A wide range of physiologic processes have been cxploitcd in the design of organ- and tissue-specific radiopharmaceuticals. The processes include excretion anddetoxification in liver and kidney, particle trapping inlung and RES, biosynthesis ofenzymes and hormonesin pancreas and adrenals, ion exchange in bone, metabolic trapping during glucose metabolism, etc. Thispaper introduces a new mechanism for radiopharma

ceutical concentration that may be applicable to a varietyofclinical studies.

Our aim was to design agents that would freely crosscell membranes (and the blood-brain barrier) but onceinside the cells would be fixed there. 2-[18F]fluoro-2-deoxyglucose enters cells by specific transport mechanisms,and onceinside is convertedto the 6-phosphate.This metabolite cannot be further metabolized ortransported back out ofcells, and is thus trapped (1).Unfortunately, the preparation of this compound isdifficult and clinical application has not been widespread. Because of the exacting structural requirementsof both the cell transport and the phosphorylation

ReceivedMay 31, I979:revisionacceptedSept.20, 1979.For reprints contact: Hank F. Kung, Dept. of Nuclear Medicine,

VA Medical Center, 3495 Bailey Ave., Buffalo, NY 14215.

mechanisms, other glucose derivatives labeled with moreconvenient nuclides have not been found.

Ammonia labeled with N- 13 is another example of anagent that passes freely across cell walls—in this casebecause it is a neutral, lipid-soluble molecule. Once inside cells it is rapidly converted to a nondiffusible formby metabolic processes (2). Here again, because of theshort half-life of N- I3 ( I0 mm) clinical applications havebeen restricted.

The compounds we have developed are neutral andlipid-soluble at blood pH (“-‘7.4) and, therefore, diffusefreely into cells. When the intracellular pH is significantly lower than blood pH, these agents, which are weakbases, pick up a hydrogen ion and become charged. Inthis form they are no longer lipid-soluble and are“trapped―because they cannot diffuse out of the cell.This apparent “trapping―is initiated as a result of theconcentration gradient of the diffusible uncharged form(lower on the intracellular, low p1-I, side) maintained by

the regional pH difference. The influence of regional pHon drug entry into the central nervous system is wellknown (3). Our work is an extension of this principle tothe design of radiopharmaceuticals.

Since no specific transport mechanisms, metabolicenzymes, or binding sites are involved, there is very littlerestriction on the size and shape of the molecule or on the

Volume 21, Number 2 I 47

PRELIMINARY NOTES

RegionalIntracellularpHShift:A ProposedNewMechanismfor

RadiopharmaceuticalUptake in Brain and Other Tissues

Hank F. Kung and Monte Blau

State University of New York at Buffalo, Buffalo, New York

This paper proposes a new mechanism for radiopharmaceutical uptake, whichmay be applicable to a variety of clinical studies. Many tissues and organs havelow intracellular pH, either normally or as a result of various metabolic disturbances. We have developed a series of compounds that are neutral and lipid-soluble at blood pH. These molecules can diffuse freely into cells. In those regionswhere intracellular pH is low, they pick up a hydrogen ion and become charged. Inthis form they are no longer lipid-soluble and are trapped because they cannotdiffuse out of the cell. Studies of the brain uptake of two compounds of thistype,Se-75labeleddi-/3-(morphollnoethyi)-selenide(MOSE)anddi-f3-(plperldlnoethyl)-selenide (PIPSE), demonstrate the application of the principle.

J NucIMed 21:147—152,1980

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KUNG AND BLAU

nuclide chosen as a label.Many tissues have low intracellular p1-I, including

actively metabolizing tissues such as brain, heart, andsome tumors (4). Furthermore, regional pH differenceswithin an organ may be present due to abnormal metabolic states or to local ischemia.

This report presents preliminary data on compoundsof this type designed for perfusion and metabolismstudiesonthebrain.

MATERIALS AND METHODS

Radiopharmaceuticals. For convenience in thesestudies (long shelf-life and stable position of label) wehave selected Se-75-labeled compounds ofthe followingtype:

RNN—(CH.))—Se—(CH@),—N

V

A series of compounds was prepared, and two of these,di-f3-(piperidinoethyl )-selenide ( P1PS E) and dif3-(morpholinoethyl)-selenide (MOSE), were chosen forfurther study (Fig. I ). The specific activity varied from30-1000 @.tCi/mg. Compounds prepared in a parallelcold synthesis were characterized by NMR, IR, and elemental analysis.

Partition coefficients. The effect of p1—Ion lipid solubility was determined by measuring octanol/bufferpartition coefficients at p1-I from 6.0 to 8.5.

The radioactive compound was mixed with I ml ofn-octanol and 1 ml of HEPES 4-(2-hydroxyethyl)-I-piperazineethanesulfonic acid, (10 mM) buffer at thedesired pH. This mixture was counted and then shakenin a water bath at 37°Cfor 2 hr. After centrifugation(3000 rpm for 5 mm), the n-octanol layer was separatedand counted. The partition coefficient was calculated bythe following equation:

Partition Coefficient =

totalcountsinn-octanol

initialcounts—(totalcountsinoctanol)

KIIDNCH2CH2SeCH2CH2N@PIPSE

O@NCH2CH2SeCH2CH2N@@,O

MOSEFIG.1. StructureofPIPSEandMOSE.

Animal distribution studies. Sprague-Dawley male rats(220—300g) were injected by femoral vein with 0.2 mlof solution (0.5—2 zCi) under light ether anesthesia.Mice (RPMI A/st. 7—10wk old) were injected (tail vein)with 0.1 ml ofsolution (0.3—I @sCi).At different timesafter the injection, animals were killed and organs ofinterest were excised and counted in a well counter.Percentage dose was estimated by comparison of tissuecounts with suitably diluted aliquots of the injectedmaterial. Total activities in blood and muscle were calculated by assuming that they are 7% and 40%, respectively, of the body weight.

Imaging studies were done on a rhesus monkey usingthe ECT scanner.* A 5.3-kg monkey, lightly sedatedwith ketamine HC1, was injected with I mCi of MOSE(specific activity ‘@-‘lmCi/mg). Five minutes later themonkey was anesthetized with pentobarbital. A seriesof tomographic images of the head was taken withroughly half-inch steps, starting at the vertex. The firstimage was started I 5 mm after injection and others wererecorded up to 2 hr later. Each image contained approximately one million counts. At the conclusion of theimaging experiment, the monkey was killed and the brainwas assayed in the dose calibrator used for measuringthe injected dose. No correction was applied for thechange in geometry between the syringe and the monkeybrain. The weight of the brain was 84 g.

RESULTS

Effect of pH on lipid solubility. Figure 2 shows theeffects of p1-I change on the octanol/water partitioncoefficients of PIPSE and MOSE.

Oldendorf (5,6) has determined that compounds withn-octanol/water partition coefficients above about 0.5can pass freely into the brain whereas compounds withlower partition coefficients cannot. It can be seen fromFig. 2 that the partition coefficient of PIPSE is strongly

U)4I

C.)

a-

pH—0--

FIG.2. Dependenceof n-octanol/waterpartitioncoefficientsonpH for PIPSE and MOSE. According to Oldendorf (5), compoundsabovedottedline can passblood-brainbaffler whereasthosebelowcannot.

U—ONOSE.—. PIPSE

I@65 70 73 75 78 80 85

THE JOURNAL OF NUCLEAR MEDICINEI48

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PRELIMINARY NOTES

60 - Brain Uptake for SE-75 PIPSE in Rats50 -40

30 -

Brain Uptake for SE—75MOSEin Rots

20

a)0'C0

C 1000'0

a)U)0

c@05

0j

a)0'Ca

Caa,

0

4)Cl)0

I@@ I I ii I 0.1123456 10

Hr

I,20 3Doys 0 20 40 60

Mm——'-6 Hr

FIG.3. UptakeandretentionofPIPSEInratbrain. FIG.4. UptakeandretentionofMOSEinratbrain.Notechangeintime scale from Fig. 3.

dependent on pH and passes thru 0.5 at pH 7.3. The pHof blood is normally about 7.4 and that inside brain cellsabout 7.0-7. 1 (4, 7). Thus PIPSE has the desired characteristic of changing from a neutral, lipid-solublemolecule at blood pH to a charged water-soluble format intracellular pH. This is the result of the molecule'spicking up a hydrogen ion intracellularly because of the

lower pH there.On the other hand, the partition coefficient of MOSE

changes more gradually with pH. In the region of interest, pH 7.0—7.5,MOSE is more lipid-soluble thanP1PSE.

Brain uptake. Figures 3 and 4 show the brain uptakefor PIPSE and MOSE. The pattern of uptake and release corresponds to the predictions based on the measurements of partition coefficient. MOSE, which is themore lipid-soluble, is taken up in brain more readily;however, because its lipid solubility changes only moderately with pH, it is not as effectively trapped. PIPSEis somewhat less lipid soluble at blood pH and therefore

is taken up in brain more slowly, but because of the sharpdecrease in lipid solubility with small pH changes, it isvery effectively trapped in the brain. (Note change in

time scales between Fig. 3 and Fig. 4.)Table l is a comparison ofthe uptake in mouse brain

of PIPSE with the published data (8) for 2-['8F]fluoro-2-deoxyglucose. At 30 mm the concentrations inbrain are not very different, and the same holds for bloodand muscle. By 2 hr there is some indication of longerretention of PIPSE in brain, with somewhat faster

clearance from muscle.Organ distribution. Table 2 shows the organ distri

butionat varioustimesafter injectionfor PIPSE andMOSE. The blood level is very low for both compoundsas early as 2 mm after injection, suggesting free passageout of blood and out of extracellular fluid into cells.Movement into cells is confirmed by the high muscle andbrain uptake at this early time.

Liver uptake is initially high and remains elevated forsome hours. Kidney is also high initially, but the leveldecreases more rapidly than in liver. Other organ uptakesare not remarkable, with the exception of the early high

TABLE 1. COMPARISONOF DISTRIBUTIONOFSe-75PIPSEANDF-18FDGIN MICE(AVG.

OF 6 MICE, % DOSE/g)

Se-75 PIPSE F-18 FDG

Blood 0.88±0.05 0.89±0.1130 mln Muscle 2.03 ±0.32 3.21 ±0.43

Brain 6.79 ±0.82 5.31 ±0.94

Blood 0.55±0.08 0.41±0.112 hr Muscle 0.87±0.09 4.97±0.78

Brain 7.76 ±0.57 3.42 ±0.28

. 2-[18F]fluoro-2-deoxyglucose (FOG) data taken from

Ref.8.

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PIPSETIME2mm30 mm1 hr2 hr 4 hr6 hr24 hr3dayBlood4.580.870.750.65

0.590.510.200.08(3.75—5.48)(0.81—0.98)(0.74—0.75)(0.59—0.71)(0.54—0.62)(0.48—0.52)(0.18—0.21)(0.07—0.10)Muscle7.3913.416.112.0

11.911.52.810.40(6.33—8.44)(11.2—17.8)(13.5—18.6)(9.88—14.4)(10.5—13.2)(9.87—12.5)(1.78—4.07)(0.22—0.57)Heart3.040.890.350.19

0.16—0.03—(2.36—4.13)(0.78—0.98)(0.30—0.42)(0. 17—0.21)(0.15—0.18)(0.02—0.05)Lung

(2)20.02.831.920.850.82—0.31—(17.5—22.9)(2.42—3.43)(1.45—2.51)(0.80—0.89)(0.63—0.94)(0.13—0.65)Pancreas0.621.421.070.84

0.60—0.11—(0.32—0.98)(0.93—1.69)(0.98—1.13)(0.68—1.06)(0.40—0.81)(0.08—0.13)Spleen0.511.310.901.03

0.610.340.100.01(0.24—0.68)(1.12—1.46)(0.69—1.10)(0.86—1.34)(0.57—0.64)(0.31—0.39)(0.06—0.14)(0.01—0.01)Liver12.014.316.615.9

16.07.664.791.72(9.44—13.1)(12.5—15.7)(15.1—17.4)(11.8—18.3)

(14.0—17.2)(7.28—8.00)(4.35—5.21)(1.38—2.01)Kidney

(2)7.149.214.432.891.530.640.380.12(6.18—8.49)(7.90—10.6)(4.02—5.02)(2.68—3.00)(1.34—1.88)(0.59—0.67)(0.31—0.47)(0.11—0.15)Brain1.091.491.531.63

1.321.180.910.16(0.96—1.28)(1.41—1.60)(1.21—1.60)(1.40—2.00)(1.20—1.41)(1.02—1.28)(0.82—1.08)(0.14—0.20)TIME2

mm5 mint15 mmMOSE 30 mm 1 hr2 hr6 hr24 hr

KUNG AND BLAU

Blood3.132.722.262.822.612.460.610.13(2.76—3.36)(2.15—3.12)(1.71—2.78)(2.63—3.02)(2.33—2.76)(2.24—2.66)(0.53—0.68)(0.11—0.15)Muscle10.515.019.414.413.617.73.430.74(9.64—1

1.0)(10.1—19.3)(14.7—28.2)(10.7—17.9)(12.3—14.7)(17.5—17.8)(3.16—3.95)(0.61—0.85)Heart0.45——0.22—0.18—0.02(0.36—0.52)(0.20—0.23)(0.

14—0.22)(0.02—0.02)Lung(2)2.77—1.79—0.94—0.04(2.

17—3.37)(1 .07—3.04)(0.75—1.30)(0.04—0.05)Pancreas0.88—0.38—0.25—0.01(0.84—0.96)(0.29—0.43)(0.

14—0.42)(0.01—0.02)Spleen0.680.871.231.55—0.880.190.10(0.42—0.96)(0.38—1

.39)(0.90—1.55)(1.24—2.11)(0.79—1.04)(0.15—0.21)(0.10—0.11)Liver18.319.722.123.329.921.74.382.15(16.4—21.1)(13.8—26.2)(15.0—28.4)(22.0—24.3)(29.4—30.6)(20.2—23.5)(3.35—5.11)(1.96—2.25)Kidney

(2)9.897.464.044.034.303.420.640.29(9.57—10.4)(6.18—10.1)(2.86—4.70)(3.77—4.52)(3.79—4.61)(3.05—3.78)(0.61—0.68)(0.26—0.33)Brain3.19'2.802.231.531.190.560.100.02(2.41—3.88)(2.46—3.54)(1.65—2.81)(1.32—1

.94)(1.07—1.32)(0.40—0.82)(0.09—0.10)(0.02—0.02)

at 2 hr after injection. Unlike the rat brain, the monkey

brain did not seem to clear MOSE rapidly, and count

rates were approximately steady for the 2-hr course of

the experiment.

DISCUSSION

Brain uptake. These preliminary studies indicate thatthe brain uptake and retention of MOSE and PIPSE

uptake of PIPSE in lung and heart.

Imaging. Section imaging of the monkey brain isshown in Fig. 5. The MOSE distribution resembles thatobserved with 2@[I8F] fluoro-2-deoxyglucose or N-I 3ammonia, with greater concentration in grey matter than

in white (9). The brain weight was only 84 g, 6% of theaverage brain weight in man. Despite the small volume,

definition ofcortical concentration is quite good.The monkey brain contained 3.7%of the injected dose

THE JOURNAL OF NUCLEAR MEDICINEISO

TABLE 2. DISTRIBUTiONOF Se-75 PIPSE AND MOSE IN RATS AFTER l.v. INJECTION: % DOSE/

. Average of 5 samples.

t Average of 6 rats.

ORGAN, AVG. OF 3 RATS (RANGE)

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1•R@@@L

PRELIMINARY NOTES

@1

I of the slow change of partition coefficient with pH.The brain washout curve for these agents is a reflec

tion of the equilibria established on both sides of theblood-brain barrier. The concentrations of the variouscharged and uncharged molecular species on both sidesdependon the pKs of the compound,the local pH, andthe transmembrane diffusion rates of the various molecular species. To a first approximation the concentration gradient and diffusion characteristics of the uncharged form determine the brain uptake and retentioncurve. Generally speaking, high initial uptake is associatedwithhighlipidsolubilityat bloodpH, andthewashout rate from brain is determined by the slope of thecurve plotting partition coefficient against pH. The influenceof transport kinetics on the washoutcurve,andof possiblenonspecificbindingto intracellularcomponents, remains to be investigated. These factors may playa significant role in the establishment of the very highbrain-to-blood concentration ratios observed at latertimes.Anotherpossibleexplanationisconcentrationincellular structures, especially lysosomes, which have avery low pH.

Brain uptake of MOSE in the monkey was 3.7% at 2hr, indicating a somewhat higher uptake and probablya slower washout of MOSE from primate brain. Thedetails of interspecies differences remain to be investigated.

The anatomical distribution within the monkey braincloselyresemblesthepublishedimagesof 2-['8F]fluoro-2-deoxyglucose and N-I 3 ammonia in humans (9).The uptake of the various agents is a complex functionoflocal perfusion rates, transport into cells, intracellularmetabolism, and washout from cells and from brain. Thecontribution of each of these processes to the distributionpattern of these new agents—and especially the role oflocalintracellularpH—remainto be elucidatedboth innormal brain and in various disease states. However,sincemanyimportantphysiologicparametersare knownto affect, or to be affected by, intracellular pH, externalvisualization of the uptake and/or clearance patterns ofthis type of compound should provide valuable clinicalinformation.

OtherpH-dependentbrainagents.Oneof theprincipalattractions of intracellular pH shift as a mechanismoflocalization is the flexibility it provides in the design ofnew agents. The curve of lipid solubility against pH canbe controlled by using groupsof higher or lower lipophilicityand by changingthe pK of the weaklybasicnitrogen atoms by adjusting the length of the chain between them and by electron donating or withdrawingmoieties. Using these techniques one can design radiopharmaceuticals that change from lipid- to water-solubleat any desiredpH and haveeither gradualor steeppH-against-lipid-solubility curves.

Since there are no steric requirements on the molecule,there is a wide range of possiblenuclide labels. For

@1

,R

Li @...

FiG.5. Tomographicscansof MOSEInbrainof live rhesusmonkey.Scans have roughly half-inch steps from vertex (top)to base. Volume of monkey braIn Is ‘s-'80 ml. Total Se-75 content of brain @‘40@zCi(‘—‘4% uptakeof a 1 mCidose).Eath view containsaboutone

million counts.Scanswere taken in periodfrom 30 mmto 2 hr afteri.v. Injection.Starpatterninvertexslice(top image)is reconstructionartifact.

generally follow the behavior expected on the basis of thepartition coefficients (Fig. 2). PIPSE is somewhat lesslipid-soluble at blood pH (‘—‘7.4)and has a lower uptake,but because of the sharp drop in lipid solubility with pH,the retention time in brain isvery long. MOSE issomewhat more lipid-soluble at blood pH and has a higherinitial uptake, but the retention time is shorter because

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KUNG AND BLAU

conveniencewehavechosenSe-75forthesepreliminarystudies. The long shelf-life (Tip 120 days) and thestabilityof the moleculesare usefulfor researchpurposes. However, Se-75 does not have optimal physical

properties for clinical studies. Iodine- 123 could easilybe incorporated into this kind of molecule. Counsell (10)has commented on the high brain uptake of an I-i 25-labeled diamine prepared as a possible putrescine analog.It isalsopossiblethatthemechanismoflocalizationforthis compound is the same as that proposed for PIPSEand MOSE.

Although the radiation dosimetry for Te-1 23m is notas favorable as for Se-75, the photon energy (1 59 keV)is very desirable.Substitution of tellurium for seleniumin molecules of the PIPSE and MOSE type would be

very straightforward.Technetium-99m-labeling of molecules capable of

entering cells and being trapped by low pH is also feasible. Starting with a neutral lipid-soluble Tc-99m-labeled molecule of the type proposed by Burns et al. (II),it should be possible to add weakly basic substituentswith a suitable pK.

Other clinical applications for pH-dependent localizingagents. Other rapidly metabolizing cells—e.g., heartmuscle(12) andsometumors—alsohaveunusuallylowintracellular pH (4). Since the lipid solubility and its pH

dependencecan bechangedin thesecompoundsat will,the development of localizing agents for heart and tumorseems to be a distinct possibility.

Of even more interest would be a radiopharmaceuticalthat would be taken up and retained in ischemic heartmuscle because of the unusually low pH in this tissue.

A positive uptake agent for ischemic areas in the heartwould significantly increase the usefulness of nuclearmedicineproceduresin cardiology.This typeof cornpound is currently under investigation in our Iaboratory.

FOOTNOTE

* Cleon 710, Union Carbide.

ACKNOWLEDGMENT

Wethank Drs.ThomasC. Hilland MichaelA. Davisforprovidingthe facilities of their laboratories for the ECT scans of the rhesusmonkey.

This research was supported by funds from the Univ. at BuffaloFoundation.Severalaspectsof the workare the subjectof a pendingpatent application from the Research Foundation of SUNY.

REFERENCES

1. GALLAGHER BM, FOWLER iS, GUTTERSON NI, et al:Metabolic trapping as a principle of radiopharmaceuticatdesign: Some factors responsible for the biodistribution of[‘8F]2-deoxy-2-fluoro-D-glucose.JNucl Med 19: 1154-1161,1978

2. PHELPS ME, HOFFMAN EJ, RAYBAND C: Factors whichaffect cerebral uptake and retention of ‘3NH3.Stroke 8:694-702, 1977

3. RAPOPORTSI: BloodBrain-Barrierin PhysiologyandMedicine.New York, RavenPress,1976,pp 154—164

4. WADDELL Wi, BATES RG: Intracellular pH. Physiol Rev49:285-329,1969

5. OLDENDORFWH:Lipidsolubilityanddrugpenetrationofthe bloodbrain-barrier. (38444).ProcSoc Exp BiolMed 147:813—816,1974

6. OLDENDORF WH: Need for new radiopharmaceuticals. JNuciMed 19:1182,1978

7. 5IEsJo BK: Brain Energy Metabolism. New York, JohnWiley and Sons, 1978,pp 304—323

8. GALLAGHER BM, ANSARI A, ATKINS H, et at: Radiopharmaceuticals XXVII. ‘8F-labeled2-deoxy-2-fluoro-D-glucose as a radiopharmaceutical for measuring regionalmyocardial glucose metabolism in vivo: Tissue distributionand imaging studies in animals. J NucI Med. 18: 990—996,I 977

9. PHELPS ME, HOFFMAN EJ, HUANG SC, et al: ECAT: Anew computerized tomographic imaging system for positron-emitting radiopharmaceuticals. J Nuci Med 19: 635—647,1978

10. HUANG CC, KORN N, COUNSELL RE: Potential organ- ortumor-imaging agents. 18. Radioiodinated diamines andbisquaternaries. J Med Chem 22: 449-452, 1979

I I. BURNS HD, MANSPEAKER H, MILLER R, et al: Preparationand biodistributionof neutral, lipidsolubleTc-99mcomplexesof bis(2-mercaptoethyl)amine ligands. J Nuci Med 20: 654,1979 (abst)

12. CLANCY RL, GONZALEZ NC, FENTON RA: Effect ofbeta-adrenoreceptor blockade on rat cardiac and skeletalmuscle pH. Am J Physiol 230: 959-964, 1976

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1980;21:147-152.J Nucl Med.   Hank F. Kung and Monte Blau  Uptake in Brain and Other TissuesRegional Intracellular pH Shift: A Proposed New Mechanism for Radiopharmaceutical

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