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Cyclotron isotopes and radiopharmaceuticals—XXIII
International Journal of Applied Radiation and Isotopes. 1978, Vol. 29, pp. 175-183 ~) Pergamon Press Ltd. Printed in Great Britain
0020-708X/78/0301-0175502.00/0
Cyclotron Isotopes and Radiopharmaceuticals XXIII.* Novel Anhydrous 18F-Fluorinating Intermediates R I C H A R D M. L A M B R E C H T , R U D I N E I R I N C K X ~ a n d A. P. W O L F Chemistry Department, Brookhaven National Laboratory, Upton, NY 11973, U.S.A. (Received 10 January 1977; accepted 1 September 1977)
The 2°Ne(d,0QlSFreaction and a high purity nickel target passivated with an anhydrous film of nickel fluoride were utilized for the preparation of anhydrous ~SF-labeled fluorinating reagents. A recovery yield of ~8.8mCi/pAh of ISF-F2 was obtained with 11 MeV deuterons incident on neon and F2 carrier at a pressure of 2.63 atm. ISF-F2 was obtained at a production rate of 1i.8 mCi/pAh with t h e 19F(p,pn)LSF and t 9 F ( p , 2 n ) t S N e ---, ~SF nuclear reactions at 31.7 MeV on I 1.5 mmolea of F2. The 2°Ne(aHe,x)l SF and JSNe 1.5.% is F nuclear reactions (x = 3p2n, :~n, 3He2n and 2p3n, Hepn, respectively) with 55.7-10MeV 3He and the 2°Ne(~,~n) 'aNe ~ ~SF and 2°Ne(:~,',pnpaF reactions at 45-33 MeV were evaluated. At the SHe beam energies available on all but the smallest compact cyclotrons the ~aF production rate was ~ 70?/oof that obtainable for the (d,a) reaction on a given accelerator. The methodology and targetry for the production of ISF-Fz, tSF-CF4, HtaF, NO~aF and ClZSF are described.
INTRODUCTION THE NEED for anhydrous (and preferably carrier-free) fluorinating reagents which are labeled with fluorine-18 has been recognizedJ 1"2) NOZAKI et al. (a) used SHe or 4He beams to irradiate a stream of oxygen gas containing carrier H F to obtain I SF-HF. WELCH et al. (4) mentioned the preparation of NO~SF by the 2°Ne(d,a)lSF nuclear reaction on Ne containing NO in the irradiation vessel. Fluorine-lSF labeled molecular fluorine (tSF-F2) was prepared and examples of its integrity and synthetic utility were given.(5'6) Preliminary reports of targetry design and experimental yields for the on-line synthesis of ISF-F2, CllSF, H1SF and N O l S F have been given.(2,5,7) Alternative approaches to obtaining anhydrous ~SF-reagents have been described.(s-t l ) Recent examples(~2-~6) of selective fluorination at a particular saturated carbon position in steroids and other monofluoraliphatic compounds by controlled direct fluorinations with F2, anhydrous HF, or N O F illustrate the need for ready availability of ~SF-labeled intermediates for radiopharmaceutical synthesis.(6.7) This paper describes the rationale, target technology * Research carried out at Brookhaven National Laboratory under contract with the U.S. Department of Energy and supported by its Division of Basic Energy Sciences. t All inquiries regarding this work should be directed to RicH^go M. LAMBRECHT.Aspects of this research were presented at the Symposium on Labeled Compounds and Radiopharmaceuticals held at Copenhagen, Denmark, 26-30 March 1973; and The International Symposium on Radiopharmaceuticals held at Atlanta, Georgia, 12-15 February 1974. :~Visiting Scientist, BNL, 1974.
and methodology for the preparation of anhydrous fluorine-18 labeled molecular fluorine, nitrosyl fluoride, chlorine fluoride and hydrogen fluoride. EXPERIMENTAL Variables were studied at a total gas pressure of 2.5-4atm with various additive/Ne concentrations. The energy of the deuterons at entry into the target gas was generally 11 MeV. The elapsed time between EOB and the anhydrous l aF removal studies was typically 0.2-1.0 hr. Vacuum line
The high toxicity and reactivity of fuorine and fluorinating agents requires careful attention to their manipulation. A metal vacuum line of the type generally recommended (17) for handling fluorine and volatile fluorides was constructed for handling anhydrous ~SF and is depicted in Fig. 1. The vacuum line was constructed of 0.25 in o.d. monel or inconel tube. Model M-4W monel diaphragm valves (Nupro Co., Cleveland, OH) were utilized in the vacuum line and target. The components were coupled with swagelok fittings or full penetration welds. The reaction vessels were fabricated(2°) from KeI-F. The 2- and 3-way solenoid (Model DV3 144AI) valves were obtained either from Fluorocarbon Co. (Anaheim, CA) or Skinner Electric Co. (New Britain, CT). The electronic mass flow controller, transducer and digital readout for purging the ~SF from the target were purchased by special order from Matheson Gas Products (East Rutherford, N J). A Vactronics (Northport, NY) VVB-50-Q continuously variable flow controller and an oilless, diaphragm, 175
176
Richard M. Lambrecht, Rudi Neirinckx and A. P. Wolf
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Cyclon isotopes and radiopharmaceuticals--XXIII
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pressure-vacuum pump (Bell & Gosset, Monroe, LA) were used for flushing or recycling the target additives or anhydrous fluorine-18. The scrubber to remove F2 before the roughing pump was constructed of a steel cylinder (12 x 4 in) loaded with technical grade soda lime and sealed with full penetration welds. The scrubber of sodium fluoride used to remove hydrogen fluoride from the fluorine was purchased from Matlieson Co. (Model 68-1008). A double valve metering arrangement (Matheson No. 940F) was located near the F2 reserve tank. The pressure-vacuum gauge was of the monel Bourdon tube type. The fluorine (usually < 100 psig) was contained in a Hoke (Cresskill, N J) 72H163 stainless steel cylinder and surrounded by a 0.25 in shield. Autoradiography was used to assure the intensity of the full l~netration weld of the Hoke model 30NM-4072 monel valve to the fluorine tank. Certain special gases were dried with a gas line purifier (R. D. Mathis Co., Long Beach, CA). The reader is referred to the Matheson Gas Data Book, Matheson, Co., Inc. pp. 211-215 and reference 20 for safety information on handling fluorine. Targetry High purity nickel 200 (Whitehead Metal Co., Harrison, N J) was chosen for the construction of the target for anhydrous lSF production. The reason for this choice was the reported °s) absence of exchange between HISF and NiF 2 on the walls of a nickel reactor. There is however some confusion on the point. Figure 2 depicts an assembly drawing of a Ni target which has provisions for circulating water at 31 rain-~ throughout the walls of the target. There are two gas inlets seal-welded into the target to facilitate filling with Ne and purging He through the target to remove l a F - F z after an irradiation. Provisions are
included for flowing a cooling gas across the window of the target during the irradiation. The advantage of the target in Fig. 2 is its portability and ease of use for synthetic research. Figures 3 and 4 depict the Mark II target utilized for large-scale anhydrous ~SF production. Certain features are in common with Fig. 2. A Ni rod was machined as indicated in Fig. 4. A Cu flange firmly held a Ni window ( l l 3 m g / c m 2) against a KeI-F " 0 " ring (C. E. Conover Co., Inc., Fairfield, N J) lightly lubricated with KeI-F grease. Tetrafluor "O" rings (Royal Industries, El Segundo, CA) were equally effective. The flange at either end of the target was provided with water flowing at 31 m i n - ~ through 0.25 in Cu tubing. The tubing was silver soldered to the flange to assure good thermal contact. Additional cooling was not provided for the target body. The target assembly was placed in a cradle mounted onto the cyclotron beam pipe. Additional construction details of the targets are available on request. "9) The target passivation procedure which was developed by experience consisted of reacting F2 with the Ni surface at 300-600°C. In addition to the metal reaction (1) M + F2--* MF2 CANNON et al/TM have proposed that the true passivation reaction involves a rapid initial reaction of fluorine with a surface oxide film; (2) MO + F2--~ MF2 + ~O2. Subsequent reactions by mechanism (1) at elevated temperatures would be expected to be diffusion controlled by migration of fluorine through the pore structure or defects in the film, or to be determined by a tunneling mechanism. (2°) A study of electron diffraction patterns of fluorinated films on Ni-200 indicated (2°) the presence of Ni metal, NiO and NiF2' 4H20. Samples exposed to F2 at 93°C exhibited some NiO(OH), Ni(OH)2 and Ni3Oz(OH)4 lines. Exposure of the" fluorine-treated samples to humid air at 27°C pro-
178
Richard M. Lambrecht, Rudi Neirinckx and A. P. Wolf
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Cyclon isotopes and radiopharmaceuticals--XXllI
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FIG. 4. Details of Fi& 3. dueed additional lines of Ni(OH)2 and NiO(OH), and subsequent exposure to F2 appeared to eliminate the hydroxide lines. We cannot speculate further on the reactions and composition of the fluoride film on our nickel target. However the effective passivation of the Ni target for ~SF work, is rapidly lost ifthe evacuated target is opened to air on a humid day. If this occurs most of the volatile ~SF recovered from the target (even in the presence of 7.5% F2 carrier) lacks the labeling integrity associated with ~SF-F2. The chemical form(s) of the volatile ~SF-activity under these circumstances has not been established. The effect of moisture on fluoride films seems to vary erratically. A freshly passivated Ni target has a dull white appearance (NiF 2 anhydrous). Increasing exposure to humidity results in the film changing to a greenish appearance (hydrated NiF2). The appearance of the films of NiF2 on the inner walls of the target are depicted in Fig. 5. Subsequent passivation procedures on the Ni target surfaces appeared to result in the production of surface blisters on the inner walls of the target. Unsuccessful attempts to obtain anhydrous tSF-intermediates with the methods described have consistently been traced to an inadequate passivation of the target and vacuum lines.
Chemicals Research grade neon of >99.998% purity was obtained from Air Products in 100 liter cylinders at 670 psig. Pressurized gases were used in the highest purity available except He and N2. Chlorine gas was vacuum dried at 600°C on 40--60 mesh activated charcoal impregnated with copper and barium as an activator. <21) Fluorine as obtained in 100psig cylinders * The expected lSF yield was based on the "measured" irradiation dose and may have been under-estimated due to uncertainty in the fraction (and the constancy of the fraction) of the diffused beam which diverged into the walls of the 35-era target.
contained ~2% N2 and 02 which was neither assayed or removed. H F present in the F2 was removed by passage of the F2 through a trap loaded with sodium bifluoride. We are not aware of an effective method for removing 02 and N2 from F2. RESULTS AND DISCUSSION
Target system performance Anhydrous lSF was produced by the 2°Ne(d,a)lSF nuclear reaction on a target of pressurized neon gas. The irradiation parameters consisted of degrading and scattering a 17.6 -I- 0.2 MeV deuteron beam with a 1.3 g/era 2 Cu foil (5 em o.d.) silver soldered to a H 2 0 cooled Cu block. The target was electrically insulated from the Cu degrader and positioned in a cradle at a distance of 10crn between the degrader window and the H 2 0 cooled Ni window of the target. If the Cu degrader was removed the "hot spots" in the beam resulted in development of pinholes in the Ni window of the pressurized Ne target if the beam current exceeded 12/+A. The pressure in the target increased by ~ 30% at full beam conditions. The irradiation assembly was found to sustain 40/JA beams under production conditions. The beam current was generally restricted to 25/JA. Irradiations of 66/zAh were successfully tested.
The 2°Ne(d,a)lSF reaction The 2°Ne(d,~)lSF target was routinely used "~ to produce 100mCi of 'SF-F2 and the maximum level of ~SF-Fz recovered from a single irradiation was 580mCi. CLARK, GOULD[NG and P^LMER(22) have produced comparable quantities of lSF (but not as ~SF-F~) with the same nuclear reaction using a 30p.A beam. The recovery of anhydrous ~SF from the target was fairly reproducible after a given passivation proeess. The radiochemical yields obtained were 25 + 5% and are based on the usable anhydrous tSF actually" recovered from the target.*
Richard M, Lambrecht, Radi Neirinckx and A, P. Wo(f
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dent protons of 31,7 MeV on I1.5 m-mole Fz was determined to be 11.8 + 1.0 mCi//~Ah or ~ 1.0 m C i / pAh/mmole F~. The excitation functions for these reactions are reported elsewhere.(24"2s) Production of *aF-F2
Anhydrous :eF was produced by either the 2°Nc~d,~):~F, 2°He(3 He, x):SNe--. :~F or :~F(p.x):aF - , :SF nuclear reactions, Direct fluorination of organic compounds with molecular *SFF2 is preferably accomplished by dynamically removing the radioreagent from the target. The Ne serves as a vehicle to carry the :eF-F2 from the target to the reaction vessel, and acts as an inert diluem with SHe RANGE (mq cm"~) IN NEON which to control molecular fluorination reactions. FIG. 6. :eF thick target saturation production rate result. The :aF--F2 was dynamically removed from the target ing from the ~He + neon reactions. by utilization of the equipment depicted in Fig. 1. An oiiless diaphragm pump was used to recirculate~) The thick target yield for the 2°Ne(d,2):SF reaction the He through the target and reaction vessel during for a neon target with the beam degraded from or subsequent to the irradiation. We prefer to purge t ' F - F 2 from a static target at a rate which corre16.5--,0MeV was determined to be 27mCi/#Ah. This corresponds to 85.gmCi/pA at saturation. The .~onds to a pressure drop in the target of 120-150 Pa yield is comparable with the yield of 28 mCi/#Ah see-:. Table I presents results obtained for the dynareported by CLARK et al. ~ ' ~ with incident deuterons mic removal of taF-F2 from a target (Fig. 3) containof 15 MeV, or calculated as ~ mCi/~Ah from the ing 0.1-7.57~ F2. The F2 additive serves as a scavenger and carrier gas of the :eF, excitation functi¢~a rept~rted by N o z ^ m er a13TM Figure 7 depicts the variation in the yield of taF-F~ The 2°Ne(~He,:<):aF and :SN¢ ~ :aF reactions " from the target as a function of the percent F2 carrier Figure 6 depicts the : ' F thick target saturation added to the neon prior to the irradiation. The total production rate resuking from the 2°N~(al'le,x)teF :°F produced was maintained constant, whereas the (x = 3p2n, ,~n, Sl-le2n) and (x = 2p3n, Sl-lepa) via recovery yield of ISF--F2 was found to be a sensitive -'°NeQHe, x)~aNe ~ : ' F nuclear reactions for al-le variable of the F2-carricr concentration, and the total panicles in the 55.7-10MeV energy region. The ~He gas pressure in the target at the time the yield of reactions on neon have been memioned pre- t g F - F 2 was sampled. That is, the :'F-F.~ removal viously,~ ' ' s ' ' ~ The portion of the curve below 20 MeV pressure is the target pressure at the time a :aF was calculated using Nozaki's excitation function, ~23~ sample was taken. The resuks are expressed as "samThe yield data for the 55,7--*0McV region was pied" production rates of ~aF-F2 at the various postexperimentally determined by both the thin and thick irradiation target pressures.* If the percentage of target methods. At the ~He beam energies available F2-carrier was >37~, the recover), yield of t~F-Fz on all but the smallest compact cyclotrons the :aF was about constant as a function of the target presproduction rate was only ~ ~ less than what one sure (at initial pressures of 2.5--4 arm). would obtain using the 2°Ne(d,a)taF and highest deuteron energy available on the given accelerator. The observation is satisfying since ~He irradiations result 5.0 % F~ in a considerably lesser environmental radiation nuis• O%F~ : ance than deuteron irradiations. Ls~ te F and ~°ble(a,al:m)taF The =°Ne(a,a~2n):aNe --*
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The direct reactions were used to produce 558.5mCi of :aF--F2. The yield of :aF-F~ with ino* The teF--F~ was sampled by aliquotin8 a fraction of the volatile : ' F from the vacuum line into a specially
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181
Cyclon is<~opes and radiopharmo,ceuticals--XXlll I
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FIG, 8. lnfluen~ of the millimoles of F~ added to the neon on the resulting yield of ~F-F~, Figure 8 depicts the effect of the mitlimoles of F2 carrier added to the neon prior to the irradiation on the yield of teF-F=. The absolute quantity of F2 carrier in the target appears to affect the yield of ~SF-Fz more so than the relative concentration of carrier under the conditions studied. If F~ carder was not added to the neon prior to the irradiation, the yield of volatile ~'F was very low at the higher pressures. The ~*F recovered under the no-carrier-added ¢ondilions was likely tSF--F, arising from reaclions of atomic t aF wi~h the NiFz passivated walls, or volatile taF impurities (see subsequent discussions). We unexpectedly found that the recovery yield of the volatile t SF under no-r~rrier-m~ded conditions increased as the target pressure was reduo~ to < 100torr. The physical properties of F~ (especially the - 1 8 8 ° b.p.) necessitated a method which permitted removal of the neon (-*..48 K b,p,) while retaining the t~F in the target. One cannot facilitate the vacuum distillation of =eF--Fz from 1',I¢ with liquid N~ ( - 1 9 5 . 8 K b.p.). The properties of liquid O~ ( - 2 1 8 K b.p.) require additional safety precautions and equipment heyond our resources. Therefore the retention of the ~SF on the target walls until low pressures were re.ached provided a satisfactory method for r~-~ovh~g the bulk of the Ne from the =SF. These observations conveniemtly provided a means of synthesizing ~aF-labeled CFaOF for use as an anhydrous fluorinating intermediate. ~2~ Produclion of H~aF, CI~SF and taF-CF,
In many instances it is desirable to have "carrierfrec" anhydrous fluorinating agents available on-line for the synthesis of organic radiopharmaceuticalstx.s.ze~ Other hard, moderate and soft teF-fluorinating reagents can in principle he conveniently prepared from the primary t~F-reagents.iZ,s~ Table I summarizes resuhs obtained for production of H=SF, CPaF and taF-F z, The relative yields for production
and recovery of usable anhydrous ~SF-intermediates are described under a number of additive/Ne concentrations. Since NOISF has been previously repurted {4; it will not he discussed, The recovery yield of anhydrous N O t ' F from the Mark ! target containing 2?4 Hz and N¢ was ~20% of the recovery of iSF-F 2 under optimum conditions, STRAATMANel al. I~°) have recently adopted various ~SF production suggestions ta'4's'~-~'2~ and used the tSF recovered from a Ni-ba~d target containing Ne + 157~ Ha for the subsequent synthesis of a 'eF-laheled fluorinating agent The exchangeta~ of H~eF with several interhalogens is complete within 3-10rain at room temperature to yield for example: leF-BrFa, IaF--CIFa, laF-SbFs, lSF-l~'Fs and lSF--IFs. The reactions of F atoms with O2 have been the subject of very few reports, °m although vibrational and mass spectra are available for FOz and OF, respectively, We do not have a method at hand for removing the Oz and Nz from our Fz source. Competitive reactions of ISF with the additive vs the Oz and N 2 impurities may contribute to the range in the recovery yields reported in Table !. A sidelight of this study was the observation that t SF-CF4 was formed in situ during the deuteron irradiation of a low concentration of carbonyl fluoride in ]'4¢ (at 2500 torr to4al pressure) in either the NiF2 passivated or a Kd-F target containing ~-0.Sg of CsF. Tetrafluoromethan¢ is not a fluorinating agea~ but ~aF-CF4 might be of interest for inhalatior) toxicolngy studies of fluorocarbons or pulmonary function determinations with a focal plane positron ernis-
182
Richard M. Lambrecht, Rudi Neirinckx and A. P. Wolf
TABLE2. Recovered production yield of tSF-CF, at several CF20 concentrations in Ne at a total pressure of 2500torr Z CF20
Production y l e l d ~Ci/~h
0.004
3.0
0.004
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was the only volatile lSF product observed by radiochromatography on a silica gel columnJ ,s) The mechanism of ~sF-CF4 formation was not determined. Non-radioactive C F , was also observed which suggest at least some role of radiolytic processes. TODD et al.(Dr) investigated the reactions of lSF generated by the t9F(~,n)iSF nuclear reaction in C F , / C H J N e mixtures and concluded that the tSF reacts as atoms rather than ions or as internally excited atoms. The t s F - C F , was removed from the Ne by purging the gas from the Ni target through molecular sieve (A-5) cooled in a slush bath of 2-chlorobutane (-131°C). After complete evacuation of the target, the molecular sieve was pumped under vacuum for 15 min. The apparent production rate of tSF-CF4 as determined by the activity on the molecular sieve at -131°C under several experimental conditions are tabulated in Table 2. Typically 35% of the lSF-CF, was lost during the step to evacuate the Ne. As the trap was warmed the released tSF-CF4 was collected in a gas syringe. The syringe contained ~0.2ml of Ne and ~50O/O of the lSF-CF,,. The laF-CF4 was injected into 5 ml of isotonic water for injection in a sterile, pyrogen-free vial. The aqueous solution contained ~ 32% of the tsF-CF4 originally produced, and gave an overall production rate of ~ 1.3 mCi/t~Ah of ' sF-CF,. CONCLUSIONS This paper describes the target technology and rationale utilized for our initial success in the production of several anhydrous tSF-labeled fluorinating agents useful for the synthesis of organic radiopharmaceuticals. Further optimization of the concepts and operating parameters are expected to lead to improved production yields. Obvious improvements include recycling the neon, and producing the tSF-fluorinating intermediates "on-line". The elapsed time for the end of bombardment, and the subsequent dynamic removal of the anhydrous tSF may have reduced the radiochemical yields due to reaction or adsorption of the ~SF. A diffused beam was required
to achieve a stable production target. Thinning of the Ne in the beam path could occur at high beam currents unless the target is operated at higher pressures. A rotating spherical target equipped with a rotating vacuum seal and a refrigerated bath to constantly wash the lower 30% of a thin rotating target wall is an intriguing possibility presently being considered{t9) for anhydrous lSF production on a compact medical cyclotron. To date four radiopharmaceuticals have been prepared at BNL using t8F-F2 prepared by the 2°Ne(d,~)'SF reaction and a Ni target. Those compounds are lSF-5-fluorouracil,(6'7'3:) tSF-5-fluorocytosine,(t's) tSF-2-fluoro2-deoxy-D-glucose,(33) and t8F-2-deoxy-2-fluoro-D-mannoseJ33) In addition, tSF-CFsOF-ISF has been prepared (27) with the Mark II targetry described. It is expected that the various anhydrous tSF-intermediates will be utilized for new routes to develop new radiopharmaceuticals.
REFERENCES 1. WOLFA.. P., CHRISTMAND. R., FOWLERJ. S. and LAMBRECHT R. i . in Radiopharmaceuticals and Labeled Compounds, Vol. 1, pp. 345-381. Vienna, IAEA (1973). 2. LAMBRECHTR. M. and WOLFA. P. in Radiopharmaceuticals (Edited by SUBRAMANIANG., RHODES B. A., COOPER J. F. and SODD V. J.) pp. 111-124. Society of Nuclear Medicine, New York (1974). 3. NOZAKIT., TANAKAY., SHIMAMURAA. and KARASAWA T. lnt. J. appl. Radiat. Isotopes 19, 27 (1968). 4. WELCHM. J., LIFTONJ. F. and GASPARP. P. J. nucl. Med. 12, 405 (1971) (Abstract). 5. LAMBRECHTR. M. and WOLFA. P. In Radiopharmaceu. ticals and Labeled Compounds, Vol. 1, pp. 275-290. Vienna, IAEA (1973). 6. FOWLERJ. S., FINNR. D., LAMBRECHTR. M. and WOLF A. P. J. nucl. Med. 14, 63 (1973). 7. LAMBRECHT R. M., MANTESCU C., FOWLER J. S. a n d WOLF A. P. J. nucl. Med. 13, 785 (1972) (Abstract). 8. CLARK J. C., GOULDING R. W. and PALMERA. J. In Radiopharmaeeuticals and Labeled Compounds, Vol. 1, pp. 411-421. Vienna, IAEA (1973). 9. CLARKJ. C., GOULOINGR. W., ROMANM. and PALMER A. J. Radiochem. Radiounal. Lett. 14, 101 (1973). 10. STRAATMANNM. G. and WELCHM. J. First Int. Symp. Radiopharmaceutical Chemistry, Brookhaven National Laboratory, Upton, NY., 21-24 September 1976. Abstract 45, unpublished. 11. CASELLA V. R., IDO T. a n d WOLF A. P. First Int. Symp. Radiopharmaceutical Chemistry, Brookhaven National Laboratory, Upton, NY, 21-24 September 1976. Abstract 44, unpublished. 12. SHARTSC. M. and SHEPPAROW. A. Org. React. 21, 125 (1974). 13. MERRITT R. E. a n d STEVENS T. E. J. Am. chem. Soc.
88, 1822 (1966). 14. BARTOND. H. R., HESSER. H., MARKWELLR. E. and PECHET M. M. J. Am. chem. Soc. 98, 3034 (1976). 15. PATRICKT. B., LE FAWREM. H. and KOERTGET. E. J. orO. Chem. 41, 3413 (1976). 16. BROCKEMULLERW. Her 64B, 5277 (1931). 17. SHRIVERB. F. The Manipulation of Air Sensitive Compounds. McGraw-Hill, New York (1969). 18. BOGGSJ. E., VAN ARTSDALEN E. R. a n d BROSI A. R. J. Am. chem. Soc. 77, 6505 (1955). 19. LAMBRECHTR. M. Chemistry Department, Brookhaven National Laboratory, Upton, NY 11973.
Cyclon isotopes and radiopharmaceuticals--XXIII
183
20. CA~,~ON W. A., ASUNMAA S. K., ENGUSH W. D. and 26. CHRISTMAN D. R., BNL Report 50028 (T-445). TXNER N. A. Trans. Metallurg. Soc. A.I.M.E. 242, 1635 (Available from D.R.C. on request.) 27. NEIRINCKX R. D., LAMBRECHT R. M. and WOLF A. P. (1968). 21. Gmelins Handbuch der Anorganischen Chemie, Chlor, Int. J. appl. Radiat. Isotopes (in press). VoL 6, p. 21. Verlag Chemie, Weinheim/Bergstr., 28. KRONRAD L., MUDRA K. and MARCK J. Radioisotopy (1968). 17(2), 155 (1976). 22. PALMER A. J., CLARK J. C., GOULDING R. W. and 29. ROGERS M. T. and KATZ J. J. J. Am. chem. Soc. 74, ROMAN M. in Radiopharmaceuticals and Labelled Com1375 (1952). pounds, VoL 1, pp. 291-302. I.A.E.A. Vienna (1973). 30. JONES W. E. and SKSLNIK E. G. Chem. Rev. 76, 563 23. NOZAKI T., IWAMOTO M. and ITO T. Int. J. Appl. (1976). Radiat. Isotopes 25, 393 (1974). 31. TODD J. F. J., COLEBOURNE N. and WOLFGANG R. J. 24. WHITEHEAD A. B. and FOSTER J. S. Can. J. Phys. 36, phys. Chem. 71, 2875 (1967). 1276 (1958). 32. FOWLER J. S., LAMBRECHTR. M. and WOLF A. P. U.S. 25. GUSAKOW M., ALSOUY G., POFFE' N. and GUSAKOW Patent 3,808,097. (30 April 1974). M. Ann. Phys. (Paris) 7, 67 (1962). 33. REIVICH M., KUHL D. et al. J. clin. Invest. (submitted).
0020-708X/78/0301-0175502.00/0
Cyclotron Isotopes and Radiopharmaceuticals XXIII.* Novel Anhydrous 18F-Fluorinating Intermediates R I C H A R D M. L A M B R E C H T , R U D I N E I R I N C K X ~ a n d A. P. W O L F Chemistry Department, Brookhaven National Laboratory, Upton, NY 11973, U.S.A. (Received 10 January 1977; accepted 1 September 1977)
The 2°Ne(d,0QlSFreaction and a high purity nickel target passivated with an anhydrous film of nickel fluoride were utilized for the preparation of anhydrous ~SF-labeled fluorinating reagents. A recovery yield of ~8.8mCi/pAh of ISF-F2 was obtained with 11 MeV deuterons incident on neon and F2 carrier at a pressure of 2.63 atm. ISF-F2 was obtained at a production rate of 1i.8 mCi/pAh with t h e 19F(p,pn)LSF and t 9 F ( p , 2 n ) t S N e ---, ~SF nuclear reactions at 31.7 MeV on I 1.5 mmolea of F2. The 2°Ne(aHe,x)l SF and JSNe 1.5.% is F nuclear reactions (x = 3p2n, :~n, 3He2n and 2p3n, Hepn, respectively) with 55.7-10MeV 3He and the 2°Ne(~,~n) 'aNe ~ ~SF and 2°Ne(:~,',pnpaF reactions at 45-33 MeV were evaluated. At the SHe beam energies available on all but the smallest compact cyclotrons the ~aF production rate was ~ 70?/oof that obtainable for the (d,a) reaction on a given accelerator. The methodology and targetry for the production of ISF-Fz, tSF-CF4, HtaF, NO~aF and ClZSF are described.
INTRODUCTION THE NEED for anhydrous (and preferably carrier-free) fluorinating reagents which are labeled with fluorine-18 has been recognizedJ 1"2) NOZAKI et al. (a) used SHe or 4He beams to irradiate a stream of oxygen gas containing carrier H F to obtain I SF-HF. WELCH et al. (4) mentioned the preparation of NO~SF by the 2°Ne(d,a)lSF nuclear reaction on Ne containing NO in the irradiation vessel. Fluorine-lSF labeled molecular fluorine (tSF-F2) was prepared and examples of its integrity and synthetic utility were given.(5'6) Preliminary reports of targetry design and experimental yields for the on-line synthesis of ISF-F2, CllSF, H1SF and N O l S F have been given.(2,5,7) Alternative approaches to obtaining anhydrous ~SF-reagents have been described.(s-t l ) Recent examples(~2-~6) of selective fluorination at a particular saturated carbon position in steroids and other monofluoraliphatic compounds by controlled direct fluorinations with F2, anhydrous HF, or N O F illustrate the need for ready availability of ~SF-labeled intermediates for radiopharmaceutical synthesis.(6.7) This paper describes the rationale, target technology * Research carried out at Brookhaven National Laboratory under contract with the U.S. Department of Energy and supported by its Division of Basic Energy Sciences. t All inquiries regarding this work should be directed to RicH^go M. LAMBRECHT.Aspects of this research were presented at the Symposium on Labeled Compounds and Radiopharmaceuticals held at Copenhagen, Denmark, 26-30 March 1973; and The International Symposium on Radiopharmaceuticals held at Atlanta, Georgia, 12-15 February 1974. :~Visiting Scientist, BNL, 1974.
and methodology for the preparation of anhydrous fluorine-18 labeled molecular fluorine, nitrosyl fluoride, chlorine fluoride and hydrogen fluoride. EXPERIMENTAL Variables were studied at a total gas pressure of 2.5-4atm with various additive/Ne concentrations. The energy of the deuterons at entry into the target gas was generally 11 MeV. The elapsed time between EOB and the anhydrous l aF removal studies was typically 0.2-1.0 hr. Vacuum line
The high toxicity and reactivity of fuorine and fluorinating agents requires careful attention to their manipulation. A metal vacuum line of the type generally recommended (17) for handling fluorine and volatile fluorides was constructed for handling anhydrous ~SF and is depicted in Fig. 1. The vacuum line was constructed of 0.25 in o.d. monel or inconel tube. Model M-4W monel diaphragm valves (Nupro Co., Cleveland, OH) were utilized in the vacuum line and target. The components were coupled with swagelok fittings or full penetration welds. The reaction vessels were fabricated(2°) from KeI-F. The 2- and 3-way solenoid (Model DV3 144AI) valves were obtained either from Fluorocarbon Co. (Anaheim, CA) or Skinner Electric Co. (New Britain, CT). The electronic mass flow controller, transducer and digital readout for purging the ~SF from the target were purchased by special order from Matheson Gas Products (East Rutherford, N J). A Vactronics (Northport, NY) VVB-50-Q continuously variable flow controller and an oilless, diaphragm, 175
176
Richard M. Lambrecht, Rudi Neirinckx and A. P. Wolf
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pressure-vacuum pump (Bell & Gosset, Monroe, LA) were used for flushing or recycling the target additives or anhydrous fluorine-18. The scrubber to remove F2 before the roughing pump was constructed of a steel cylinder (12 x 4 in) loaded with technical grade soda lime and sealed with full penetration welds. The scrubber of sodium fluoride used to remove hydrogen fluoride from the fluorine was purchased from Matlieson Co. (Model 68-1008). A double valve metering arrangement (Matheson No. 940F) was located near the F2 reserve tank. The pressure-vacuum gauge was of the monel Bourdon tube type. The fluorine (usually < 100 psig) was contained in a Hoke (Cresskill, N J) 72H163 stainless steel cylinder and surrounded by a 0.25 in shield. Autoradiography was used to assure the intensity of the full l~netration weld of the Hoke model 30NM-4072 monel valve to the fluorine tank. Certain special gases were dried with a gas line purifier (R. D. Mathis Co., Long Beach, CA). The reader is referred to the Matheson Gas Data Book, Matheson, Co., Inc. pp. 211-215 and reference 20 for safety information on handling fluorine. Targetry High purity nickel 200 (Whitehead Metal Co., Harrison, N J) was chosen for the construction of the target for anhydrous lSF production. The reason for this choice was the reported °s) absence of exchange between HISF and NiF 2 on the walls of a nickel reactor. There is however some confusion on the point. Figure 2 depicts an assembly drawing of a Ni target which has provisions for circulating water at 31 rain-~ throughout the walls of the target. There are two gas inlets seal-welded into the target to facilitate filling with Ne and purging He through the target to remove l a F - F z after an irradiation. Provisions are
included for flowing a cooling gas across the window of the target during the irradiation. The advantage of the target in Fig. 2 is its portability and ease of use for synthetic research. Figures 3 and 4 depict the Mark II target utilized for large-scale anhydrous ~SF production. Certain features are in common with Fig. 2. A Ni rod was machined as indicated in Fig. 4. A Cu flange firmly held a Ni window ( l l 3 m g / c m 2) against a KeI-F " 0 " ring (C. E. Conover Co., Inc., Fairfield, N J) lightly lubricated with KeI-F grease. Tetrafluor "O" rings (Royal Industries, El Segundo, CA) were equally effective. The flange at either end of the target was provided with water flowing at 31 m i n - ~ through 0.25 in Cu tubing. The tubing was silver soldered to the flange to assure good thermal contact. Additional cooling was not provided for the target body. The target assembly was placed in a cradle mounted onto the cyclotron beam pipe. Additional construction details of the targets are available on request. "9) The target passivation procedure which was developed by experience consisted of reacting F2 with the Ni surface at 300-600°C. In addition to the metal reaction (1) M + F2--* MF2 CANNON et al/TM have proposed that the true passivation reaction involves a rapid initial reaction of fluorine with a surface oxide film; (2) MO + F2--~ MF2 + ~O2. Subsequent reactions by mechanism (1) at elevated temperatures would be expected to be diffusion controlled by migration of fluorine through the pore structure or defects in the film, or to be determined by a tunneling mechanism. (2°) A study of electron diffraction patterns of fluorinated films on Ni-200 indicated (2°) the presence of Ni metal, NiO and NiF2' 4H20. Samples exposed to F2 at 93°C exhibited some NiO(OH), Ni(OH)2 and Ni3Oz(OH)4 lines. Exposure of the" fluorine-treated samples to humid air at 27°C pro-
178
Richard M. Lambrecht, Rudi Neirinckx and A. P. Wolf
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FIG. 4. Details of Fi& 3. dueed additional lines of Ni(OH)2 and NiO(OH), and subsequent exposure to F2 appeared to eliminate the hydroxide lines. We cannot speculate further on the reactions and composition of the fluoride film on our nickel target. However the effective passivation of the Ni target for ~SF work, is rapidly lost ifthe evacuated target is opened to air on a humid day. If this occurs most of the volatile ~SF recovered from the target (even in the presence of 7.5% F2 carrier) lacks the labeling integrity associated with ~SF-F2. The chemical form(s) of the volatile ~SF-activity under these circumstances has not been established. The effect of moisture on fluoride films seems to vary erratically. A freshly passivated Ni target has a dull white appearance (NiF 2 anhydrous). Increasing exposure to humidity results in the film changing to a greenish appearance (hydrated NiF2). The appearance of the films of NiF2 on the inner walls of the target are depicted in Fig. 5. Subsequent passivation procedures on the Ni target surfaces appeared to result in the production of surface blisters on the inner walls of the target. Unsuccessful attempts to obtain anhydrous tSF-intermediates with the methods described have consistently been traced to an inadequate passivation of the target and vacuum lines.
Chemicals Research grade neon of >99.998% purity was obtained from Air Products in 100 liter cylinders at 670 psig. Pressurized gases were used in the highest purity available except He and N2. Chlorine gas was vacuum dried at 600°C on 40--60 mesh activated charcoal impregnated with copper and barium as an activator. <21) Fluorine as obtained in 100psig cylinders * The expected lSF yield was based on the "measured" irradiation dose and may have been under-estimated due to uncertainty in the fraction (and the constancy of the fraction) of the diffused beam which diverged into the walls of the 35-era target.
contained ~2% N2 and 02 which was neither assayed or removed. H F present in the F2 was removed by passage of the F2 through a trap loaded with sodium bifluoride. We are not aware of an effective method for removing 02 and N2 from F2. RESULTS AND DISCUSSION
Target system performance Anhydrous lSF was produced by the 2°Ne(d,a)lSF nuclear reaction on a target of pressurized neon gas. The irradiation parameters consisted of degrading and scattering a 17.6 -I- 0.2 MeV deuteron beam with a 1.3 g/era 2 Cu foil (5 em o.d.) silver soldered to a H 2 0 cooled Cu block. The target was electrically insulated from the Cu degrader and positioned in a cradle at a distance of 10crn between the degrader window and the H 2 0 cooled Ni window of the target. If the Cu degrader was removed the "hot spots" in the beam resulted in development of pinholes in the Ni window of the pressurized Ne target if the beam current exceeded 12/+A. The pressure in the target increased by ~ 30% at full beam conditions. The irradiation assembly was found to sustain 40/JA beams under production conditions. The beam current was generally restricted to 25/JA. Irradiations of 66/zAh were successfully tested.
The 2°Ne(d,a)lSF reaction The 2°Ne(d,~)lSF target was routinely used "~ to produce 100mCi of 'SF-F2 and the maximum level of ~SF-Fz recovered from a single irradiation was 580mCi. CLARK, GOULD[NG and P^LMER(22) have produced comparable quantities of lSF (but not as ~SF-F~) with the same nuclear reaction using a 30p.A beam. The recovery of anhydrous ~SF from the target was fairly reproducible after a given passivation proeess. The radiochemical yields obtained were 25 + 5% and are based on the usable anhydrous tSF actually" recovered from the target.*
Richard M, Lambrecht, Radi Neirinckx and A, P. Wo(f
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dent protons of 31,7 MeV on I1.5 m-mole Fz was determined to be 11.8 + 1.0 mCi//~Ah or ~ 1.0 m C i / pAh/mmole F~. The excitation functions for these reactions are reported elsewhere.(24"2s) Production of *aF-F2
Anhydrous :eF was produced by either the 2°Nc~d,~):~F, 2°He(3 He, x):SNe--. :~F or :~F(p.x):aF - , :SF nuclear reactions, Direct fluorination of organic compounds with molecular *SFF2 is preferably accomplished by dynamically removing the radioreagent from the target. The Ne serves as a vehicle to carry the :eF-F2 from the target to the reaction vessel, and acts as an inert diluem with SHe RANGE (mq cm"~) IN NEON which to control molecular fluorination reactions. FIG. 6. :eF thick target saturation production rate result. The :aF--F2 was dynamically removed from the target ing from the ~He + neon reactions. by utilization of the equipment depicted in Fig. 1. An oiiless diaphragm pump was used to recirculate~) The thick target yield for the 2°Ne(d,2):SF reaction the He through the target and reaction vessel during for a neon target with the beam degraded from or subsequent to the irradiation. We prefer to purge t ' F - F 2 from a static target at a rate which corre16.5--,0MeV was determined to be 27mCi/#Ah. This corresponds to 85.gmCi/pA at saturation. The .~onds to a pressure drop in the target of 120-150 Pa yield is comparable with the yield of 28 mCi/#Ah see-:. Table I presents results obtained for the dynareported by CLARK et al. ~ ' ~ with incident deuterons mic removal of taF-F2 from a target (Fig. 3) containof 15 MeV, or calculated as ~ mCi/~Ah from the ing 0.1-7.57~ F2. The F2 additive serves as a scavenger and carrier gas of the :eF, excitation functi¢~a rept~rted by N o z ^ m er a13TM Figure 7 depicts the variation in the yield of taF-F~ The 2°Ne(~He,:<):aF and :SN¢ ~ :aF reactions " from the target as a function of the percent F2 carrier Figure 6 depicts the : ' F thick target saturation added to the neon prior to the irradiation. The total production rate resuking from the 2°N~(al'le,x)teF :°F produced was maintained constant, whereas the (x = 3p2n, ,~n, Sl-le2n) and (x = 2p3n, Sl-lepa) via recovery yield of ISF--F2 was found to be a sensitive -'°NeQHe, x)~aNe ~ : ' F nuclear reactions for al-le variable of the F2-carricr concentration, and the total panicles in the 55.7-10MeV energy region. The ~He gas pressure in the target at the time the yield of reactions on neon have been memioned pre- t g F - F 2 was sampled. That is, the :'F-F.~ removal viously,~ ' ' s ' ' ~ The portion of the curve below 20 MeV pressure is the target pressure at the time a :aF was calculated using Nozaki's excitation function, ~23~ sample was taken. The resuks are expressed as "samThe yield data for the 55,7--*0McV region was pied" production rates of ~aF-F2 at the various postexperimentally determined by both the thin and thick irradiation target pressures.* If the percentage of target methods. At the ~He beam energies available F2-carrier was >37~, the recover), yield of t~F-Fz on all but the smallest compact cyclotrons the :aF was about constant as a function of the target presproduction rate was only ~ ~ less than what one sure (at initial pressures of 2.5--4 arm). would obtain using the 2°Ne(d,a)taF and highest deuteron energy available on the given accelerator. The observation is satisfying since ~He irradiations result 5.0 % F~ in a considerably lesser environmental radiation nuis• O%F~ : ance than deuteron irradiations. Ls~ te F and ~°ble(a,al:m)taF The =°Ne(a,a~2n):aNe --*
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181
Cyclon is<~opes and radiopharmo,ceuticals--XXlll I
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FIG, 8. lnfluen~ of the millimoles of F~ added to the neon on the resulting yield of ~F-F~, Figure 8 depicts the effect of the mitlimoles of F2 carrier added to the neon prior to the irradiation on the yield of teF-F=. The absolute quantity of F2 carrier in the target appears to affect the yield of ~SF-Fz more so than the relative concentration of carrier under the conditions studied. If F~ carder was not added to the neon prior to the irradiation, the yield of volatile ~'F was very low at the higher pressures. The ~*F recovered under the no-carrier-added ¢ondilions was likely tSF--F, arising from reaclions of atomic t aF wi~h the NiFz passivated walls, or volatile taF impurities (see subsequent discussions). We unexpectedly found that the recovery yield of the volatile t SF under no-r~rrier-m~ded conditions increased as the target pressure was reduo~ to < 100torr. The physical properties of F~ (especially the - 1 8 8 ° b.p.) necessitated a method which permitted removal of the neon (-*..48 K b,p,) while retaining the t~F in the target. One cannot facilitate the vacuum distillation of =eF--Fz from 1',I¢ with liquid N~ ( - 1 9 5 . 8 K b.p.). The properties of liquid O~ ( - 2 1 8 K b.p.) require additional safety precautions and equipment heyond our resources. Therefore the retention of the ~SF on the target walls until low pressures were re.ached provided a satisfactory method for r~-~ovh~g the bulk of the Ne from the =SF. These observations conveniemtly provided a means of synthesizing ~aF-labeled CFaOF for use as an anhydrous fluorinating intermediate. ~2~ Produclion of H~aF, CI~SF and taF-CF,
In many instances it is desirable to have "carrierfrec" anhydrous fluorinating agents available on-line for the synthesis of organic radiopharmaceuticalstx.s.ze~ Other hard, moderate and soft teF-fluorinating reagents can in principle he conveniently prepared from the primary t~F-reagents.iZ,s~ Table I summarizes resuhs obtained for production of H=SF, CPaF and taF-F z, The relative yields for production
and recovery of usable anhydrous ~SF-intermediates are described under a number of additive/Ne concentrations. Since NOISF has been previously repurted {4; it will not he discussed, The recovery yield of anhydrous N O t ' F from the Mark ! target containing 2?4 Hz and N¢ was ~20% of the recovery of iSF-F 2 under optimum conditions, STRAATMANel al. I~°) have recently adopted various ~SF production suggestions ta'4's'~-~'2~ and used the tSF recovered from a Ni-ba~d target containing Ne + 157~ Ha for the subsequent synthesis of a 'eF-laheled fluorinating agent The exchangeta~ of H~eF with several interhalogens is complete within 3-10rain at room temperature to yield for example: leF-BrFa, IaF--CIFa, laF-SbFs, lSF-l~'Fs and lSF--IFs. The reactions of F atoms with O2 have been the subject of very few reports, °m although vibrational and mass spectra are available for FOz and OF, respectively, We do not have a method at hand for removing the Oz and Nz from our Fz source. Competitive reactions of ISF with the additive vs the Oz and N 2 impurities may contribute to the range in the recovery yields reported in Table !. A sidelight of this study was the observation that t SF-CF4 was formed in situ during the deuteron irradiation of a low concentration of carbonyl fluoride in ]'4¢ (at 2500 torr to4al pressure) in either the NiF2 passivated or a Kd-F target containing ~-0.Sg of CsF. Tetrafluoromethan¢ is not a fluorinating agea~ but ~aF-CF4 might be of interest for inhalatior) toxicolngy studies of fluorocarbons or pulmonary function determinations with a focal plane positron ernis-
182
Richard M. Lambrecht, Rudi Neirinckx and A. P. Wolf
TABLE2. Recovered production yield of tSF-CF, at several CF20 concentrations in Ne at a total pressure of 2500torr Z CF20
Production y l e l d ~Ci/~h
0.004
3.0
0.004
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0.040
3.9
0.080
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0.280
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was the only volatile lSF product observed by radiochromatography on a silica gel columnJ ,s) The mechanism of ~sF-CF4 formation was not determined. Non-radioactive C F , was also observed which suggest at least some role of radiolytic processes. TODD et al.(Dr) investigated the reactions of lSF generated by the t9F(~,n)iSF nuclear reaction in C F , / C H J N e mixtures and concluded that the tSF reacts as atoms rather than ions or as internally excited atoms. The t s F - C F , was removed from the Ne by purging the gas from the Ni target through molecular sieve (A-5) cooled in a slush bath of 2-chlorobutane (-131°C). After complete evacuation of the target, the molecular sieve was pumped under vacuum for 15 min. The apparent production rate of tSF-CF4 as determined by the activity on the molecular sieve at -131°C under several experimental conditions are tabulated in Table 2. Typically 35% of the lSF-CF, was lost during the step to evacuate the Ne. As the trap was warmed the released tSF-CF4 was collected in a gas syringe. The syringe contained ~0.2ml of Ne and ~50O/O of the lSF-CF,,. The laF-CF4 was injected into 5 ml of isotonic water for injection in a sterile, pyrogen-free vial. The aqueous solution contained ~ 32% of the tsF-CF4 originally produced, and gave an overall production rate of ~ 1.3 mCi/t~Ah of ' sF-CF,. CONCLUSIONS This paper describes the target technology and rationale utilized for our initial success in the production of several anhydrous tSF-labeled fluorinating agents useful for the synthesis of organic radiopharmaceuticals. Further optimization of the concepts and operating parameters are expected to lead to improved production yields. Obvious improvements include recycling the neon, and producing the tSF-fluorinating intermediates "on-line". The elapsed time for the end of bombardment, and the subsequent dynamic removal of the anhydrous tSF may have reduced the radiochemical yields due to reaction or adsorption of the ~SF. A diffused beam was required
to achieve a stable production target. Thinning of the Ne in the beam path could occur at high beam currents unless the target is operated at higher pressures. A rotating spherical target equipped with a rotating vacuum seal and a refrigerated bath to constantly wash the lower 30% of a thin rotating target wall is an intriguing possibility presently being considered{t9) for anhydrous lSF production on a compact medical cyclotron. To date four radiopharmaceuticals have been prepared at BNL using t8F-F2 prepared by the 2°Ne(d,~)'SF reaction and a Ni target. Those compounds are lSF-5-fluorouracil,(6'7'3:) tSF-5-fluorocytosine,(t's) tSF-2-fluoro2-deoxy-D-glucose,(33) and t8F-2-deoxy-2-fluoro-D-mannoseJ33) In addition, tSF-CFsOF-ISF has been prepared (27) with the Mark II targetry described. It is expected that the various anhydrous tSF-intermediates will be utilized for new routes to develop new radiopharmaceuticals.
REFERENCES 1. WOLFA.. P., CHRISTMAND. R., FOWLERJ. S. and LAMBRECHT R. i . in Radiopharmaceuticals and Labeled Compounds, Vol. 1, pp. 345-381. Vienna, IAEA (1973). 2. LAMBRECHTR. M. and WOLFA. P. in Radiopharmaceuticals (Edited by SUBRAMANIANG., RHODES B. A., COOPER J. F. and SODD V. J.) pp. 111-124. Society of Nuclear Medicine, New York (1974). 3. NOZAKIT., TANAKAY., SHIMAMURAA. and KARASAWA T. lnt. J. appl. Radiat. Isotopes 19, 27 (1968). 4. WELCHM. J., LIFTONJ. F. and GASPARP. P. J. nucl. Med. 12, 405 (1971) (Abstract). 5. LAMBRECHTR. M. and WOLFA. P. In Radiopharmaceu. ticals and Labeled Compounds, Vol. 1, pp. 275-290. Vienna, IAEA (1973). 6. FOWLERJ. S., FINNR. D., LAMBRECHTR. M. and WOLF A. P. J. nucl. Med. 14, 63 (1973). 7. LAMBRECHT R. M., MANTESCU C., FOWLER J. S. a n d WOLF A. P. J. nucl. Med. 13, 785 (1972) (Abstract). 8. CLARK J. C., GOULDING R. W. and PALMERA. J. In Radiopharmaeeuticals and Labeled Compounds, Vol. 1, pp. 411-421. Vienna, IAEA (1973). 9. CLARKJ. C., GOULOINGR. W., ROMANM. and PALMER A. J. Radiochem. Radiounal. Lett. 14, 101 (1973). 10. STRAATMANNM. G. and WELCHM. J. First Int. Symp. Radiopharmaceutical Chemistry, Brookhaven National Laboratory, Upton, NY., 21-24 September 1976. Abstract 45, unpublished. 11. CASELLA V. R., IDO T. a n d WOLF A. P. First Int. Symp. Radiopharmaceutical Chemistry, Brookhaven National Laboratory, Upton, NY, 21-24 September 1976. Abstract 44, unpublished. 12. SHARTSC. M. and SHEPPAROW. A. Org. React. 21, 125 (1974). 13. MERRITT R. E. a n d STEVENS T. E. J. Am. chem. Soc.
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