Synthesis of 15O-labeled butanol via organoborane chemistry

Int J Appi Radtat Isot Vol 36, No II.pp 853-855. 1985 Pnnted m Great Bntmn All rights reserved

0020-708X/85 $300+000 Copyright ~ 1985 Pergamon Press Lid

Synthesis of tSO-Labeled Butanol via Organoborane Chemistry* G W KABALKA, t R M LAMBRECHT, 2 M SAJJAD: J S FOWLER," S A KUNDA, t G W McCOLLUM ~ and R MACGREGOR 2 'Chermstry Department, Umverstty of Tennessee, Knoxvdle, "IN 37996-1600 and 2Chemistry Department, Brookhaven Nanonal Laboratory, Upton, NY 11973, U S A

(Recewed 2 Aprd 1985) Oxysen-15 labeled I-butanol and 2-butanol were prepared by the reacUon of O2-tsO with m-nbutylborane and tn-sec-butylborane m tetrahydrofuran The reaction products were isolated and tdennfied via reversed-phase high performance column chromatography and gas chromatography Radlochemlcal yields of 50°,/o(EOB) were obtamed The use of tsO-labeled butanol ts suggested for cerebral blood flow measurements m conjuncuon w~th PET

Introduction Positron enuttmg radtotracers are of current mterest in nuclear medlCane However, the synthesis of tsO-labeled molecules presents a formidable challenge to the syntheuc chemist due to the lame restraint imposed by the short half-hfe (2 04mm) of ~sO Because of thxs severe lame restraint, statable methods to prepare ~SO-labeled alcohols are vlrtually noneYastent (t) Organoboranes have proven to be useful mtermechates for rapidly mcorporalang isotopes of carbon, todme, brormne and mtrogen c2~In fact, organoboranes have been utihzed to prepare 170-labeled alcohols contalmng a wide variety of substttuents ¢3) Since the react×on of organoboranes wtth oxygen IS rapid ¢4~ and since ~SO-labeled butanol would have nearly ideal chetmcal and decay properties for the measurement of cerebral blood flow using PET, we have mveslagated the utdity of organoboranes m the syntheses of t~O-labeled alcohols

R~B~

R-lSOH

Experimental Tetrahydrofuran was chsulled prior to use Tn-nbutylborane and tn-sec-butylborane were purchased from Aldrich Chermcal Co. and used as recelved A Perkm-Elmer Senes 3B hquid chromatograph was fitted wath either a Sphensorb 5 0 D S column (25 c m × 4 6 m m I d.) or a Whatrnan Parusd 5 ODS-31[AC If/10 (16 c m × 4 6 m m i d.) column A refractave * Prehnunary aspects of thss research were reported at the 5th lnternattonal Symposmm on Radlopharmaceutacal Chermstry, Tokyo, Japan, July 9-13, 1984 IV-P-24, p 265

mdex detector was uuhzed to detect butanol The solvent system was 28% EtOH/water (v/v) and a flow rate of 1 0 mL/mm was employed The effluent samples were analyzed for radloaclavlty using a Packard LS 9000 scmUllauon spectrometer The O2J50 samples were counted m I0 mL synnges GC data were collected on a Perkm-Elmer Sigma 300 H W D chromatograph using a 6ft × 0 25m Porapak Q (80-100 mesh) column and a thermal conducuwty detector The column temperature was 75°C and a flow rate of 30 mL/mm of behum was employed The GC was connected to a LC 1-100, Perkm-Elmer laboratory computmg integrator Samples were collected every 30 s on actzvated charcoal and the radloacUvlty measured usmg a NaI(TI) well counter

Preparation of tSO-labeled oxygen O2-t~O was generated vm the t4N(d, n)'50 reacUon on the JSW 1710 cyclotron A gas mixture (49:1) of ~4N2 and t602 was used as the target Typxcally, 33 mCl of O2-~50 per 0.1 L of target gas was obtmned at saturauon after the gas was passed through soda hme and actlvated charcoal to remove t~CO2, CtSO2, ~3NO 2 and U N O Analysm ~s~of the gas used for the reaclaon revealed 0 2 % U N as N2, the rernamder was O2-~sO The method of Vera Rulz ~6~ was used to produce [tsO]H20 Synthesis o f tsO-Labeled Butanol A reacuon vessel eqmpped wtth a burrell seal inlet, a magneuc sttrnng bar and a gas outlet connected to a mercury bubbler was employed in the reaclaons

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KABALKA et al

The reactaon vessel was cooled to 0°C 0ce bath) and flushed with nitrogen Tn-n-butylborane (1 5 mL of a 1 M solution in THF, 1 5 mmol) was placed m the reaction vessel and stirred for approximately 15 mm to allow thermal equtltbratmn. 150 gas (4 5/amol, 5 mL of 2% 02, ~ 1 5 mC0 was added to the solution vm a gas ught synnge The product was isolated :mmedaately after the addmon of the O,-tsO The activity of the O2-J50 was measured before the reaction The gas above the reaction mixture was analysed after the reaction was complete Essentmlly all of the O2-t~O was found to be m the solution

IO

I . . . . . .

I

O

ACTIVITY

REFRACTIVE INDEX I-

A 8Z X

;= *o

,,*n

=o_

z_

x O

w

>--05

H P L C study A 50/~L sample of the reactlon mixture was injected into the HPLC which was fitted with a 200/~L preparative loop All the retention t~mes were confirmed by using appropriate standards RetenUon times for tetrahydrofuran and 15D-labeled butanol were 7 0 and 8 5 mm respectively uuhzang the Sphensorb 5 0 D S column [In an effort to shorten the HPLC ~solat~on time, we investigated the use of a short, high performance Whatman RAC column Although the condmons were not optimized, we found that we could achieve basehne separation between water and butanol and that l-butanol exhibited a decreased retention txme (2 0 mm) The Whatman RAC columns could prove valuable m future studies aimed at prepanng tSO-labeled alcohols intended for biomedical research or chmcal apphcatlons ] Samples were collected every 30 s The activity of each sample was measured and extrapolated back to time zero, ~e the end of bombardment (EOB) The profile of radaoactivity is plotted m Fig 1 along with the trace of the refractive index detector of the HPLC The tsO a c t m t y is associated with the butanol and the water peaks The activity of the contents of the reaction vessel was measured after each reaction and revealed a quanutatwe absorption of the I~O into the solution The radiochemtcal yield of [tSO]butanol was generally found to be ~ 50% (EOB) GC study Tn-n-butylborane (2 0 m L of a 1 M solution m THF, 2mmol) was reacted with O2-tsO Then l-butanol (100pL) and water (80/~L) was added to the nuxture. A 200/~ L sample of the reactmn mixture was analyzed by GC. Samples were collected every 30 s and analyzed Approramately 50~ of the radaoacUv~ty was assocmted with 1-butanol

Synthesis o f lSO-Labeled

2-Butanol The reactmns were performed as outlined m the preparataon of l-butanol, using tn.sec.butylborane and O2JSO Analyses were carried out m a s~mdar fashion The results indicated that [tsO]2-butanol was formed m approximately 4 0 ~ radiochemtcal ymlds

>FkcJ ,<

0

5 IO ELUTION TIME (ram)

15

Fig 1 Profile of radloacttvRy and chermcal detecuon of the reaction tmxture on the HPLC

Results tSO-Labeled butanol ts formed m good ymids ( ~ 5 0 ~ ) wa the reaction of tnbutylborane with O2-~50 All O2JSO is consumed and although the remaining radioactavtty has the same retention time as water the chemmal form has not been identified The exchange of I~O from H2-150 with butanol was found to be negligible ( < ! 0 - 2 ~ ) dunng the time required for the preparataon and purification of [150]butanol The addmon of sodaum pyrosulphite to the reacUon mixture dad not stgmficanfly increase the ymld of the labeled alcohol mdacatang that there ~s neghgable formation of 1*O-labeled peroxide.

Discussion Labeled alcohols have been uuhzed m a variety of physiological studms, especaally m cerebral blood flow (CBP) measurements. Eklof et al (~ and Ramhle et ul (s) found a daffuslon hnutation using ethanol, leading Ralchle m) to suggest the use of [ltC]lsopropanol for CBF measurements [t4C]Butanol was reported(910) to be a freely daffusable tracer over a wide range of CBF and does not appear to vary with regqonal pathology Subsequently(It i2) [itC]butano I was prepared Ramhle et al then recommended that [tiC]butanol be used as a standard for CBF tracers after showing It to be freely permeable up to a CBF of ~> 180 mL (100 g mm -I) and having vahdated its

Synthes~s of ~O.labeled butanol use with PET oJ ~4) However, it has been pomted out that the PET measurement of CBF reqmres that measurements be made dunng the first 1 nun after mjectaon and therefore that the same amount of +-enutter labeled tracer Is reqmred independent of the half-hfe of the nuchde o5~ Thus ~50 would appear to be an ~deal agent from the standpoint of rad~aUon doslmetry The preparatton of ~50-labeled butanol is modeled after the previously reported preparation of alcohols from the reactaon of oxygen with tnalkyiboranes (3) In the preparaUve scale reacuon of organoboranes to yield alcohols, l 5 tool of O2 reacts per mole of tnalkyiborane to y~eld 3 tool of alcohol In the chemistry reported tn this paper, 4 5/~mol of O2-~50 is allowed to react with 2 mmol of R3B Since the R3B ts m large excess, the mlually formed peroxide would be expected to rearrange instantaneously upon hydrolysis to produce ~50-iabeled butanol m 50% radlochenual yield (4 t6) The remaining 50% of the ~50 would then be associated with the bonnate byproduct whtch, because of Its polar character, could be responsible for the acUvlty observed m the solvent front Thts study demonstrated that tt is feasible to use the reaction of tnbutylborane with oxygen to prepare 1~O-iabeled butanol However, because of the short half-hfe of ~sO, the need for about 50mC~ of [~O]butanol for a PET study on a human subject, and the des~rabfitty of producing a product of h~gh specific actavtty, a mod~ficaUon of the experimental design which was used for this feas~bthty study would be reqmred For example, the continuous flow target of mtrogen with 2% oxygen carrier (which was used for convemence) would not be appropnate because of the large amount of earner which is introduced Instead, astattc target would be used and the amount of carrier oxygen reduced In ad&taon, a system which would allow the O2-t~O to be trapped effic:ently at the lugh flow rates reqmred to empty the target w~th a nummum loss due to decay would be desirable Finally, an exceedingly raptd punficauon method which y~elds the product m an mjecuble soluuon will be reqmred In the present study, the use of tetrahydrofuran, a toxic chemical, comphcates the ~solat~on Fortunately, the organoboranes react with oxygen m the absence of solvent°~-~ and this approach may prove valuable for future chmcal stu&es

855 Conclusion

The ease and short reaction tame of the reaction of organoboranes with O:-~O suggest that th~s reaction ~s potenUally useful for the syntheses of a variety of 150-labcled alcohols Further stu&es are planned Acknowledgements--The research was performed at Brook-

haven NaUonal Laboratory under contract DE-AC0276CH00016 with the U S Department of Energy supported by its Office of Health and Environmental Research and also supported by Nauonal Insututes of Health Grant NS-15380 The Umverslty of Tennessee also acknowledges support from the U S Department of Energy (Office of Health and Environmental Research, DE-AS0580EV10363) References ! Wolf A P, Chnstman D R , Fowler J S and Lambrecht R M Radzopharmaceutwals and Labeled Compounds, Vol 1, pp 345-381 (IAEA, Vienna, 1973) 2 Kabalka G W Acct Chem Re$ 17, 215 0984) 3 Kabalka G W , ReedT J and KundaS A Synth Commun 13(9), 737 (1983) 4 Brown H C, Midland M M and Kabalka G W J Am Chem Soc 93, 1024 (1971) 5 SaJJad M, Lambrecht R M and Wolf A P Manuscnpt m preparatton 6 Vera Rmz H and Wolf A P J Labeled Compd Radzopharm 15, 185 (1978) 7 Eklof B, Lassen N A , Ndsson L, Norberg K , Slesjo B K and Torlof P Acta Phys,ol Scand 91, I (1974) 8 Ralchle M E, Elchhng J O Straatman M G , Welch M J, Largon K B and Terpogosslon M M Am J Phystol 230, 547 (1976) 9 Schaefer J A , Gjedde A and Plum F Neurology 26, 394 (1976) 10 Gledde A , Hansen A J and Slemkowlcz E Acta Phystol Scand 108, 321 (1980) 11 Oberdorfer F , Helus F , M~uer-Borst W and Sdvester D J Radwchem Rad,oanal Left 53, 237 0982) 12 Dischmo D D , Welch M J, IOlboum M R and Ralchle M E J Nucl Med 24 1030 (1983) 13 R~uchle M E, Martin W R W, Herscovltch P, Kllbourn M R and Welch M J J Nucl Med 24, 63 (1983) 14 Herscowtch P, Ralchle M E, Kllbourn M, Welch M Abstracts of 14th Ann Mtg of the Soewty for Neurosciences, Anaheim, Ca No 10, Part 2, p 792 (1984)

15 Rmchle M E, Martin W R W, Herscovltch P, Mmtum M A and Markham J J Nucl Med 24, 790 0983) 16 Abraham M andDavlesA J Chem Soc 1129(1959) 17 JohnsonJ R and VanCampenM G J Am Chera Soc 60, 121 (1938) 18 Abraham M and Davl~ A J Chcm Soc 429 0959) 19 Mtrvlss S J Am Chem Soc 83, 3051 (1961)