Available online at www.sciencedirect.com

Nuclear Medicine and Biology 37 (2010) 943–948www.elsevier.com/locate/nucmedbio

A quartz-lined carbon-11 target: striving for increased yield andspecific activity

Jacek Koziorowskia, Peter Larsenb, Nic Gillingsc,⁎aCyclotron and Radiochemistry Unit, Herlev University Hospital, Copenhagen, Denmark

bScansys ApS, Værløse, DenmarkcPET and Cyclotron Unit and Centre for Integrated Molecular Brain Imaging, Copenhagen University Hospital Rigshospitalet,

DK-2100 Copenhagen, Denmark

Received 18 February 2010; received in revised form 4 June 2010; accepted 18 June 2010

Abstract

Introduction: The increased demand for high specific radioactivity neuroreceptor ligands for positron emission tomography (PET) requiresthe production of high specific radioactivity carbon-11 in high yields. We have attempted to address this issue with the development of a newquartz-lined aluminium target for the production of [11C]methane or [11C]carbon dioxide.Methods: The new target has been tested with respect to yields of [11C]methane and [11C]carbon dioxide, and the effect of the quartzliner has been evaluated. The specific radioactivities of a large number of radiopharmaceuticals produced using this target have alsobeen measured.Results: The described target produces [11C]-labelled gases in excellent yields, and losses of radioactivity in the target on production of [11C]methane have been reduced significantly by the use of a quartz liner. Radiopharmaceuticals with specific radioactivities up to 9000 GBq/μmol at end of bombardment (EOB) (243 Ci/μmol) have been produced using this target.Conclusions: We have developed a reliable, high-yielding carbon-11 gas target which is now routinely used in our department for theproduction of high specific activity radiopharmaceuticals.© 2010 Elsevier Inc. All rights reserved.

Keywords: Target; Carbon-11; Methane; Specific activity; PET

1. Introduction

The increased demand for high specific activity ligandshas necessitated the production of high specific activitycarbon-11 in high yields. Since carbon dioxide is ubiquitousin the atmosphere, [11C]methane is the starting material ofchoice. Furthermore, the synthesis route for the productionof [11C]methyl iodide or methyl triflate is shorter utilizingmethane. It has previously been demonstrated that, atsufficient irradiation energies, nitrogen/hydrogen gas mix-

⁎ Corresponding author. PET and Cyclotron Unit, CopenhagenUniversity Hospital Rigshospitalet, DK-2100 Copenhagen, Denmark. Tel.:+45 35451678; fax: +45 35453898.

E-mail address: nic@pet.rh.dk (N. Gillings).

0969-8051/$ – see front matter © 2010 Elsevier Inc. All rights reserved.doi:10.1016/j.nucmedbio.2010.06.008

tures yield large amounts of [11C]methane [1]. Unfortunate-ly, it appears that increasing beam current and irradiationlength results in a significant drop in the amounts of [11C]methane that can be recovered from the target as comparedwith theoretical yields [2]. It seems that the expected amountof carbon-11 is produced but some is trapped in the target,probably due to beam–wall interactions [2,3]. Large volumetargets, where beam wall interactions are less likely, produceresults more in line with theory. The choice of targetmaterial in small- to medium-sized targets is thereforeproposed to be one of the most important factors foroptimising [11C]methane yields. Furthermore, target designand manufacture are also critical for production of highspecific activity gases [4,5]. Previously, a niobium target for[11C]methane production showed improved results com-pared with other materials [6]. Our hypothesis was that theuse of an inert material with low carbon content would

944 J. Koziorowski et al. / Nuclear Medicine and Biology 37 (2010) 943–948

maximise specific radioactivities and, by minimising surfaceadsorption of methane and other radioactive species,increase overall yields. Quartz as a target material seemsto be a good choice due to its chemical inertness, low carboncontent and the fact that it is manufactured without the use ofany potential carbon sources, such as lubricants. A quartz-lined target has previously been used for the recoil synthesisof high specific activity [11C]hydrogen cyanide [7], and hereit was reported that greater than 90% of the carbon-11 couldbe removed in the gas phase. We designed and constructed atarget based on an aluminium body fitted with a quartz liner,thus combining the inertness of quartz with the ease ofassembly of aluminium.

Here we describe the evaluation of this target with respectto yields of [11C]CH4 and [11C]CO/CO2, with and without

Fig. 1. Diagram of target design and photo of the a

the quartz liner, and specific activities of radiopharmaceu-ticals produced using this target via [11C]CH4.

2. Experimental

2.1. Target

The target consists of a water-cooled aluminium body[AlMg3 (AA 5754), length 250 mm, ID 22.3 mm]. Thequartz liner is a straight tube (22 mm OD, wall thickness 1.2mm, 249.5 mm long). The beam is collimated to 10 mm andpasses through two helium-cooled Havar foils (25 and 50μm, respectively). All aluminium parts in contact with targetgas were machined without the use of petroleum-basedlubricants. Fig. 1 shows an exploded view of the target,

ssembled target (quartz tube in foreground).

945J. Koziorowski et al. / Nuclear Medicine and Biology 37 (2010) 943–948

where all parts can be seen, and a photo of the assembledtarget. The target volume is 75 ml with the quartz liner and98 ml without.

2.2. Target cleaning

All target parts were initially cleaned in an ultrasonic bathfilled with a 10% solution of Branson Industrial Strengthcleaner (VWR International) heated to ca. 60°C for 10 min.This was followed by the same treatment but using a 10%solution of Branson General Purpose cleaner (VWRInternational) for 30 min. Then all parts were rinsedthoroughly with distilled water to remove all signs ofdetergent followed by sonication in and rinsing with distilledwater (repeated three times). Finally, all parts were rinsedwith HPLC-grade water and dried in an oven at 120°C for 60min. The target was not “baked out” at high temperatures orin a vacuum oven as has been reported for other high specificactivity targets [5,8].

2.3. Irradiations

Irradiations were performed using the Scanditronix MC-32 cyclotron at Copenhagen University Hospital Rigshospi-talet. H− ions were accelerated to 17.2 MeV, giving a targetentrance energy of ca. 16 MeV. The target gas consisted ofultrapure gases [AGA, Sweden, grade 6.0 (N99.99995%)].For methane production, 10% hydrogen in nitrogen wasused, and for carbon dioxide, 2% oxygen in nitrogen wasused. The filling pressure was initially varied from 15 to 30bar in order to estimate the effective target thickness and thetarget pressure at various beam currents. For most experi-ments, a filling pressure of 26 bar was chosen, based on foilrupture pressure experiments without beam. For the experi-ments without the quartz liner, the fill pressure was 30 bar(thus giving the same pressure during irradiation for bothsystems). Initially, the target gases were used without inlinepurifiers. However, it became clear that the supplied gas

Fig. 2. GC chromatograms of target gas after irradiation of (A) nit

mixtures vary in purity and an inline purifier was installed(ALL-Pure gas purifier, Alltech, USA).

2.4. Analysis

Following irradiations, [11C]-labelled gases were releasedfrom the target by simply opening a valve and transferred toa hot cell. Activity was trapped using a 6-mm OD stainlesssteel tube containing Carbosphere (60/80 mesh, 4 cm3) in asmall Dewar filled with liquid nitrogen and placed in a dosecalibrator (Capintec CRC-25 PET or CRC-15R). In thissetup, N90% of the target gas could be trapped within 3 min.Approximately 1 min after release of the gas from the target,a 2-ml sample was transferred to a gas chromatograph (GC,Shimadzu 8A) and analysed on a packed GC column(Supelco 60/80 Carboxen-1000, SS, length 15 ft, OD 1/8 in.,ID 2.1 mm, helium carrier gas pressure 600 kPa, temperature120°C) with online FID and radiodetection.

Specific activity of the generated gases was not measureddirectly. We have, however, measured the specific activity ofa large number of radiopharmaceuticals synthesised byconverting [11C]CH4 to [11C]methyl iodide or [11C]methyltriflate via a fully automated gas phase system [9,10] andreacting with the appropriate precursor. The concentration ofthese radiopharmaceuticals was measured by quantitativeHPLC analysis in order to determine the specific activities.HPLC analyses were performed using a Gilson HPLCsystem with a Dionex UVD 100 detector, controlled usingChromeleon software (Dionex Corp., USA).

3. Results

Analysis of the target gas mixtures after irradiation by gaschromatography revealed that the hydrogen/nitrogen mixturegives [11C]methane along with ca. 29% [13N]nitrogen, whichis slightly higher than previously reported [11]. There were[11C]carbon oxides detected after the first few conditioningruns, after which [11C]methane was the only carbon-11

rogen with 10% hydrogen or (B) nitrogen with 2% oxygen.

946 J. Koziorowski et al. / Nuclear Medicine and Biology 37 (2010) 943–948

species detected. The oxygen/nitrogen mixture gave rise to[11C]CO2, a small amount of [11C]CO (8%) and [13N]nitrogen (38%). The amount of [11C]CO would be predictedto be reduced if the amount of oxygen were reduced [3]. Theuse of 2% oxygen was based entirely on the availability ofthis mixture at the time. The relatively large amounts of [13N]nitrogen are produced by the 14N(p,d)13N reaction which isprevalent at 16 MeV with some contribution from the 16O(p,α)13N reaction in the oxygen/nitrogen mixture. Thenitrogen peak on the GC chromatogram presumably alsocontained [14O]oxygen, produced by the 14N(p,n)14Oreaction, but this can only be attributed to a maximum of10% of the peak at the time of measurement, based on thepublished saturation yield data [12]. The fact that not all theproduced carbon-11 is removed from the target also leads to ahigher relative amount of [13N]nitrogen. All the above resultsare decay corrected to end of bombardment (EOB) and basedon 40-min irradiations at 25 μA. Representative gaschromatograms are shown in Fig. 2.

Fig. 3. Theoretical and production yields expressed as gigabecquerel at EOBformethane (A) or carbon oxides (B)with a beamcurrent of 25μA. Theoreticalyield (●); target with quartz insert (▲); target without quartz insert (■).

Due to the high flow of the target gas through the cooledCarbosphere trap, it was found that only small amounts of[13N]nitrogen were trapped along with the carbon-11methane or carbon oxides. We estimated that this would atworst case contribute only 5% to the decay-corrected carbon-11 yields. All yield data was based on the measured values ataround 7–10 min after EOB. A radioactive waste gascontainment system was present to collect the relatively largeamounts of [13N]nitrogen gas produced, thus preventingrelease into the atmosphere.

The target yields for methane and carbon oxides areshown in Fig. 3 for a beam current of 25 μA andirradiations up to 60 min. The estimated theoretical thicktarget yields at saturation are 6.90 GBq/μA for methane and7.17 GBq/μA for carbon oxides at 16 MeV and 10%hydrogen in nitrogen and 2% oxygen in nitrogen,respectively, based on published yields calculated for the14N(p,n)11C reaction [13]. The effect of the quartz insertcan be seen in Fig. 4: both methane and carbon oxide yields

ig. 4. Production yields expressed as percentage of the theoretical yield forethane (A) or carbon oxides (B). Data for 10 μA with (■) and withoutuartz insert (●) and for 25 μA with (▲) and without quartz insert (◆).

Fmq

Fig. 5. Specific activities of [11C]radiopharmaceuticals (EOB) produced from [11C]methane.

947J. Koziorowski et al. / Nuclear Medicine and Biology 37 (2010) 943–948

were higher in the quartz-lined target. This effect was seenboth at 10 and at 25 μA.

The target has been used for routine production of a rangeof radiopharmaceuticals produced from methane (quartz-lined target), and specific activities up to ca. 9000 GBq/μmol at EOB (243 Ci/μmol) have been measured. Specificactivities for all the productions so far are depicted in Fig. 5.These values were initially a factor of four to five highercompared with our old target (conical, aluminium 750 mlvolume) but, after installation of an inline gas purifier,followed by installation of a new gas cylinder, the specificactivities have further increased. The last 26 productionshave given an average of specific activity of 5479±1735GBq/μmol at EOB. The large variation in specific activitiesseems unavoidable at such high values and generallyincreases with repeated irradiations and radiosyntheses on

Fig. 6. Percentage of theoretical yield for [11C]methane (EOB) as a functionof beam current. Twenty-minute irradiations, target fill pressure 26 bar,target gas 10% hydrogen, with quartz insert.

the same day. This can be attributed to a conditioning effect,whereby cold carbon is flushed from the target andradiochemistry system. It was demonstrated that reasonablespecific activities could be restored after only three to fourirradiations following foil change and reassembly of thetarget (results not presented). This compares favourably tothe results published by Andersson et al. [14] where ca. 20runs were needed to achieve stable performance.

4. Discussion

The increasing deviation from theoretical yields withincreased irradiation dose (μAh) has been reported earlier[2,3]. Intuitively, one would expect that the yield is moredependent on beam current than on irradiation time, as theformer should give more unfavourable beam–wall interac-tions with increasing current (Fig. 6). In fact, the yield dropappears to be just as dependent on irradiation time (Fig. 4).

The only feasible explanation for the drop in yields, withincreasing irradiation times and increasing beam current, isthat radioactive species remain adsorbed to the target. Theunderlying mechanism(s) of this phenomenon has yet to beelucidated, although there is data published describing the

able 1itted parameters A and a for targets used for production of [11C]CH4 and1C]CO2/CO

arget chamber [11C]CH4 [11C]CO/CO2

A a (×10,000) A a (×10,000)

iobium cylindera 95±2 40±4 – –uartz-lined aluminiumcylinderb

170±6 45±11 187±5 15±8

luminium cylinderb 168±10 85±26 174±15 14±23a Ref. [6], 12 MeV, 20 μA.b Present results, 16 MeV, 25 μA.

TF[1

T

NQ

A

948 J. Koziorowski et al. / Nuclear Medicine and Biology 37 (2010) 943–948

base catalysed polymerisation of hydrogen cyanide [15],which could be a plausible explanation for the observedretention of radioactivity. No matter what, it is clear from theresults presented here that the quartz liner increases therecoverable yields of [11C]methane and (to a lesser extent)[11C]carbon oxides.

Buckley et al. [6] proposed an exponential equationwhich target production data could be fitted to:

Y = Ae−at I SF

Where Y is the decay-corrected yield (mCi), A the fittedpre-exponential term (mCi/μA), a the fitted exponential term(min−1), I the beam current, t the irradiation time (min) andSF the saturation correction factor (1−e−λt). The authorsclaimed that, while the A term represents production rates inthe target, the a term represents losses due to activityretained in the target. We have fitted our data to this equationand the results are shown in Table 1. As can be seen from thea term, in terms of retention of activity in the target, thequartz-lined target chamber performs well compared with theniobium target chamber, with the pure aluminium chamberperforming slightly less well. The results from fitting the[11C]CO/CO2 data, although somewhat uncertain, alsosuggest that the a term is mainly associated with retentionof carbon-11 in the target, since we do not expect CO/CO2 tobe retained to any great extent.

In conclusion, the described target has a smaller volume,thus enabling trapping of [11C]methane in a short period oftime; gives high, stable and predictable yields of [11C]methane and [11C]carbon oxides; and enables routineproduction of [11C]-labelled compounds with very highspecific radioactivities.

References

[1] Christman DR, Finn RD, Karlstrom KI, Wolf AP. The production ofultra high 11C-labeled hydrogen cyanide, carbon dioxide, carbonmonoxide and methane via the 14N(p,α)11C reaction (XV). Int J ApplRadiat Isot 1975;26:435–42.

[2] Buckley KR, Huser J, Jivan S, Chun KS, Ruth TJ. 11C-Methaneproduction in small volume, high pressure gas targets. Radiochim Acta2000;88:201–5.

[3] Ache HJ, Wolf AP. The effect of radiation on the reactions of recoilcarbon-11 in the nitrogen-oxygen system. J Phys Chem 1968;72:1988–93.

[4] Suzuki K, Yamazaki T, Sasaki M, Kubodera A. Specific activity of[11C]CO2 generated in a N2 gas target; effect of irradiation dose,irradiation history, oxygen content and beam energy. Radiochim Acta2000;88:211–5.

[5] Noguchi J, Suzuki K. Automated synthesis of the ultra high specificactivity of [11C]Ro15-4513 and its application in an extremely lowconcentration region to an ARG study. Nucl Med Biol 2003;30:335–43.

[6] Buckley KR, Jivan S, Ruth TJ. Improved yields for the in situproduction of [11C]CH4 using a niobium target chamber. Nucl MedBiol 2004;31:825–7.

[7] Lamb JF, James RW, Winchell HS. Recoil synthesis of high specificactivity 11C-cyanide. Int J Appl Radiat Isot 1971;22:475–9.

[8] Björk H, Dahlström K, Bergström JO, Truong P, Halldin C. Productionof in-target 11CH4 on a specific activity optimized 11C PETtrace target.Proceedings of the 10th International Workshop on Targetry andTarget Chemistry, Madison, Wisconsin, USA, August 13th–15th;2004, pp. 12.

[9] Larsen P, Ulin J, Dahlstrøm K, Jensen M. Synthesis of [11C]iodomethane by iodination of [11C]methane. Appl Radiat Isot 1997;48(2):153–7.

[10] Gillings N, Larsen P. A highly flexible modular radiochemistrysystem. J Label Compd Radiopharm 2005;48:S338.

[11] Le Bars D. A convenient production of [13N]nitrogen for ventilationstudies using a nitrogen gas target for 11C production. J Label CompdRadiopharm 2001;44:1–5.

[12] Kovács Z, Scholten B, Tárkányi F, Coenen H, Qaim SM. Crosssection measurements using gas and solid targets for production of thepositron-emitting radionuclide O-14. Radiochim Acta 2003;91:185–9.

[13] Qaim SM, Tárkányi F, Takács S, Hermanne A, Nortier M, ObložinskýP, et al. Positron Emitters (14N(p,n)11C). Charged particle cross-sectiondatabase for medical radioisotope production: diagnostic radioisotopesand monitor reactions. Vienna: IAEA; 2001, pp. 235–40. (IAEA-TECDOC-1211), Chapter 5.2.1 (http://www-nds.iaea.org/medical/n4p11c0.html).

[14] Andersson J, Truong P, Halldin C. In-target produced [11C]methane:increased specific radioactivity. J Label Compd Radiopharm 2009;67:106–10.

[15] Mamajanova I, Herzfeld J. HCN polymers characterized by solid stateNMR: chains and sheets formed in the neat liquid. J Chem Phys 2009;30:134503.