goemaat-Yisser, Mar

cel van der Pluijm and Michiel de Roo for their expert technicalassistance and Michael Stabin for providing the S-value tables for

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