Echo planar imaging of perfluorocarbons

Magnerrc Resonance Imaging, Vol. ! I, pp. Printed in the USA. All rights raened.

0730-725X/93

1165%1173, 1993

Copyright

$6.00

Q 1993 Pergamon

+ .oO

Press Ltd.

0 Original Contribution ECHO PLANAR IMAGING OF PERFLUOROCARBONS BRUCE Department

R. BARKER,

RALPH

P. MASON,

AND RONALD

M.

PESHOCK

of Radiology, University of Texas Southwestern Medical Center, Dallas, TX 75235-9085, USA

Emulsions of perfluorotributylamine (FTBA) and perflubron were evaluated for their utility in 19F echo planar imaging. Fluorine images of the emulsions were obtained in a phantom and two mice that had been predosed. Both agents, but particularly perflubron, show potential for fluorine echo planar studies because of the long spinspin relaxation times of the CF3 resonances. High resolution thin slice images obtained in as little as 26.6 ms are presented.

Kevwords: Perfluorotributylamine

(FTBA): Perflubron; resVonance (NMR); Echo planar imaging (EPI).

Perfluorooctylbromide

excited with steady-state free precession12 or driven equilibrium spin-echo,13 or it can be fully excited in one-shot echo planar imaging (EPI).14 All three alternatives exhibit high sensitivity in reIation to scan duration when T,and T,*are long. We have investigated emulsions of perfluorotributylamine (FTBA) and of perflubron, now the preferred name for perfluorooctylbromide (PFOB), as agents for fluorine echo planar imaging.

INTRODUCTION

There is a developing interest in the application of 19F NMR to follow the pharmacodynamics of drugs and probe tissue physiology. 19F MRI of freon has been used to monitor cerebral blood flow with a time resolution of 16 s.’ The vascular distribution of perfluorocarbon (PFC) emulsion has been used to examine tumor perfusion2 Sequestered or vascular PFC has been

used to measure pOZ in tumor,3s4 heart,’ braim6 eye,’ liver,3,8 and abscess.9 In every case, temlporal resolution is important, but hitherto measurements have generally required minutes to hours.3,4*7,‘0Echo planar imaging (EPI), in which a two-dimensional image is made from a single excitation, usually in less -than 100 ms, offers the prospect of detecting changes loccurring over seconds to minutes if 19F EPI images of sufficient quality can be made. “F MRI of perfluorocarbons (PFCs) is complicated by long spin-lattice relaxation times (T,), short spin-spin relaxation times (Tz) of some resonances, multi-resonant spectra and J-modulation. Oxygen reduces relaxation times of perfluorocarbons through a paramagnetic effect,3 from around 1-3 s under anoxic conditions to around 0.7- 1.7 s at atmospheric oxygen tension.” Even the lower r, s limit the signal-to-noise ratio (SNR) of rapid gradient-echo sequences, which are popular in proton imaging, through partial saturation. The available magnetization can be more fully RECEIVED 3/12/93; ACCEPTED 6/ 14/93.

Address

correspondence

to Ralph

P. Mason,

Dept. of

(PFOB); i9F nuclear magnetic

MATERIALS

AND

METHODS

Experiments were performed on an Omega CSI 4.7 T system with actively shielded gradients (AcustarTH, Bruker Instruments, Inc., Fremont, CA, USA). A cylindrical Alderman-Grant slotted-tube resonator coil of 25.4 mm i.d. was used for transmission and reception. The perfluorocarbons used were Oxypherol-ET’” (Green Cross Corp., Osaka, Japan), containing FTBA, and Imagent BP’” (Alliance Pharmaceutical Corp., San Diego, CA, USA) consisting of emulsified perflubron. The EPI sequences used were single-shot MBEST,i5 a single-spin-echo EPI sequence with “blipped” phase encoding. The read gradient waveform was trapezoidal. Although data were acquired continuously during the read gradient train, only the data acquired during read gradient plateaus and between phase encoding “blips” were reconstructed. Data from odd-numbered echoes were time reversed prior to Fourier transform Radiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75235-9058, USA. 1165

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Magnetic Resonance Imaging 0 Volume 11, Number 8, 1993

magnitude reconstruction.r6 For r9F EPI, the instrument frequency was set to the CF, resonance. Spectroscopic Studies Spectra of both agents were obtained. To determine the decay of signal intensity due to T2 and J modulation, a series of spin-echo studies was done on each compound with the spectrometer frequency on the CF3 peak. Hard pulses were used for nonselective excitation (7r/2 = 40 ps), and, in separate experiments, soft pulses were used for selective excitation of CF3. Phantom Imaging A phantom consisting of two concentric cylinders was constructed to minimize field nonuniformity due to magnetic susceptibility. The axis of the phantom was aligned with the magnetic field. The outer cylinder was filled with perflubron emulsion, the inner with Oxypherol stem emulsion, containing 26.6% w/v FTBA. The perflubron emulsion was diluted to 59% w/v so that the emulsions would have equal concentrations (approximately 1.19 M) of CF3 groups. Both emulsions were maintained at atmospheric ~0~. Fourteen shim currents were adjusted on the water proton signal through the instrument’s automated shimming routine using the imaging sequence without readout or phase encoding gradients until the line width was minimized. The sequence parameters were as follows: TE 33.5 and 180 ms (in separate experiments), excitation bandwidth 2 kHz, receive bandwidth 66.7 kHz, 32 x 32 points reconstructed from the central 480 ~LSof each 720 ps, field of view 80 mm (readout) x 40 mm (encoding), read gradient 20.8 mT/m, and slice thickness 5 mm. Data were thus acquired in 23 ms. The 180 ms TE represented the first refocusing of homonuclear J modulation in perflubron (TE = l/J). Since the excitation bandwidth was equivalent to 10.6 ppm, all off-resonance peaks except P-CF2 (-2 ppm) of FTBA were offset completely out of the CF3 slice. The @-CF2peak was offset 0.94 mm in the slice direction, 0.45 mm (0.2 pixels) in the read direction, and 11 mm (8.7 pixels) in the phase-encode direction. The + 18 ppm (3395 Hz) peak of perflubron, the next nearest, was separated 8.5 mm in the slice direction, 4.1 mm (1.6 pixels) in the read direction, and 98 mm (78 pixel lengths) in the phase-encode direction. Using inner-volume imaging, whereby phase-encode gradient is applied with the 180” refocusing pulse to select only the unaliased field of view of the resonant peak in the phase-encode direction, all off-resonance peaks except &CF2 were eliminated.” The signal intensity measurements for the Imagent signal in the annulus were averaged among ROIs in the top, bottom, left, and right sides. Noise was measured outside the phantom.

Animal imaging Fresh emulsions were administered to two 22-g mice in three equal daily doses: a total of 1.8 ml of Oxypherol-ET (0.536 mmol FTBA) was given to one mouse and a total of 0.9 ml of 90% w/v Imagent BP (1.6 mmol perflubron) was given to the other. The mice were sacrificed and frozen 36 hr after the last dose and were thawed for the studies. For organ identification, highresolution proton and fluorine multislice image sets were acquired by conventional spin-echo techniquesI The following coronal single-shot “F MBEST studies were performed on each mouse: (1) low resolution EPI: TE 38 ms, excitation bandwidth 2 kHz, receive bandwidth 62.5 kHz, 32 x 32 points reconstructed from the central 512 ps of each 832 ps, field of view 60 mm (readout) x 40 mm (encoding), read gradient 26 mT/m, slice thickness 5 mm, and acquisition time 26.6 ms; and (2) high resolution EPI: TE 53.9 ms, excitation bandwidth 2 kHz, receive bandwidth 76.9 kHz, 64 x 32 points reconstructed from the central 832 of each 1222 ps, field of view 64 mm (readout) x 32 mm (phase encoding), read gradient 30.0 mT/m, slice thickness 5 and 10 mm, and acquisition time 39.1 ms, almost halving the read resolution to 1.O mm. RESULTS Spectroscopic Studies Spectra of Oxypherol-ET and Imagent BP are shown in Fig. 1. The CFXresonances are essentially coincident; the CF3 is arbitrarily assigned to 0 ppm. Spin-echo T2 decay curves for the CF3 peak of each emulsion are shown in Fig. 2. Nonselective excitation results in J modulation as shown for Oxypherol (Fig. 2A) and lmagent (Fig. 2B). Suppressing J modulation with selective excitation in Oxypherol (Fig. 2C) increases the apparent T,, measured over TE 5 50 ms, from 20 ms to at least 50 ms. The true T2 appears to be at least 70 ms, estimated from TE = 4 ms (
Echo planar imaging of perfluorocarbons

20

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ET AL.

-30

-20

-10

0

0 B.R. BARKER

1

rCF3

J L 20

/L I’

10

t

i

I

J

I I’

I

0

”

I

”

”

I

”

”

-20

-10

I

”

Ll

“I’

-30

-40

mm Fig. 1. Spectra

of Oxypherol-ET

stem emulsion

(A) and Imagent

BP emulsion

(B).

I

Magnetic Resonance Imaging 0 Volume 11,Number

1168 Table 1. EPI Signal-to-noise

Raw SNR FTBA Perflubron Perflubron/FTBA ratio SNR divided by perfluorocarbon mass per voxel (mg-‘) FTBA Perflubron Perflubron/FTBA ratio

ratios (phantom

age (Fig. 3B) with the anatomy identifiable in the ‘H image (Fig. 3A) shows concentrations of Oxypherol in liver and spleen, with a greater concentration in spleen. Liver and spleen are evident in the echo planar images (Figs. 3C and 3D). High resolution imaging of this animal with useful signal/noise required a lo-mm slice (Fig. 3D). Images of a section of the Imagent-dosed mouse are shown in Fig. 4. Imagent appears in liver, spleen, major vessels, and lungs as demonstrated in the fluorine spin-warp study, Fig. 4B. It appears that much of the emulsion remains vascular: Intense signal, comparable to that of the spleen, is observed in the major blood vessels, and lungs, with weaker signal in the liver. The

study)

TE = 33.5 ms

TE = 180 ms

19.2 -t 2.6 29.0 + 2.6 1.5 t 0.24

7. k2 24. *2 3.4* 1

4.6 k 0.6 3.1 k 0.3 0.7 rt 0.07

1.7 * 0.5 2.6 k 0.4 1.5 + 0.5

FTBA = perfluorotributylamine.

0

50

100

150

8, 1993

200

250

300

350

400

TE lmsj -(A)

---u--~(B)

-

(C) ~mm*--- (D) 1

Fig. 2. Normalized spin-echo decay curves for the CF, resonances of (A,C) Oxypherol and (B,D) perflubron. Curves (A) and (B) were obtained with nonselective RF pulses, (C) and (D) with only the CF, resonance selected. Selective excitation suppresses J-modulation in each case, substantially increasing the detected signal.

(B)

0%

Fig. 3. Coronal sections of a mouse dosed with Oxypherol-ET; (A)-(C) are of the same 5-mm section; (D) is of a IO-mm section at the same level. (A) jr,-weighted conventional proton spin-echo image; acquisition parameters are: TR 2000 ms, TE 50 ms, excitation bandwidth 2 kHz, receive bandwidth 33 kHz, matrix 256 x 128,2 excitations, field of view 60 mm x 40 mm, acquisition time 8.5 min. A lung is marked “Lu,” the liver is marked “Li,” and the spleen is marked “S.” (B) 19F conventional (spin warp) spin-echo image; acquisition parameters are: TR 2000 ms, TE 20 ms, excitation bandwidth 2 kHz, receive bandwidth 20 kHz, matrix 128 x 128, 4 excitations, field of view 60 mm x 40 mm, acquisition time 17 min. The larger, upper area of high signal intensity represents liver and the smaller, lower area spleen. (C) 19F echo planar (single-shot MBEST) low-resolution image; acquisition parameters are: TE 38.2 ms, excitation bandwidth 2 kHz, receive bandwidth 62.5 kHz, 32 x 32 points reconstructed, field of view 60 mm x 40 mm, acquisition time 26.6 ms. (D) 19F EPI high resolution image; acquisition parameters: TE 53.9 ms, excitation bandwidth 2 kHz, receive bandwidth 76.9 kHz, 64 x 32 points reconstructed, field of view 64 mm x 32 mm, acquisition time 39.1 ms. The increased slice thickness was necessary for a useful signal/noise ratio at l-mm resolution. Liver and spleen are evident in all cases.

Magnetic Resonance Imaging 0 Volume 11, Number

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(B)

Fig. 4. A coronal 5-mm section of a mouse dosed with perflubron. Acquisition parameters for (A) and (B) are the same as for Figs. 3A and 3B, respectively. In (B), it appears that

much of the perflubron remains vascular: Intense signal, comparable to that of the spleen, is observed in the major blood vessels and lungs, with weaker signal in the liver. (C) A high resolution fluorine echo planar image of the same section, with the parameters: TE 53.9ms, excitation bandwidth 2 kHz, receive bandwidth 76.9 kHz, 64 x 32 points reconstructed,

field of view 64 mm x 32 mm, slice thickness 5 mm, acquisition time 39.1 ms.

Ima gent signal was strong enough for high resolution, thin slice EPI (Fig. 4C: 1 x 1 x 5 mm voxels). DISCUSSION emulsions are desirable imaging F‘erfluorocarbon age] Its in that they provide physiological information,

such as p’02, temperature, vascularity, and biodistribution, and have relatively low toxicity.” PFC emulsions are in clii nical use*O and have been detected in patients by NMR .*I The Tl and T2 of PFC emulsions depend on P% ,9 but in contrast to other classes of molecule, such as ;anesthetics,** the line widths of Oxypherol

Echo planar imaging of perfluorocarbons

have not been found to be otherwise tissue dependent.23 The ability to collect fluorine images every few seconds opens up the possibility of rapid time-course studies of agent uptake, clearance and oxygenation. Echo planar images may be useful even if resolution and image quality do not permit them to be interpreted alone. Structures may be identified as they have been here, by correlation with high resolution proton images acquired conventionally before or after a time-course study. The broad range of chemical shifts in many fluorinecontaining compounds requires measures to avoid chemical shift artifact. Various solutions have been proposed, including selective excitation,‘3v24 selective saturation, 25deconvolution, 26chemical shift imaging,27,28 exploitation of differential transverse relaxation rates or J modulation,18~23*29 and, as in the present study, selective refocusing. 24 Because chemical shift offsets slices, the validity of oeconvolution is largely limited to projection28 and volumetric (3D) imaging.30 Many methods require substantial separation of peaks27 or large differences in effective T2 or scalar coupling constant.23 Echo planar imaging is particularly sensitive to chemical shift artifact because of the relatively long time data are acquired after one excitation (i.e., high frequency resolution). Unless deconvolution or chemical shift imaging are employed, a suitable EPI agent should have a narrow, well-isolated peak so that chemical shift may be avoided. Perfluorotributylamine (FTBA) lacks a well-isolated peak (Fig. lA), but its CF, peak (designated 0 ppm) may be acceptable for MRI because of the difference in T2 between that peak and the sole nearby peak at -2 ppm. Perflubron is attractive as a 19F MRI agent since its CF3 peak, coresonant with the CF3 of FTBA, and its CF2Br peak (18 ppm) are both well isolated in frequency (Fig. 1B). The cluster of peaks at -40 + 1 ppm in perflubron, representing eight fluorines, produces more signal at very short TE than other peaks, but the 2 ppm width of the cluster would create significant chemical shift artifact in EPI. To avoid blurring and distortion, the peak used in EPI should have a long T;, comparable to or greater than the duration of data acquisition31 which is typically 30-100 ms. The spectral line width should therefore be less than or approximately equal to the reciprocal of the acquisition time. For a PFC emulsion with long T2, such as Imagent, high resolution images could be acquired by sampling the echo for up to 100 ms without unacceptable distortion if a shim = 10 Hz could be attained. The full advantage of the long T2 of a material such as perflubron could then be realized: namely, a choice between higher signal to noise ratio (sensitivity to lower concentrations) and higher resolution. Although gradient-echo EPI has been reported using

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the proton resonance at fields of 52 T32,33and may be performed with TE = 10 ms or less, this sequence is problematic at higher fields because of the high sensitivity of image quality and SNR to susceptibility and inhomogeneity. (Spin-echo and stimulated echo EPI techniques have been used at 4.7 T.34,35)In our experience, the shortest feasible TE for spin-echo EPI is around 25-30 ms, comparable to the minimum acquisition time. T; should therefore be at least 30 ms. In the EPI experiments presented here, the best obtainable line width, 36 Hz, required that the acquisition train be kept below about 28 ms to avoid significant distortion. The high resolution mouse images, acquired in 39.1 ms, appear useful despite the distortion that is presumably present. If absolute B. homogeneity is better at a lower field, the high resolution echo planar strategy may be even more successful. Homonuclear scalar coupling (J modulation), if not refocused, reduces the effective T2. In the echo planar experiments reported here, homonuclear J modulation other than that between the 0 and -2 ppm peaks of FTBA was largely avoided because the peak separations exceeded the bandwidth of the transmitted pulses. The -2 ppm peak of FTBA overlapped 8 1% of the desired slice, with the result that the effective T2 and hence the signal intensity of both peaks were sharply reduced. Although we have successfully imaged both Oxypherol and Imagent the latter offers several distinct advantages. First, it is stable at higher concentrations (9OYow/v, or 1.8 M, for Imagent vs. 25% w/v, or 0.37 M, for Oxypherol), a fact that is useful in vascular studies involving replacement of animal blood to a high fluorocrit .24Second, the T2 of the CF3 peak of perflubron is considerably longer, providing greater residual signal and permitting studies at higher resolution or lower concentration. Third, the peak is well isolated, favoring selective excitation to avoid J modulation. Fourth, perflubron has a second well-isolated, long- T2 peak (CF2Br, + 18 ppm), which could be used with an appropriate sequence and reconstruction for simultaneous multislice imaging or higher SNR.28 On the other hand, the presence in FTBA of three equivalent CF3 groups per molecule, compared to one for perflubron, permits lower concentrations of FTBA to be used at short TE. Still more efficient agents could be those with essentially a single resonance, as reported for anesthetics,22 the PFC emulsion PTBD,36 and specifically labelled polymers.37 At TE = 33.5 ms in the phantom EPI study, the SNR was approximately 3.1 for each micromole of FTBA per voxel and half that for each micromole of perflubron per voxel. Using 4 x 4 x 10 mm voxels, then, local concentrations of approximately 10 mM FTBA (6.8 g/kg organ mass, or 1.6 pmol/voxel) or 20 mM perflubron (10 g per kilogram of organ mass, or 3.2 cl.mol/

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voxel) could be detected with a SNR of 5. Because PFCs are confined, first to the vasculature, then to certain organs, the whole-body averages can be an order of magnitude less. The whole-body average doses per voxel that were used successfully in the high resolution animal EPI studies at TE = 38 ms were approximately 0.24 pmol for FTBA (with 1 x 1 x 10 mm voxels) and 0.41 pmol for perflubron (with 1 x 1 x 5 mm voxels), both approximately one seventh the predicted requisite local concentrations. We note, however, that the Imagent-dosed mouse required only half the volume of emulsion administered to the Oxypherol-dosed mouse. Early studies of perfluorocarbons in animals required around l-3 h3* to achieve thin (6 mm) slice images following similar doses to those of this study. Imaging times have fallen progressively to 17 min,39 4 min,40 and finally 39 s13 in projection imaging. At higher resolution or lower concentration, more time is required: Recent images in a rat heart took 19 hr for 230 pm in-plane resolution with 2.5 mm slice thickness.5 We have demonstrated the feasibility of 19F echo planar MRI of perfluorocarbon emulsions in animals with acquisition times as low as 26.6 ms. This is two to three orders of magnitude faster than previously reported studies1,‘3 and opens the possibility for real time investigation of tissue perfusion or transport of fluorinated molecules. EPI was proposed well over a decade ago,41 but practical application was delayed due to constraints of magnet and gradient homogeneity and switching times. ‘H EPI is now applied in many situations,33s42 but this may be the first report of 19F EPI. Although the resolution is somewhat lower than that routinely used in conventional sequences, the general distribution is well defined, and it is clear from the 19F EPI images that the 19F signal is localized to specific regions of the animal. Fluorine EPI might significantly enhance the temporal resolution of studies of types reported previously, for example, cerebral blood flow,’ perfusion,43 tumor vasculature,2 drug uptake and biodistribution,37 anesand gastrointestinal blockage.38 thetic distribution,22 Rapid studies of tissue physiology based on the response of PFC spin-lattice relaxation to p02 and temmay become feasible by using inversion perature’,” recovery EPI. Dynamic studies of 19F uptake with clearance could combine previous or subsequent high resolution ‘H and 19F images with rapid EPI images to determine changes in response to changes of state, including ischemia followed by reperfusion. Acknowledgments-The authors thank Bret Lesan and Dr. Anca Constantinescu for technical assistance and are grateful to Alliance Pharmaceutical Corp. and the American Heart Association (Texas Affiliate) for support.

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