imaging paracest agents using frequency labeledd exchange ... · g multiple modul g efficiency. in...

1
1 Advan Ken Introd identif counte resonan exchan transfe compo comes paraCE transfe separat The aim Mater series o selectiv becaus applyin labelin depend be des solutio and a t follow signal excitat numbe water s Fig. 1. paraCE Result The FL FLEX frequen water ( signal bound red: pa paraCE likely d functio and 6.4 to the z Conclu allowe for in v Refere 822-83 2011. 7 nced Imaging Resa nnedy Krieger Insti duction: Currently ication by MRI s erparts is that they nce. Consequently nging compounds erred within a give ounds with such ra with an increase EST studies. Frequ er. Using spectrosc ting these out usin m of this study wa rial & Methods: T of n label-transfer ve 90 x /90 -x RF pul se fresh z-magneti ng multiple modul ng efficiency. In co ding on the frequen cribed (Eq. 2) by on of EuDOTA-(gl third a 4% agarose ed by a fast spin-e was acquired by v tion (0 ppm) (7) a er of LTMs = 0, 10 signal without LTM . FLEX FIDs (LT EST solution mixe ts & Discussions: LEX FIDs and spe spectrum (green ncy Δω so1 of 18,00 (0 ppm) due to the drop due to MT in solute water (18,0 araCEST agent; b EST agent but not due to a shorter T on of number of LT 4 mM for agarose z-axis after the evo usion: The first im ed separation of M vivo imaging of pa ence: 1. J. Zhou, 31, 2009. 4. J.I. Fr 7. J. Cavanagh, et PTR s = x s Imaging par Chien-Yua arch Center, Unive itute, Baltimore, M Hopkins Univers y, there is an incre such as temperatu y can be engineere y, saturation pulses can be used whi en time frame, resu apid exchange rate in conventional m uency labeled exc copy, it has been sh ng FLEX time dom as to implement the The FLEX approac modules (LTMs) lses is applied, in zation is present f les during the prep ontrast to CEST, ncy difference bet a free induction d ly) - 4 , a second the e solution as a con echo acquisition w varying t evol from and keep high effi 00, 300, 500, 700, Ms. TM=500) and corr ed with agarose: bl ectra in the three s line) of the short 00Hz and generate e limited excitatio n the first 20-30 μ 000 Hz) and free w black: free water). t in the agarose-on 1w and a potential TMs according to phantoms (Fig. 2b olution time, whic mages from FLEX MT and exchange t araCEST agents. et al., PNMRS, 4 riedman., et al., JA al., in Protein NM λ s (1 e k ex, s raCEST Agen n Lin 1,2 , Nirbhay N ersity of Texas Sou Maryland, United S sity, Baltimore, Ma easing effort under ure, glucose, pH, ed to have large c s can be applied w ile still adhering t ulting in an increa es (k ex ~ 10 4 s -1 ) re magnetization tran change transfer (FL hown that FLEX a main analysis (5,6) e FLEX technique ch has been descri . Within each LTM between which ch for the solute proto paration time. The which detects the tween the offset fre decay (FID). Thre same paraCEST s ntrol. All MRI dat ith a TR of 5 s, a T 1μs to 196 μs usi iciency for labelin , 1000, and 1500. responding Fourie lue FID). Fig. 2. FL samples are shown T 2 * component o ed a peak at 50 ppm on of bulk water. I μs, followed by a m water (38,000 Hz) . FLEX-MRI obta nly sample. The m increase in partial the FLEX theory b). The concentrati h accumulates wh X-MRI experimen transfer effects in 48: 109-136, 2006 ACS, 132:1813-18 MRS: principle and t exch ) e {1+ ( i =1 n nts Using Freq N Yadav 2,3 , S. Jam uthwestern Medica States, 3 Division of aryland, United Sta rway to design par nitric oxide, and chemical shift dif well away from the to the slow excha ase of transfer effi equires a high B 1 l nsfer (MT) effects LEX) (4) is a new allows detection o . This presents the e on preclinical MR ibed in detail prev M, exchangeable s hemical shift evol ons at the start of e PTR can be expr decrease of water equency (o1) of th ee phantoms in tri solution mixed wit ta were acquired a TE of 8.65 ms, a F ing time intervals ng paraCEST agen Signal differences er-transform spectr LEX-MRI (LTM= n in Fig.1. The rap of the semi-solid M m (red line). Notic In the combined sa more gradual deca components, the f ained by pixel-by mismatch of signal l saturation of the (Eqs.1,2), we dete ion underestimatio en applying multip nts on a paraCEST the time domain a . 2. A.D. Sherry e 15, 2010. 5. C.Y. practice, 912, 200 i 1)/ n } t prep / T 1 w quency Labeled mes Ratnakar 1 , A. D al Center, Dallas, f MR Research, Ru ates, 4 University o ramagnetic chemic d enzyme activity ferences (Δω >10 e water resonance, ange limit (k ex < iciency as express level to achieve at s in biological tis w approach that de f rapidly exchangi e potential for imag RI systems and to viously (4-6). Brie solute protons are f lution of the excha each LTM, allow essed as Eq. 1, wh r signal, FLEX me he 90 x excitation p s buffer (pH=7) w th 4% agarose in o at 37°C on a Vari FOV of 1.5 cm, a s of 5 μs (dwell tim nts (50 ppm). The s with respect to th ra in three differe =500) and calculate pid initial decay in MT effect. The w ce that the 50 ppm ample (paraCEST ay. Using time do fitted FLEX spect y-pixel time doma l magnitude betwe water pool due to ermined the concen on is probably due ple LTMs. T agent solution a and provided quan et al., Annu Rev B Lin, et al., Procee 07. w [1] d Exchange T Dean Sherry 1,4 , and Texas, United Sta ussell H. Morgan D of Texas at Dallas, cal exchange satur (1-3). The main 0 ppm) between th , thus avoiding off Δω) necessary fo sed by the proton t t least partial RF ssues, which, desp etects exchanging ing water molecul ging the distributio evaluate the possi efly, the pulse sequ frequency labeled angeable protons wing multiple oppo here χ s is the fract easures modulatio pulse and the solut were prepared for order to generate M ian 9.4T MRI syst slice thickness of 5 me). The o1 of la e other parameter he average water ent phantoms (Ag ed concentration i n the FLEX FID o water signal modul m resonance in the T agent mixed with omain analysis wit trum could be sepa ain fitting (Fig. 2a een the pure soluti o MT exchange br ntration of the par e to exchange trans at physiologic tem ntitative concentra Biomed Eng, 10: edings of 19 th ISM I w = PTR s e s Transfer (FLE d Peter C. M. van ates, 2 F.M. Kirby C Dept. of Radiolog , Dallas, Texas, Un ration transfer (pa benefit of paraC he resonances of f-resonance satura or CEST. This all transfer ratio (PTR saturation before pite the large Δω, protons using fre es k ex >10,000s -1 w on of functional pa ibility for imaging uence contains a p d and transferred to occurs over a peri ortunities to transf tional concentratio on in the water sig e resonance (Δω so MRI acquisition. MT effect similar tem. FLEX image 5 mm, and a matrix abeling pulse = 95 rs for FLEX data signal after decay garose only: green image of paraCEST of the agarose pha lation in the paraC FLEX spectrum ( h agarose), the FL th the prior knowl arated into three s a) shows the para ion (2.9%) and so roadening. Fortuna raCEST agent to b sfer of additional d mperature and pH ation images. Thes 391-411, 2008. 3. MRM, 709, 2011. 6 ( k ex,s +1 / T 2s * )t evol EX) MRI Zijl 2,3 Center for Function gy and Radiologica nited States araCEST) agents f CEST agents over the exchanging p ation of bulk water lows for more sat R). However, dete exchange occurs. can still complic quency transfer in without interferenc araCEST agents in of paraCEST agen preparation time (t o water. In the lab iod, t evol . Signal am er labeled protons on of the solute (s) gnal as a function o1 ). The effect on th One contained a to that observed i es were measured b x size of 64 *64 m 5 ppm was calcula acquisition were: y were normalized n FID; paraCEST T agent. antom corresponds CEST agent soluti (red line) is much LEX FID (blue line edge (Eq.2) about ignal components aCEST signal in p olution mixed with ately, by fitting the be identical, 6.6 mM dephased signal th are presented. Th se findings demon . S. Aime, et al., A 6. van Zijl et al., M cos( Δω sol t evol )[2] nal Brain Imaging al Science, Johns for biological targe r their diamagneti pools and the wate r. In addition, faste turated spins to b ection of paraCES Unfortunately, thi cate the analysis i nstead of saturatio ce of MT effects b n biological tissues nts. t prep ) consisting of eling part, a pair o mplification occur s to the water whe ) protons and λ s th of t evol in a manne he water signal ca 10 mM paraCES in biological tissue by multiple LTMs mm. The FLEX FID ated to avoid wate t exch = 400 μs an with respect to th solution: red FID s to the broad ban ion modulated at larger than the fre e) indicates a rapi t frequencies of th (green: MT effec phantoms with th h agarose (1.5%) i e FLEX signal as M for pure solutio hat was not returne he FLEX approac nstrate the potentia Acc Chem Res, 42 MRM, 65:927-948 ] g, et ic er er be T is n n y s. a of rs n he er an T e, s, D er nd he D; nd a ee d he t; he is a n d h al 2: 8, 3379 Proc. Intl. Soc. Mag. Reson. Med. 20 (2012)

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Page 1: Imaging paraCEST Agents Using Frequency Labeledd Exchange ... · g multiple modul g efficiency. In co ing on the frequen cribed (Eq. 2) by n of EuDOTA-(gl hird a 4% agarose ed by

1AdvanKen

Introdidentifcounteresonanexchantransfecompocomes paraCEtransfeseparatThe aimMaterseries oselectivbecausapplyinlabelindependbe dessolutioand a tfollowsignal excitatnumbewater s

Fig. 1.paraCEResultThe FLFLEX frequenwater (signal bound red: paparaCElikely dfunctioand 6.4to the zConcluallowefor in vRefere822-832011. 7

nced Imaging Resannedy Krieger Insti

duction: Currentlyfication by MRI serparts is that theynce. Consequently

nging compounds erred within a giveounds with such ra

with an increase EST studies. Frequer. Using spectroscting these out usinm of this study wa

rial & Methods: Tof n label-transfer ve 90x/90-x RF pulse fresh z-magneting multiple modul

ng efficiency. In coding on the frequencribed (Eq. 2) by

on of EuDOTA-(glthird a 4% agaroseed by a fast spin-ewas acquired by v

tion (0 ppm) (7) aer of LTMs = 0, 10signal without LTM

. FLEX FIDs (LTEST solution mixets & Discussions: LEX FIDs and spespectrum (green

ncy Δωso1 of 18,00(0 ppm) due to thedrop due to MT insolute water (18,0

araCEST agent; bEST agent but notdue to a shorter Ton of number of LT4 mM for agarose z-axis after the evousion: The first im

ed separation of Mvivo imaging of paence: 1. J. Zhou, 31, 2009. 4. J.I. Fr7. J. Cavanagh, et

PTR s = x s ⋅

Imaging parChien-Yua

arch Center, Univeitute, Baltimore, M

Hopkins Univers

y, there is an incresuch as temperatuy can be engineerey, saturation pulses

can be used whien time frame, resuapid exchange rate

in conventional muency labeled exccopy, it has been shng FLEX time domas to implement theThe FLEX approac

modules (LTMs)lses is applied, in zation is present fles during the prepontrast to CEST, ncy difference beta free induction d

ly)-4, a second the

e solution as a conecho acquisition wvarying tevol from and keep high effi00, 300, 500, 700,Ms.

TM=500) and corred with agarose: bl

ectra in the three sline) of the short

00Hz and generatee limited excitation the first 20-30 μ000 Hz) and free wblack: free water).t in the agarose-on

T1w and a potential TMs according to phantoms (Fig. 2bolution time, whicmages from FLEX

MT and exchange taraCEST agents. et al., PNMRS, 4

riedman., et al., JAal., in Protein NM

⋅ λs ⋅ (1 − e− kex, s ⋅

raCEST Agenn Lin1,2, Nirbhay Nersity of Texas Sou

Maryland, United Ssity, Baltimore, Ma

easing effort underure, glucose, pH, ed to have large cs can be applied wile still adhering tulting in an increaes (kex ~ 104 s-1) remagnetization tran

change transfer (FLhown that FLEX a

main analysis (5,6)e FLEX techniquech has been descri. Within each LTMbetween which ch

for the solute protoparation time. Thewhich detects the

tween the offset fredecay (FID). Thresame paraCEST s

ntrol. All MRI datith a TR of 5 s, a T1μs to 196 μs usi

ficiency for labelin, 1000, and 1500.

responding Fourielue FID). Fig. 2. FL

samples are shownT2* component o

ed a peak at 50 ppmon of bulk water. Iμs, followed by a mwater (38,000 Hz) . FLEX-MRI obtanly sample. The mincrease in partialthe FLEX theory

b). The concentratih accumulates whX-MRI experimentransfer effects in

48: 109-136, 2006ACS, 132:1813-18

MRS: principle and

texch )⋅ e{−1+ (

i=1

n∑

nts Using FreqN Yadav2,3, S. Jamuthwestern MedicaStates, 3Division ofaryland, United Sta

rway to design parnitric oxide, and

chemical shift difwell away from theto the slow exchaase of transfer effiequires a high B1 lnsfer (MT) effectsLEX) (4) is a newallows detection o. This presents the

e on preclinical MRibed in detail prev

M, exchangeable shemical shift evolons at the start of

e PTR can be exprdecrease of water

equency (o1) of thee phantoms in trisolution mixed witta were acquired aTE of 8.65 ms, a Fing time intervalsng paraCEST agenSignal differences

er-transform spectrLEX-MRI (LTM=

n in Fig.1. The rapof the semi-solid Mm (red line). NoticIn the combined samore gradual decacomponents, the f

ained by pixel-bymismatch of signall saturation of the (Eqs.1,2), we deteion underestimatioen applying multip

nts on a paraCESTthe time domain a

. 2. A.D. Sherry e15, 2010. 5. C.Y. practice, 912, 200

i−1) / n} tprep / T1w

quency Labeledmes Ratnakar1, A. Dal Center, Dallas, f MR Research, Ruates, 4University of

ramagnetic chemic

d enzyme activityfferences (Δω >10e water resonance,ange limit (kex < iciency as expresslevel to achieve ats in biological tis

w approach that def rapidly exchangi

e potential for imagRI systems and to viously (4-6). Briesolute protons are flution of the exchaeach LTM, allowessed as Eq. 1, whr signal, FLEX mehe 90x excitation ps buffer (pH=7) wth 4% agarose in oat 37°C on a Vari

FOV of 1.5 cm, a sof 5 μs (dwell tim

nts (50 ppm). Thes with respect to th

ra in three differe=500) and calculate

pid initial decay inMT effect. The wce that the 50 ppmample (paraCESTay. Using time dofitted FLEX spect

y-pixel time domal magnitude betwewater pool due to

ermined the concenon is probably dueple LTMs. T agent solution aand provided quan

et al., Annu Rev BLin, et al., Procee

07.

w [1]

d Exchange TDean Sherry1,4, andTexas, United Staussell H. Morgan Dof Texas at Dallas,

cal exchange satur(1-3). The main

0 ppm) between th, thus avoiding offΔω) necessary fo

sed by the proton tt least partial RF

ssues, which, despetects exchanginging water moleculging the distributioevaluate the possi

efly, the pulse sequfrequency labeledangeable protons

wing multiple oppohere χs is the fracteasures modulatio

pulse and the solutwere prepared for order to generate Mian 9.4T MRI systslice thickness of 5me). The o1 of lae other parameterhe average water

ent phantoms (Aged concentration i

n the FLEX FID owater signal modulm resonance in the T agent mixed withomain analysis wittrum could be sepaain fitting (Fig. 2aeen the pure solutio MT exchange brntration of the par

e to exchange trans

at physiologic temntitative concentra

Biomed Eng, 10: edings of 19th ISM

Iw = PTRs ⋅ e

s∑

Transfer (FLEd Peter C. M. van

ates, 2F.M. Kirby CDept. of Radiology, Dallas, Texas, Un

ration transfer (pabenefit of paraC

he resonances of f-resonance saturaor CEST. This alltransfer ratio (PTRsaturation before

pite the large Δω,protons using frees kex >10,000s-1 won of functional paibility for imaginguence contains a p

d and transferred tooccurs over a peri

ortunities to transftional concentratioon in the water sigte resonance (Δωso

MRI acquisition. MT effect similar tem. FLEX image5 mm, and a matrixabeling pulse = 95rs for FLEX data signal after decay

garose only: greenimage of paraCEST

of the agarose phalation in the paraCFLEX spectrum (

h agarose), the FLth the prior knowlarated into three sa) shows the paraion (2.9%) and so

roadening. FortunaraCEST agent to bsfer of additional d

mperature and pH ation images. Thes

391-411, 2008. 3.MRM, 709, 2011. 6

−(kex,s +1 /T2s* )⋅tevol ⋅

EX) MRI Zijl2,3

Center for Functiongy and Radiologica

United States

araCEST) agents fCEST agents over

the exchanging pation of bulk waterlows for more satR). However, deteexchange occurs. can still complicquency transfer in

without interferencaraCEST agents in of paraCEST agen

preparation time (to water. In the labiod, tevol. Signal am

fer labeled protonson of the solute (s)gnal as a function o1). The effect on th

One contained ato that observed i

es were measured bx size of 64 *64 m

5 ppm was calculaacquisition were:

y were normalized

n FID; paraCEST T agent.

antom correspondsCEST agent soluti(red line) is much

LEX FID (blue lineedge (Eq.2) aboutignal components aCEST signal in polution mixed withately, by fitting thebe identical, 6.6 mMdephased signal th

are presented. Thse findings demon

. S. Aime, et al., A6. van Zijl et al., M

cos( Δω sol ⋅ tevol )[2]

nal Brain Imagingal Science, Johns

for biological targer their diamagnetipools and the water. In addition, fasteturated spins to bection of paraCESUnfortunately, thi

cate the analysis instead of saturatioce of MT effects bn biological tissuesnts. tprep) consisting of eling part, a pair omplification occurs to the water whe) protons and λs thof tevol in a mannehe water signal ca10 mM paraCES

in biological tissueby multiple LTMs

mm. The FLEX FIDated to avoid wate

texch = 400 μs anwith respect to th

solution: red FID

s to the broad banion modulated at larger than the free) indicates a rapit frequencies of th(green: MT effec

phantoms with thh agarose (1.5%) ie FLEX signal as M for pure solutio

hat was not returne

he FLEX approacnstrate the potentia

Acc Chem Res, 42MRM, 65:927-948

]

g,

et ic er er be T is n n y s.

a of rs n

he er an T e, s, D er nd he

D;

nd a

ee d

he t;

he is a n d

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2: 8,

3379Proc. Intl. Soc. Mag. Reson. Med. 20 (2012)