2=65s ), an improved PET tracer for rCBF measurement

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Applied Radiation and Isotopes 62 (2005) 525–532 www.elsevier.com/locate/apradiso

Production of [17F]CH3F (t1=2 ¼ 65 s), an improved PET tracer for rCBF measurement T.E. Barnharta,, A.K. Conversea, K.A. Dabbsa, M.J. Schuellera, C.K. Stonea, R.J. Nicklesa, A.D. Robertsa,b a

Medical Physics, University of Wisconsin, 1500 N. Highland Ave. T-121 Waisman Center, Madison, WI 53705, USA b Manchester Molecular Imaging Center, University of Manchester, M20 3LJ, UK Received 7 July 2004; received in revised form 17 August 2004; accepted 17 August 2004

Abstract Production of 17F (t1=2 ¼ 65 s) in the form of [17F] F2 has been achieved using both the 20Ne(p,a)17F and 16O(d,n)17F reactions with 11 MeV protons and 6 MeV deuterons, respectively. Yields have proven suitable for subsequent radiosynthesis of the blood flow tracer, [17F]CH3F (460 mCi in saline), currently in use for fast repetition human studies of regional cerebral blood flow with positron emission tomography. Thick target yields of 15 mCi/mA for protons and 44 mCi/mA for deuterons have been measured for [17F]F2. r 2004 Elsevier Ltd. All rights reserved. Keywords:

17

F; Fluoromethane; PET

1. Introduction Fluoromethane labeled with 18F (t1=2 ¼ 110 min) has been used to determine regional cerebral blood flow (rCBF) (Gatley et al., 1981), but is ill suited to fast repetitions needed for cerebral activation protocols. Fluorine-17 (t1=2 ¼ 65 s) has a half-life well matched to blood flow in cerebral gray matter, shows signal-to-noise ratio improvements over 15O tracers (t1=2 ¼ 122 s) (Martin et al., 1999), and allows for faster scan repetition. Production of [17F] fluoromethane in sufficient quantities for animal studies via the 16O(d,n)17F reaction has been reported (Mulholland et al., 1999). The production of [17F]F2 has the advantage of a high production yield, but the subsequent radiosynthesis into Corresponding author. Tel.: +608-2656604; fax: +6082658737. E-mail address: [email protected] (T.E. Barnhart).

[17F] fluoromethane suffers from its synthesis in an oxygen-rich atmosphere. Nonetheless, high yields can be achieved, well in excess of those needed for use in rCBF study protocols with positron emission tomography (PET). Production by 20Ne(p,a)17F has the dual advantage of production in an inert environment for improved fast radiochemistry, and ease of implementation on low-energy proton cyclotrons. The purpose of this work was to develop improved radiotracers for rCBF measurement under activation protocols with PET. As outlined below, the University of Wisconsin is investing heavily on the infrastructure needed for the broad application of neuroimaging techniques, including PET and fMRI, particularly for investigations of the neurobiological basis of emotion. The timing is right for a fundamental reevaluation of the methods of functional neuroimaging. While recognizing that fMRI is increasingly the method of choice for many activation paradigms, these

0969-8043/$ - see front matter r 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.apradiso.2004.08.044

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generally focus on cortical regions. The circuitry most critical for emotion includes limbic territories, as well as portions of the prefrontal cortex, ventral and orbital, that have extensive anatomical reciprocity with certain limbic structures such as the amygdala. Some of these brain regions, particularly the orbital prefrontal cortex, are associated with massive susceptibility artifact in fMRI studies because of their proximity to the sinus cavity. It is going to be essential in studies of emotion activation to continue to use PET to image these critical components of the circuitry. Furthermore, there continues to be a need for blood flow investigations where PET has some clear advantages, such as when auxiliary equipment or subject restrictions make fMRI impractical. As an example, current studies in humans use transcranial magnetic stimulation to probe brain function (Ferrarelli et al., 2004), a difficult task in the MR environment. Other applications arise when combining blood flow imaging with tracer concentration imaging of sensitive neuroreceptor function, such as dopamine response (Converse et al., 2004).

2. Background It has long been recognized that functional brain activation is associated with increased neuronal metabolism (Kennedy et al., 1975), and that these changes are simultaneously associated with changes in rCBF (Raichle et al., 1976). One of the most successful techniques for determining regional cerebral oxygen utilization and blood flow in vivo has been to detect the annihilation photons from positron decay of 15O-labeled tracers. The tracers and administration methods have varied, including carotid artery injection of 15O-labeled blood (Ter-Pogossian et al., 1970), steady-state inhalation of [15O]CO2 (Jones et al., 1976; Frackowiak et al., 1980), and bolus intravenous injection of [15O]water (Huang et al., 1983) or [15O]butanol (Berridge et al., 1991). Of these, the most common procedure for rCBF determination by PET today is bolus injection of [15O] water. The advantages of this method, particularly in the early development of the field, were the partial decoupling of the scan from the operation of the accelerator, the ease of 15O production via the 14 N(d,n)15O reaction on inexpensive natural abundance N2 gas, and the simple radiochemistry, usually by mixing H2 and [15O]O2 over a heated palladium catalyst (Clark and Buckingham, 1975). Although [15O]H2O has seen widespread use due to simplicity, with a large body of literature devoted to its application and analysis, the rationale for its selection has diminished. For instance, the reliable and simple modern control systems available for almost all small

accelerators eliminate the perceived need to separate accelerator operation from the scanning procedure. Also, the increased use of proton-only cyclotrons means using the 15N(p,n)15O reaction on expensive isotopically enriched [15N]N2, negating the advantages of using natural enrichment gas targets. Several issues are of greater fundamental importance in the consideration of bolus [15O]H2O for rCBF, and the method has some important drawbacks for current applications. Water is not fully freely diffusible across the blood brain barrier (Eichling et al., 1974; Herscovitch and Raichle, 1985; Herscovitch et al., 1987), resulting in a flow-dependent extraction efficiency into brain tissue and an underestimation of rCBF in highflow regions. Also, the 2-min half-life of 15O means equilibrium between flow and decay takes several minutes to establish, and typically only four to six scans per hour can be performed. The issue of incomplete extraction has been approached in several ways. Butanol has superior partitioning across the blood brain barrier (Dischino et al., 1983; Herscovitch et al., 1987). Butanol labeled with either [15O] or [11C] is more difficult to produce than water, but some groups have had success with rapid multi-batch systems (Moerlein et al., 1993). Another approach is to use the truly inert, freely diffusible gas fluoromethane, labeled with either 18 F (t1=2 ¼ 110 min) (Gatley et al., 1981, 1991; Holden et al., 1981) or 11C (t1=2 ¼ 20 min) (Stone-Elander et al., 1986). These have the significant advantages of gas administration and the potential for accurate quantitation without arterial blood sampling (Koeppe et al., 1985), but are inappropriate for steady-state infusion or rapid repeat scans because of the long half-lives of 18 F and 11C. Beyond the advantages of rapid scan repetition, there is a significant improvement in the measurement sensitivity to rCBF changes with shorter lived tracers. Using the single-compartment steady-state flow model (Jones et al., 1976; Huang et al., 1979; Kearfott et al., 1983), we can consider the sensitivity of an rCBF measurement on the basis of tracer half-life only. If one adopts a single-compartment model for freely diffusible blood flow tracers, with an assumed blood brain barrier partition coefficient of unity (for simplicity), the flow per unit volume f is given by Eq. (1). Here l is the tracer decay constant (l ¼ lnð2Þ=t1=2 ), C a the arterial tracer concentration, and C b the equilibrium concentration of the tracer in the brain. A measure of the sensitivity to rCBF changes is then the relative change in C b for a given flow change from f 1 to f 2 (Eq. (2)). When comparing the relative sensitivity as a function of tracer half-life, one must also include some consideration of decay during the transit time from lung to brain. Assuming a leading edge transit time of 6 s, the relative sensitivity can be expressed according

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l ; CaCb  1

(1)

DC b C b ðf 2 Þ  C b ðf 1 Þ f 2 ðl þ f 1 Þ ¼  1; ¼ Cb C b ðf 1 Þ f 1 ðl þ f 2 Þ

½relative sensitivity /

(2)

DC b ðl 6 Þ e : Cb

(3)

Fig. 1 shows the relative sensitivity to a 10% rCBF change in typical gray matter ðf 0:01 s1 Þ as a function of radiotracer half-life. The maximum efficiency is near 20 s, typical for most flow regions in the brain, and drops to about 55% of the maximum at 122 s (the 15O halflife). While this illustration is given under steady-state conditions for simplicity, similar arguments have been made to demonstrate significant signal-to-noise improvements using bolus techniques with 17F versus 15 O-based tracers (Martin et al., 1999). Practical experience with bolus injection protocols has shown significant signal improvements with [17F]CH3F in direct comparison with [15O] water (Ferrarelli et al., 2004). The methods of Jones (Jones et al., 1976) succeeded with steady-state [15O]CO2 administration, but the long half-life limits the control/stimulation repetition rate required for behavioral and emotional activation work and the sensitivity to rCBF changes is low. One shorter-lived candidate explored was 19Ne (t1=2 ¼ 18 s), which has an ideal half-life and is completely inert (Kearfott et al., 1983). However, it proved impractical because of the low solubility in blood. Another promising candidate is 10C (t1=2 ¼ 19 s)labeled CO2, which is currently being investigated at Rigshospitalet, Copenhagen, in collaboration with Professor Nickles at Wisconsin (Nickles et al., 1998).

relative sensitivity

1.2 1 0.8 0.6 gray f0=0.01 sec-1

0.4 0.2

35 10

C

30 % change in brain radioactivity concentration

f ¼

Two highly promising radioisotopes suggested for development have been 14O (t1=2 ¼ 71 s; E MAX ¼ 1:80 MeV; bþ ) and 17F (t1=2 ¼ 64 s; E MAX ¼ 1:74 MeV; bþ ). The positron energies are close to that for 15O (E MAX ¼ 1:73 MeV; bþ ), so spatial resolution for a given activity distribution is comparable. The decreased lifetime greatly improves the control/stimulation retest rate. The modeled dosimetry suggests at least a 28% reduction in dose to the critical organ (heart wall) over [15O] water (Schueller et al., 2001). Further, the half-life analysis comparison shows 35–50% improvement in the sensitivity to rCBF changes in high-flow regions over 15 O (Fig. 2). Although the advantages of 14O and 17F for rCBF have long been recognized (Nickles et al., 1979; Martin

25 17

F

20 14

O

15 15

10

0 0

60 80 half-life (sec)

100

120

30

40

50

17

F

gray f0 = 0.01 s-1

40 14

O 17

F

14

O

20

white f0 = 0.003 s-1

0

0 40

20

60

0

20

10

% change in flow (f1=0.01sec-1)

(a)

(b) 0

O

5

% improvement in sensitivity vs. 15O

to Eq. (3):

527

140

Fig. 1. Relative sensitivity to a 10% rCBF change vs. radioisotope half-life for steady-state administration of inert flow tracers. Free diffusion across the blood brain barrier, uniform lung-blood extraction, and 6 s lung-brain transit time is assumed.

10

20

30

40

50

60

70

% flow increase

Fig. 2. Half-life comparison of 10C, 14O, 17F, and 15O for freely diffusible rCBF tracers. Constant C a is assumed. (a) Brain radioactivity concentration vs. rCBF change in high-flow regions (gray matter) calculated according to Eq. (2). (b) Ratio of 14O and 17F sensitivity in high- and low-flow brain regions. 10 C improvements range from 60% to 80% for white matter, and 160–200% for gray matter.

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et al., 1999), neither has been fully developed for activation work. The reasons for this are primarily technical. First, as discussed earlier, there was a desire in early development to separate the operation of the accelerator from the scanning procedure. In the case of 14 O the yield is fairly low at modest proton beam energies (2 mCi/mA at 11 MeV), the radioisotopic purity is extremely low due to simultaneous production of 11C, 13 N, and 15O, and the decay is accompanied by a 2.31 MeV gamma ray. The extra gamma ray is highly problematic for shielding in single-photon detection, but becomes less important with energy gated 511 keV coincidence detection. Difficulties with 17F may be related to the long-standing difficulties with the targetry for the highly reactive fluorine gas systems for 18F. Production of [17F] fluoromethane was suggested in a work-in-progress abstract from Michigan (Mulholland et al., 1999) but further developments and reports were not forthcoming. The problems of fluorine production targetry have been significantly reduced in recent years, from our work at the University of Wisconsin (Roberts et al., 1995, 1996) and elsewhere (Bida et al., 1991; Bishop et al., 1996).

3. Target operation 3.1. Reaction methods As mentioned above, the two main reaction channels available for producing 17F at low energy are 20Ne(p,a)17F and 16O(d,n)17F. Fig. 3 shows the total crosssection vs. energy and Fig. 4 shows the calculated thick target yields for each of the reactions from literature data (Gruhle et al., 1972; Gruhle and Kober, 1977). Each of these channels has been pursued at UW, using the two available accelerators.

120 20

Ne(p,α)17F O(d,n)17F

100 Saturation Yield (mCi/ A)

528

16

80 60 40 20 0 0

2

4

6

8

10

Energy (Mev)

Fig. 4. Saturation yield of 17F via 20Ne(p,a)17F (Gruhle and Kober, 1977) and 16O(d,n)17F (Gruhle et al., 1972) reactions. Calculated thick target yields from the data are 28 mCi/mA at saturation for 10.5 MeV protons and 44 mCi/mA at saturation for 5.54 MeV deuterons, respectively.

In the first case, F-17 is produced by proton irradiation of natural neon gas at 11 MeV. Radioisotope production targets are mounted on the CTI RDS 112 cyclotron. This accelerator delivers up to 50 mA of 11.4 MeV protons on target. The beam is collimated to 1.0 cm with an aperture 4 cm upstream from the target. At the target entrance, the beam size is approximately 6 mm FWHM vertical and 8 mm FWHM horizontal. The second reaction was investigated using the 6 MeV deuteron beam available in the UW Keck Laboratory for functional brain imaging, and is currently being used for our human PET studies at UW. The accelerator is an electrostatic tandem (National Electrostatic Corp. 9SDH-2 Pelletron), designed to provide 100 mA of 6 MeV protons or deuterons within a maximum 10 mm diameter beam spot. The Torvis multi-cusp ion source (Sundquist et al., 1999) has demonstrated reliable continuous low-energy beam output in excess of 300 mA overnight. The two dome charging chains are rated at 150 mA, and accelerated beam currents in excess of 120 mA have been demonstrated. The dome voltage of 2.94 MV required for 6 MeV single charge beams (with a 115 keV ion source voltage) is conservative, and the accelerator regularly operates at 3.375 MV (for a 6.8 MeV beam). The beam tuning components include low-energy steering, and high-energy quad focusing and steering magnets. The tuning capabilities coupled with an in-line rotating wire beam position monitor allow for fine, continuous control of the beam shape and position. 3.2. Targetry

Fig. 3. Previously published total crosssection data for the 20 Ne(p,a)17F (Gruhle and Kober, 1977) and 16O(d,n)17F reactions (Gruhle et al., 1972).

In each reaction the target chamber was a cylindrical or conical bore aluminum chamber. Aluminum has been

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shown to be an ideal material for fluorine gas target chambers compared to the previously used nickel targets. The tedious process of surface passivation to fluorine has been eliminated, and performance is independent of the level of prior F2 exposure, provided the target is thoroughly cleaned of all organic contaminants and water (Roberts et al., 1995). Regardless of the reaction methods, [17F]F2 is produced in the target by mixing a small amount of carrier fluorine gas in the target gas stream. While a premixed gas source is generally simpler and preferred, the target gases used for this system are supplied by separate sources of primary gas (oxygen or neon) and a low flow of 5% fluorine in helium (Fig. 4). In our case, [17F]F2 is produced by the deuteron irradiation of natural oxygen gas with 5% of a mixed gas containing 5% F2 in He. This results in a nominal 0.25% F2 mix in 100 psig oxygen flowing at 400 sccm. Target gases are fed via a 1/8" OD stainless tube with a short PTFE section for electrical isolation. The gas enters the target at the downstream end through a stainless steel 1/8-NPT fitting, and exits through the upstream end. The radioactive gas is then delivered to the radiosynthesis station though a short 1/16" PTFE tube followed by 10–20 m of HPLC grade 0.8 mm ID stainless steel tube. The target pressure is monitored with a corrosionresistant capacitance manometer (Entran) mounted on the gas line. In the case of 20Ne(p,a)17F, targets were designed to couple to the standard CTI RDS 112 cyclotron heliumcooled double foil system (Wieland, 1985), which can safely accommodate 11 MeV proton beam currents in excess of 50 mA. The target body is identical to that published previously for the production of [18F]F2 (Roberts et al., 1995), modified with an additional gas port at the downstream end to allow for continuous flow-through operation. Vacuum seals for the watercooled target body are either Teflon or Viton to minimize reactions with the highly corrosive fluorine gas. The helium-cooled target entrance foil is 32 mm Havar. The energy loss through the double-foil system is 0.23 MeV through the upstream 25 mm aluminum foil, and 0.77 MeV through the Havar foil. The 12.2 cm target bore starts with a 1 cm long cylindrical section, followed by a nominal 51 included angle taper for the next 10 cm, and then is cylindrical to the downstream end. The entrance diameter is 1.0 cm, and the exit is 2.0 cm. The target bore volume is 23 ml. Thorough cleaning and drying of the target bore is required to remove hydrocarbons and water. After fabrication the target was cleaned with soap and water to remove the bulk of the cutting oil. Targets used for the 16O(d,n)17F reaction are a large aluminum cylindrical bore which are easily produced compared to those of conical design. The cylindrical target chamber was 19 mm ID and 127 mm in length.

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The target is mounted to the beamline on a KF-40 stainless steel flange with a 19 mm beam port. A single 25.4 mm aluminum vacuum window is used, supported by a water-cooled aluminum grid of 76 1.6 mm holes in a hexagonal arrangement (Barnhart et al., 2003). Despite the proportionally larger energy loss of low-energy deuterons in the window (0.45 MeV for 6 MeV deuteron in 25 mm aluminum), the grid system is robust at full beam current, with no failures in over 1000 mA h of [17F]CH3F production runs. Static single irradiation production by proton irradiation of [18O]O2 plus F2 has been demonstrated successfully (Bida et al., 1991; Bishop et al., 1996), but is not widely used due to the expense of isotopically enriched [18O]O2. However, for 17F production, natural O2 is used, allowing for continuous flow production. The static target work does demonstrate that the major fraction of the recovered reactive activity in O2/F2 irradiation is in the form of F2 (85%), with the remainder as OF2 plus trace FONO2 (Bishop et al., 1996). The high F2 fraction is also consistent with the work of Mulholland (1999) for [17F]F2.

4. Radiochemistry [17F]F2 is delivered in the mixed gas stream (95% O2/ 4.75% He/0.25% F2 for oxygen reaction, 95% Ne/ 4.75% He/0.25% F2 for neon reaction) via 1/16" stainless steel tubing at a typical total flow rate of 400 ml/min. The gas is combined with methane flowing at 20 ml/min, or approximately 20 times the total fluorine rate of 1 ml/min. The mixed gas flows through a 10 cm long 1/4" stainless steel tube packed with silver oxide, heated in a tube furnace to 365 1C. While this process uses a direct reaction of [17F]F2 with methane, other compounds like methylbromide were also found to be efficient (Roberts et al., 2000), but the added concerns with safety and handling made these compounds unattractive. Any unreacted fluorine is then trapped in a soda-lime column. The gas is then concentrated in two C-18 Sep Paks (Waters WAT020515) chilled to 70 1C in a dry ice/ethanol slurry. After a typical trap time of 2–3 min, the gas is diverted and the C-18 warmed to release the [17F]CH3F. The product can be collected in saline for injection with a 5 ml wash of the C-18, or in gas for inhalation or chemical analysis. Fig. 5 shows the schematic layout of the complete production system. The basic operation is identical whether 20Ne(p,a)17F or 16 O(d,n)17F is used, requiring only a change of primary target gas. Further studies with the deuteron reaction on oxygen have shown that a 129 1C cold trap (coiled tubing immersed in chilled n-pentane) can be added to the target gas line prior to the methane addition to reduce ozone contaminant. While this increases the fluoromethane

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conversion yield by as much as 50%, the yields are sufficiently high for human PET studies without it, reducing complication in the standard operation.

Functionally, this system easily operates from several hours to an entire day as may be required by scanning protocols. The production manifold gas is turned on and the oven is brought to temperature 1 h prior to the beginning of scans. Soda lime is replaced after approximately 20 h, minimizing the possibility of F2 breakthrough. Silver oxide is replaced accordingly, keeping maximum conversion efficiency. After soda lime and silver oxide replacement, the rig is conditioned for 2 h, or until [17F]CH3F production approaches typical values.

5. Results

Fig. 5. Schematic layout of the target systems used for [17F]CH3F production.

Both the 20Ne(p,a)17F reaction with 11 MeV protons and the 16O(d,n)17F reaction with 6 MeV deuteron provide ample [17F]F2 for use in PET. The yield at saturation for [17F]F2 measured in a soda lime trap outside the accelerator vaults is 15 mCi/mA for the 20 Ne(p,a)17F reaction, with over 150 mCi easily produced. Trace 18F is co-produced, presumably from the 21 Ne(p,a)18F reaction on the natural 0.3% abundant 21 Ne in the target gas, at a negligible 3 105 number

Fig. 6. Gas chromatograms for [17F]CH3F produced using the 16O(d,n)17F reaction system. The gas in the stream from the production system is typically490% radichemically pure, improving to499% after cryogenic trapping of the [17F]CH3F on C-18 Sep-Pak at 70 1C.

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ratio (3 103 saturation yield). With the 16O(d,n)17F at 6 MeV incident deuteron energy, the total measured yield is 30 mCi/mA, and over 2.5 Ci produced at 100 mA. In our continuous production method using the oxygen target, 5–10% of the total activity is converted to [17F]CH3F of which, o7% are comprised of radiochemical impurities [17F]CHF3 and[17F]CF4. The majority of these impurities are removed with Sep-Pak filters at 70 1C in an ethanol slurry, which trap [17F]CH3F and reduce radiochemical contaminants to o1% (Fig. 6.).

6. Conclusion Production of 17F and subsequent conversion to [ F]CH3F in viable quantities for PET studies is easily achievable on both commercially available PET cyclotrons with the 20Ne(p,a)17F reaction, as well as on lower energy deuteron accelerators (e.g. NEC 9SDH-2) using the 16O(d,n)17F reaction. While the deuteron reaction easily has the advantage in saturation yield at low energies, high conversion efficiency in the neon environment makes the proton reaction just as practical. With the abundance of proton cyclotrons, the neon reaction should become the predominant method of 17F and [17F]CH3F production. Subsequent use of [17F]CH3F as a blood flow tracer has yet to be reported outside of the University of Wisconsin. Here, it has been used as a cerebral blood flow tracer (Roberts et al., 2003; Ferrarelli et al., 2004), and to investigate cardiac perfusion, both using bolus injections of [17F]CH3F in saline. rCBF and activation in primates (Dabbs et al., 2001; Converse et al., 2004) and humans (Roberts et al., 2003; Barnhart et al., 2004a, 2004b) show promise for the ability of [17F]CH3F for more sensitive measurements of blood flow. 17

Acknowledgments The NIH Radiological Sciences Training Grant T32 CA09206-26, administered through the NCI, provided partial funding for this work. The Keck Laboratory for Functional Brain Imaging and the UW Medical Physics Cyclotron Lab also provided developmental support.

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