Pulak K. Chakraborty et al- High Yield Synthesis of High Specific Activity R-( -)-[^11-C]Epinephrine for Routine PET Studies in Humans

8/3/2019 Pulak K. Chakraborty et al- High Yield Synthesis of High Specific Activity R-( -)-[^11-C]Epinephrine for Routine PET

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Nucl. Med. Biol. Vol. 20, No. 8, pp. 939-944, 1993Printed in Great Britain. All rights reserved 0969-8051/93 6.00+ 0.00Copyright 0 1993Pergamon Press Ltd

High Yield Synthesis of High SpecificActivity R-( -)-[*C]Epinephrine for RoutinePET Studies in Humans*

PULAK K. CHAKRABORTY, DAVID L. GILDERSLEEVE,DOUGLAS M. JEWETT, STEVE A. TOORONGIAN1_,

MICHAEL R. KILBOURN, MARKUS SCHWAIGER andDONALD M. WIELANDt:Division of Nuclear Medicine, Department of Internal Medicine, University of Michigan Medical School,Ann Arbor, MI 48109-0552, U.S.A.

(Received 29 March 1993)

R-( -)-[ClEpinephrine ([CIEPI) has been synthesized from R-( -)-norepinephrine by direct methyl-ation with [Clmethyl iodide or [Clmethyl triflate. The total synthesis time including HPLC purificationwas 3540min. The radiochemical yields (EOB) were S-10% for [Clmethyl iodide and 15-25% for[Clmethyl triflate. Radiochemical purity was >98%; optical purity determined by radio-chiral HPLCwas > 97%. The [Clmethyl triflate technique produces R-( -)-[Clepinephrine in quantities(8&l 70 mCi) sufficient for multiple positron emission tomography studies in humans. The two syntheticmethods are generally applicable to the production of other N-[Clmethyl phenolamines and N-[Clmethyl catecholamines.

IntroductionN-[ClMethylation is a rapid radiosynthetic reactionadaptable to remote control. Many useful tracershave been synthesized in single-step processes fromtheir normethyl precursors. Usually [Clmethyliodide is the reagent of choice, although N-[C]methylation has also been achieved by reductivealkylation using [Clformaldehyde (Mulhollandet al., 1988). Yields are generally good, especiallywhen amides are methylated in the presence of strongbases such as sodium hydride. The technique, how-ever, has not been generally applied to amines, es-pecially chiral biogenic amines. The work reportedhere was prompted by our intent to synthesize[C]EPI to study the sympathetic nervous system ofthe human heart.

*Parts of this study were first reported in abstract form:Chakraborty P. K., Gildersleeve D. L., ToorongianS. A., Kilbourn M. R., Schwaiger M. and Wieland D.M. (1993) Synthesis of [Clepinephrine and otherbiogenic amines by direct methylation of normethylprecursors. 9th International Symposium on Radiophar-maceutical Chemistry, 5-10 April 1992, Paris, France. J.Labeled Cmpd. Radiopharm. 32, 172.tPresent address: Nuclear Medicine Department, SUNY atBuffalo, Buffalo, NY 14214, U.S.A.fAl1 correspondence should be addressed to: Dr Donald M.Wieland, 3480 Kresge III Bldg, University of MichiganMedical School, Ann Arbor, MI 48109-0552, U.S.A.

The first, and to our knowledge, the only synthesisof [C]EPI was reported by Soussain et al. in1984. They employed phenylethanolamine-N-methyltransferase (PNMT) with S-adenosyl-L-[methyl-Clmethionine (SAM) to methylateR-(-)-norepinephrine. The SAM itself was syn-thesized from [Clmethyl iodide and L-homocysteinethiolactone. This elegant natural enzymatic ap-proach, unfortunately, produced low yields (1.5 mCi)of [C]EPI with specific activities (< 200 Ci/mmol) solow as to preclude human studies. The authors brieflynoted that low yields of [C]EPI were also obtainedwhen direct methylation of R-( -)-norepinephrinewith [Clmethyl iodide or reductive alkylation with[Clformaldehyde were attempted.

Normally, direct methylation of primary amineswith [Clmethyl iodide is not a viable preparativeroute to the respective N-methylamines because ofcompetitive polymethylation. However, it can be asuccessful radioalkylation route using [Clmethyliodide because the parent amine is present in largeexcess, thereby reducing the probability of poly-methylation. Under neutral conditions, methylationof phenolamines with [Cjmethyl iodide producesN-[Clmethyl products in acceptable yields withoutsignificant competing 0-methylation of the phenolgroup. We have demonstrated this with the synthesisof N-[Clmethyl-meta-hydroxyephedrine (MHED)from metaraminol free base by direct methylation

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940 PULAK K. CHAKRABORTY et al.with [Clmethyl iodide (Rosenspire et al., 1990). Atpresent, MHED is routinely synthesized in our PETCenter for clinical research studies in both nuclearcardiology (Schwaiger et al., 1990, 1991) and nuclearoncology (Shulkin et al., 1992). More recently wehave radiolabeled other phenolamines by this ap-proach including paru-hydroxyephedrine and (+)-(lS,2S)-three-MHED (Hutchins et al., 1991; Hakaet al., 1990).

In view of the chemical instability of catechol-amines, we anticipated that reaction of norepi-nephrine with [Clmethyl iodide might give loweryields than those obtained from phenolamines suchas metaraminol. This was, as reported here, indeedthe case. However, an alternative pathway to [CIEPIwas suggested by the work of Jewett (1992) whoreported the synthesis of the more reactive methyl-ating agent [Clmethyl triflate. In view of the avail-ability of [Clmethyl triflate at our institution, wehave applied this new reagent to the N-methylationof R-( -)-norepinephrine. Accordingly, we reporthere a rapid, high-yield synthesis of [CIEPI with aspecific activity sufficiently high to permit positronemission tomography (PET) studies of this hormonein humans.

Materials and MethodsR-( -)-Norepinephrine hydrochloride samples

were newly purchased from Aldrich Chemical Co.,Milwaukee, Wis. and Fluka Chemical Co.,Ronkonkoma, N.Y.; an older batch of the hydro-chloride salt, no longer available, had been obtainedfrom Schweizerhall, Piscataway, N.J. R-( -)-Epi-nephrine-D-bitartrate was newly purchased fromRBI, Natick, Mass. Anhydrous dimethyformamide(DMF) and dimethyl sulfoxide (DMSO), 2,3,4,6-tetra-0 -acetyl-/I -D-glucopyranosyl isothiocyanate(GITC), ( f )-epinephrine, ( f )-norepinephrinehydrochloride, ( f )-normetanephrine hydrochloride,tetrabutylammonium hydroxide (1 M solution inmethanol) and hydrazine hydrate were obtained fromAldrich Chemical Co. The [Clmethyl iodide wasprepared from [Clcarbon dioxide produced by the14N(p, a)C reaction in a nitrogen target containingtraces of oxygen under pressure (Marazano et al.,1977). [C]Methyl triflate was prepared from[Clmethyl iodide according to the procedure ofJewett (1992).Synthesis of R -( -)-[Cjepinephrine using[Cjnethyl iodide

R-( -)-Norepinephrine hydrochloride (1 Omg) wasweighed in a reaction vial and its free base generatedin situ by the addition of 0.8-0.9 equivalents oftetrabutylammonium hydroxide (3.9 PL of 1 M sol-ution in methanol). Following evaporation of themethanol with a nitrogen purge, the residue wasdissolved in 0.25 mL of DMF/DMSO (3/l). Thereaction vial was cooled to -35C in a heat-

ing/cooling block to trap [Clmethyl iodide as it wasbubbled through the reaction mixture. After maxi-mum radioactivity had accumulated, the vial wassealed and heated at 85C for 5 min. The reactionmixture was then cooled to ambient temperature andpurified by HPLC. Pure [CIEPI eluted at approx.9 min from a strong cation exchange column (Optisil10 pm SCX, 250 x 4.6 mm, Phenomenex, Inc., Tor-rance, Calif.) using 0.01 M NaH,PO,, (2.8 mL/min)as mobile phase. Column effluent was monitored witha radiation detector. A two-way valve was used todivert waste and to collect the desired radiolabeledproducts.Radiochemical purity of the final product wasdetermined independently on an analytical reversed-phase column (Ultremex 5 Cl8 IP, 250 x 4.6 mm;Phenomenex Inc.). The column was eluted with anaqueous solution of 0.1 M AcOH, 5 mM pentanesul-fonate sodium salt and 1.5 mM EDTA disodiumsalt/CH,OH (9: 1, v/v) at a flow rate of 1 mL/min.Column effluent was monitored by an absorbancedetector at 280 nm and radiation detector inseries. The mass of both residual norepinephrineprecursor and epinephrine in the final product wasdetermined by comparison with standard curvesobtained by injections of authentic samples of knownconcentration.Syn thesis of R- ( -)-[Cjepinephrine using[Cjnethyl triJate

The synthesis, purification and analysis of [CIEPIproduced with [Clmethyl triflate was identical tothat described above for the synthesis of [C]EPIusing [Clmethyl iodide except for the substitution of[Clmethyl triflate for [Clmethyl iodide.Ass ay of opt ical purity of R -(-)-[Cjepinephrine

To a 100 PL aliquot of HPLC-purified R-(-)-[Clepineplirine in 0.01 M NaH,PO, was added135 p L of 2,3,4,6-tetra-0 -acetyl-/I-n-glucopyranosylisothiocyanate (GITC) in DMF (20mg/mL). Afterthe reaction mixture was warmed to 50C for 10 minand then cooled to room temperature, 30 PL ofhydrazine hydrate (5 pL/mL) in DMF was added toinactivate excess reagent. The mixture was analyzedby reversed-phase HPLC (Ultremex 5 Cl8 IP,50 x 4.6 mm; Phenomenex) using 0.01 M KH2P04/CH,OH (67.5: 32.5) as mobile phase at a flow rate of1.0 mL/min. The retention times of the (+)- and(-)-epinephrine-GITC derivatives were determinedby subjecting ( f )-epinephrine to this procedure;optical identity of the peaks was determined byspiking ( f )-epinephrine with authentic (-)-epi-nephrine before derivatization.Assay of optical purity of R-(-)-norepinephrine

The optical purity of various commercial samplesof R-(-)-norepinephrine was determined by chiralHPLC using a CrownPak CR( +) column(150 x 4.6 mm, Daicel, J. T. Baker, Phillipsburgh,


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Synthesis of R-( -, )-[ClepinephrineN.J.); with 23 mM perchloric acid (0.5 ml/mm) aseluent. To determine if racemization of R-(-)-norepinephrine occurs during the course of the syn-thesis of [C]EPI, the following experiment wasperformed. To R-( -)-norepinephrine hydrochloride(1.0 mg) was added 0.8 equivalent of tetrabutylam-monium hydroxide, 1 M in methanol (3.9 pL), in asealed vial. The methanol was removed by nitrogenpurge and the residual solid dissolved in 0.25 mL ofDMF/DMSO (3/l). The vial was placed in a heatingblock, warmed for 5 min at 85C and then returnedto room temperature. After addition of 2mL ofmilli-Q water, the solution was applied to a neutralalumina Sep-Pak and washed with 10mL of water.Norepinephrine was eluted from the column with1.0 M perchloric acid (1 mL). Optical analysis wasperformed by HPLC as described above.

was chosen to partially neutralize the hydrochloridesalt because the small amount of base required(0.8-0.9 eq.) to generate the free base could be addedwith reasonable accuracy, and the methanol could beremoved by purging with nitrogen gas prior to redis-solving the residue in DMF/DMSO (3: 1).

Results and DiscussionSynthesis of R -( -)-[Cjepinephrine

We have previously reported the synthesis of[CIMHED by direct methylation of metaraminolfree base with [Clmethyl iodide under neutral con-ditions (Rosenspire et al., 1990). The yield andspecific activity of the [CIMHED produced weresufficient to permit the use of this radiotracer inclinical trials. For the synthesis of [CIEPI, however,this method had to be modified because of the greatersusceptibility of norepinephrine free base to air oxi-dation. This modification simply involved the in situgeneration of free base norepinephrine from thehydrochloride salt under oxygen-free conditions.Tetrabutylammonium hydroxide (1 M in methanol)

In our initial syntheses of [CIEPI, [C]methyliodide was used as the methylating agent. The specificactivity of the product was 1000-2000 Ci/mmol(EOS) but only a 510% radiochemical yield (EOB,N = 10) could be achieved in a synthesis time of3540 min. Jewett (1992) reported the conversion of[C]methyl iodide to the more powerful methylatingagent [C]methyl triflate. The availability of thiscarbon-l 1 precursor prompted us to apply it to thesynthesis of [C]EPI in the hope of obtaining higheryields and possibly higher specific activities. Indeed,a yield of 15-25% (EOB, N = 20) with a specificactivity of 900-2200 Ci/mmol (EOS) was obtained for[CIEPI (Fig. 1). At present, a typical production runproduces SO-170 mCi of [C]EPI in 10 mL of finalformulation. The amount of norepinephrine hasranged from 0.15 to 0.77 pg/mL; the amount ofepinephrine present has ranged from 0.23 to2.06 pg/mL.HPLC pur$cation and quality control of R-(-)-[Clepinephrine

We have previously reported that a C-l 8 reversed-phase column with 0.24 M monobasic sodium phos-phate as mobile phase provided adequate resolutionof metaraminol and MHED for the purification of[CIMHED (Rosenspire et al., 1990). For the muchmore polar catecholamines, however, this system was

1) (~-Bu)~N+OH

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HO - HCl HO 3R-(-)-Norepinephrine R-(j -W]Epinephrine

1) (n-Bu)4N+OH-2) CF3s03CH3

85iC. 5 min1 S-25%

Fig. 1. Radiochemical syntheses of [CIEPI.


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942 PULAKK. CHAKFUBORTYt al.not sufficiently efficient to resolve [C]EPI fromnorepinephrine without the addition of ion-pair tothe mobile phase, which would have complicated thepurification methods. Switching to a strong cationexchange column with 0.01 M monobasic sodiumphosphate as eluent did provide the necessaryefficiency and resolution for the purification of[CIEPI. Under these conditions, norepinephrineeluted at + 5 min and epinephrine eluted at -9 min.The unreacted norepinephrine and a large radioactivepeak, which eluted at N 3 min, were diverted to waste.[CIEPI was collected through an in-line 0.22pmsterile filter into a sterile vial in a total volume of6.5-7.0 mL of eluent; 3.g3.5 mL of 0.45 M sodiumacetate buffer, pH 5.0, containing 0.3% sodium-L-ascorbate, was added to adjust both pH and ionicstrength for iv. injection.

The radiochemical and chemical purity of the finalproduct were determined by a separate analyticalHPLC system. The U.V. detection limit for bothnorepinephrine and epinephrine using this HPLCsystem was 25 pmol. A representative absorbance andradioactivity chromatogram are shown in Fig. 2. Themost likely by-product in these labeling experimentswould be 3-O-methyl norepinephrine [C]nor-metanephrine), potentially formed by methylation ofthe phenol group. However, [Clnormetanephrinehas not been detected in the crude product. Neither[Clmetanephrine nor N-methyl[C]epinephrinewould be an expected by-product since norepi-nephrine is present in vast excess of either [Clmethyliodide or [C]methyl triflate. The radiolytic stabilityof [C]EPI up to 1 h EOS in either the HPLC eluentor the formulation has been confirmed by analyticalHPLC monitoring.Opt ical purity of R-(-)-norepinephrine and R-(-)-[C]epinephrine

For research or clinical use of [C]EPI, the tracermust be enantiomerically pure. To achieve this goal,the precursor R-(-)-norepinephrine must also beoptically pure. We have analyzed the enantiomericpurity of R - ( -)-norepinephrine obtained from sev-eral commercial sources using a CrownPak CR(+)column. The R-( -)- and S-( +)-enantiomers of nor-epinephrine eluted at 12.4 and 13.5 min, respectively.R-( -)-norepinephrine hydrochloride obtained fromboth Fluka and Aldrich was found to have anenantiomeric purity >97% and was deemed suitablefor use in the clinical synthesis of [C]EPI. Table 1summarizes the results obtained for a number ofcommercial sources. The enantiomeric stability ofR-( -)-norepinephrine under the reaction conditionsused for the synthesis of [C]EPI was also confirmedby use of the CrownPak CR(+) column.Unfortunately chiral HPLC with the CrownPakCR( +) column does not separate the enantiomers ofepinephrine. However, Allgire er al. (1985) havereported the derivatization of epinephrine with thechiral reagent 2,3,4,6-tetra-o-acetyl-fi-o-glucopyra-

1 2 3 4 5 6 7 8 9 10MINUTES

lb)

Fig. 2. Chemical and radiochemical purity of HPLC-purified [C]EPI determined by analytical HPLC. (a) Ultra-violet absorbance trace shows both norepinephrine (NE)and epinephrine (EPI); (b) radioactivity trace shows only[C]EPI. Traces are from a 1 mCi injection.

nosy1 isothiocyanate (GITC) in DMF. We havesuccessfully formed the epinephrineGITC derivativenot only in DMF, but also in DMF/DMSO (3: I),and even in 0.01 M NaH,PO,. The diastereomericGITC derivatives of (-)- and (+)-epinephrine wereresolved by reversed-phase HPLC with U.V. detectionat 254 nm. Figure 3 presents the HPLC chro-matograms of the GITC-derivatized solutions of[C]EPI synthesized from R-( -)-norepinephrineobtained from two different commercial sources. The

Table 1. Optical purity of R-( - )-norepinephrinefrom commercial sources*Company source % ( - ) % (+)Aldrich Chemical 91 3Fluka Chemical 91 3RBI 91 9Schweizerhallt 90 10*Optical purity was determined by chiral HPLCusing a CrownPak CR(+) column.tThis material was an old sheif sample; all othernorepinephrine samples were recently pur-chased.


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Synthesis of R-( -)-[Clepinephrine 943(4 (-IEf;l-GTCl-lII

(k) EPI-GITC(b)

IL-L1 -EPI-GITCI I ,

Fig. 3. Optical purity of [C]EPI determined by radio-HPLC. Radioactivity traces of crude solutions of[Clepinephrine-GITC derivatives synthesized using R-(-)-norepinephrine from Schweizerhall (a) and Fluka (b).

(-)- and (+)-epinephrine_GITC derivatives elutedat approx. 7.3 and 9.3 min, respectively. Underiva-tized epinephrine eluted at 0.8 min. Two unidentified,t.v.-absorbing peaks, eluting at 2.5 and 5.8 min, werealso observed in the reaction mixture. We have alsoderivatized authentic racemic normetanephrine withGITC by the same procedure. Analysis of the prod-ucts by the same HPLC system gave two peaks at- 10.7 and - 11.9 min, which are well resolved fromthe epinephrine-GITC derivatives. The isomeric iden-tity of these two peaks was not determined.The enantiomeric purity of [CIEPI was deter-mined in both the crude reaction mixture and thefinal purified product. In both cases, HPLC analysisof the GITC-derivatized product showed a major andminor radioactive peak which co-eluted with thecorresponding authentic (-)- and (+)-epinephrine-GITC derivatives. The radioactivity peak ratios wereidentical to the U.V. peak ratios obtained on chiralHPLC for the R-( -)-norepinephrine hydrochlorideused as precursor. There was no radioactive peakcorresponding to the (-)- or (+)-normetanephrine-GITC adducts. To rule out the possibility that otherradioactive impurities might interfere with our deter-

mination of the enantiomeric purity, we performedan identical blank experiment, using [C]methyl tri-flate, in the absence of R-( -)-norepinephrine hydro-chloride. HPLC analysis of the crude mixture showedthat all radioactivity eluted in the first 2 min. TheseHPLC analyses provide strong evidence that noracemization occurred during either the C-labelingprocedure or purification of the [CIEPI. The chiralanalyses also confirm our previous finding that, underthese C-methylation conditions, no O-C-methylderivative (i.e. [Qrormetanephrine) is formed.S pecific activity considerations

The methylation methods described above give aminimum specific activity of approx. 1000 Ci/mmolfor [CIEPI. At this level, a 20 mCi i.v. injection of[CIEPI will contain 3.66 pg of carrier epinephrine.The iv. dose of epinephrine known to induce apressor response in adults is 100-250 pg administeredvery slowly (Harvey, 1990). Other sources suggestthat this dose level can be administered over anapprox. 1 min duration (McEnvoy, 1992). Since iv.injections of radiotracers for PET studies are gener-ally administered in 1 min or less, injection of 20 mCiof [CIEPI, 1000 Ci/mmol, is most likely below theanticipated dose range for a vasopressor effect. How-ever, in view of the variability in patient pressorresponse to epinephrine (McEvoy, 1992) it will beimportant to closely monitor patient blood pressureand heart rate during i.v. administration of [CIEPI,especially if bolus injection times of considerably lessthan 1 min are employed. The presence of precursornorepinephrine is of equal concern since it has apressor potency greater than epinephrine; approx.2-10 ng/min is the recommended adult i.v. dose rate(McEvoy, 1992). Fortunately, in our most recentexperience, norepinephrine levels have been keptbelow 1 Opg/20 mCi of [CIEPI by careful attentionto the HPLC purification. We continue to optimizethis synthetic procedure to maximize both the specificactivity and effective specific activity of the [CIEPI.Exclusion of ambient carbon sources, in particulartraces of methanol that might be entrained in thetetrabutylammonium hydroxide, is very important inachieving this goal. For human PET studies at ourinstitution, an i.v. injection of lo-20 mCi of [CIEPIis utilized. Upper dose limits of 9 pg for epinephrineand 1 pg for norepinephrine have been set for adultsweighing 50 kg or more. Adherence to this limitassures that the patient will receive a subpharmaco-logical dose of catecholamines. It is of paramountimportance to obtain a specific activity as high aspossible, preferably greater than 2500 Ci/mmol, alevel which we have approached in our most recentsyntheses.

The critical importance of specific activityhas arisen previously with other catecholamineslabeled with positron-emitting radioisotopes, such as6-[*F]fluorodopamine (6-FDA). Although dopamineis considerably less potent than epinephrine, the


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944 PULAK K. CHAK XABORTY et al.extremely low specific activity (0.5-10 Ci/mmol) of6-FDA produced by electrophilic fluorination(Goldstein et al., 1990, 1991) places it outside the truetracer range needed for PET studies. The nucleophilic[*F]fluoride method of 6-FDA preparation (Dinget al . , 199la), however, provides 6-FDA in loo-foldhigher specific activity and hence, the true tracerlevels needed for cardiac PET studies. Similarly, highspecific activity 6-[*F]fluoronorepinephrine hasbeen reported using the nucleophilic [Flfluorideapproach (Ding et al., 199lb). Thus, whether C- or*F-labeled tracers are used to track endogenouscatecholamines, attention must be paid to the com-pelling need to optimize the specific activity of thetarget tracer.

SummarySimple, rapid, chiral syntheses of [C]EPI by direct

methylation of R-( -)-norepinephrine with either[C]methyl iodide or [Clmethyl triflate have beendescribed. The latter method, due primarily to itshigher yields, has been adopted for the routine clini-cal production of [*C]EPI. These procedures appearto be generally applicable to the syntheses ofother N-[Clmethyl phenolamines and N-[Clmethylcatecholamines.Acknowledgements-This work was supported by NationalInstitutes of Health Grants ROl HL27555 and ROlHL41047 and Department of Energy Grant DE-FGOZ90ER6091. We thank Linder Markham for assistance inpreparing the manuscript.

ReferencesAllgire J. F., Juenge E. C., Damo C. P., Sullivan G. M. andKirchhoeffer R. D. (198% High-nerformance liauidchromatographic determi&tion I _of d-/l-epinephhneenantiomer ratio in lidocaine-epinephrine local anesthet-ics. J. Chromatogr. 325, 249.Ding Y. S., Fowler J. S., Gatley S. J., Dewey S. L., Wolf

A. P. and Schlyer D. J. (199la) Synthesis of high specificactivity 6-[sF]fluorodopamine for positron emission tom-ography studies of sympathetic nervous tissue. J. Med.Chem. 34, 861.Ding Y. S., Fowler J. S., Gatley S. J., Dewey S. L. and WolfA. P. (1991b) Synthesis of high specific activity ( + )- and( - )-6-[sF]fluoronorepinephrine via the nucleophilic aro-matic substitution reaction. J. Med. Chem. 34, 767.

Goldstein D. S., Chang P. C., Eisenhofer G., Miletich R.,Finn R., Bather J. et al. (1990) Positron emission imagingof cardiac sympathetic innervation and function. Circu-lat ion 81, 1606.Goldstein D. S., Grossman E., Tamrat M., Chang P. C.,Eisenhofer G., Bather J. et al. (1991) Positron emissionimaging of cardiac sympathetic innervation and functionusing *F-6-fluorodopamine: effects of chemical sympath-ectomy by 6-hydroxydopamine. J. Hypertension 9, 417.Haka M. S., Jung Y.-W., Rosenspire K. C. and WielandD. M. (1990) Synthesis of [Cl-para-hydroxyephedrine(PHED)

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Pulak K. Chakraborty et al- High Yield Synthesis of High Specific Activity R-( -)-[^11-C]Epinephrine for Routine PET Studies in Humans