In Vivo Detection of PARACEST Agents With Relaxation Correction
Identifieur interne : 000380 ( Pmc/Corpus ); précédent : 000379; suivant : 000381In Vivo Detection of PARACEST Agents With Relaxation Correction
Auteurs : Craig K. Jones ; Alex X. Li ; Mojmír Such ; Robert H E. Hudson ; Ravi S. Menon ; Robert BarthaSource :
- Magnetic Resonance in Medicine [ 0740-3194 ] ; 2010.
Abstract
Several pulse sequences have been used to detect paramagnetic chemical exchange saturation transfer (PARACEST) contrast agents in animals to quantify the uptake over time following a bolus injection. The observed signal change is a combination of relaxation effects and PARACEST contrast. The purpose of the current study was to isolate the PARACEST effect from the changes in bulk water relaxation induced by the PARACEST agent in vivo for the fast low-angle shot pulse sequence. A fast low-angle shot–based pulse sequence was used to acquire continuous images on a 9.4-T MRI of phantoms and the kidneys of mice following PARACEST agent (Tm3+-DOTAM-Gly-Lys) injection. A WALTZ-16 pulse was applied before every second image to generate on-resonance paramagnetic chemical exchange effects. Signal intensity changes of up to 50% were observed in the mouse kidney in the control images (without a WALTZ-16 preparation pulse) due to altered bulk water relaxation induced by the PARACEST agent. Despite these changes, a clear on-resonance paramagnetic chemical exchange effect of 4-7% was also observed. A four-pool exchange model was used to describe image signal intensity. This study demonstrates that in vivo on-resonance paramagnetic chemical exchange effect contrast can be isolated from tissue relaxation time constant changes induced by a PARACEST agent that dominate the signal change. Magn Reson Med 63:1184–1192, 2010. © 2010 Wiley-Liss, Inc.
Url:
DOI: 10.1002/mrm.22340
PubMed: 20432289
PubMed Central: 3427884
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">In Vivo Detection of PARACEST Agents With Relaxation Correction</title><author><name sortKey="Jones, Craig K" sort="Jones, Craig K" uniqKey="Jones C" first="Craig K" last="Jones">Craig K. Jones</name><affiliation><nlm:aff id="au1"><institution>Centre for Functional and Metabolic Mapping, Robarts Research Institute, The University of Western Ontario</institution><addr-line>London, Ontario, Canada</addr-line></nlm:aff></affiliation></author><author><name sortKey="Li, Alex X" sort="Li, Alex X" uniqKey="Li A" first="Alex X" last="Li">Alex X. Li</name><affiliation><nlm:aff id="au1"><institution>Centre for Functional and Metabolic Mapping, Robarts Research Institute, The University of Western Ontario</institution><addr-line>London, Ontario, Canada</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="au2"><institution>Department of Medical Biophysics, The University of Western Ontario</institution><addr-line>London, Ontario, Canada</addr-line></nlm:aff></affiliation></author><author><name sortKey="Such, Mojmir" sort="Such, Mojmir" uniqKey="Such M" first="Mojmír" last="Such">Mojmír Such</name><affiliation><nlm:aff id="au1"><institution>Centre for Functional and Metabolic Mapping, Robarts Research Institute, The University of Western Ontario</institution><addr-line>London, Ontario, Canada</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="au3"><institution>Department of Chemistry, The University of Western Ontario</institution><addr-line>London, Ontario, Canada</addr-line></nlm:aff></affiliation></author><author><name sortKey="Hudson, Robert H E" sort="Hudson, Robert H E" uniqKey="Hudson R" first="Robert H E" last="Hudson">Robert H E. Hudson</name><affiliation><nlm:aff id="au3"><institution>Department of Chemistry, The University of Western Ontario</institution><addr-line>London, Ontario, Canada</addr-line></nlm:aff></affiliation></author><author><name sortKey="Menon, Ravi S" sort="Menon, Ravi S" uniqKey="Menon R" first="Ravi S" last="Menon">Ravi S. Menon</name><affiliation><nlm:aff id="au1"><institution>Centre for Functional and Metabolic Mapping, Robarts Research Institute, The University of Western Ontario</institution><addr-line>London, Ontario, Canada</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="au2"><institution>Department of Medical Biophysics, The University of Western Ontario</institution><addr-line>London, Ontario, Canada</addr-line></nlm:aff></affiliation></author><author><name sortKey="Bartha, Robert" sort="Bartha, Robert" uniqKey="Bartha R" first="Robert" last="Bartha">Robert Bartha</name><affiliation><nlm:aff id="au1"><institution>Centre for Functional and Metabolic Mapping, Robarts Research Institute, The University of Western Ontario</institution><addr-line>London, Ontario, Canada</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="au2"><institution>Department of Medical Biophysics, The University of Western Ontario</institution><addr-line>London, Ontario, Canada</addr-line></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">20432289</idno><idno type="pmc">3427884</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3427884</idno><idno type="RBID">PMC:3427884</idno><idno type="doi">10.1002/mrm.22340</idno><date when="2010">2010</date><idno type="wicri:Area/Pmc/Corpus">000380</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000380</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">In Vivo Detection of PARACEST Agents With Relaxation Correction</title><author><name sortKey="Jones, Craig K" sort="Jones, Craig K" uniqKey="Jones C" first="Craig K" last="Jones">Craig K. Jones</name><affiliation><nlm:aff id="au1"><institution>Centre for Functional and Metabolic Mapping, Robarts Research Institute, The University of Western Ontario</institution><addr-line>London, Ontario, Canada</addr-line></nlm:aff></affiliation></author><author><name sortKey="Li, Alex X" sort="Li, Alex X" uniqKey="Li A" first="Alex X" last="Li">Alex X. Li</name><affiliation><nlm:aff id="au1"><institution>Centre for Functional and Metabolic Mapping, Robarts Research Institute, The University of Western Ontario</institution><addr-line>London, Ontario, Canada</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="au2"><institution>Department of Medical Biophysics, The University of Western Ontario</institution><addr-line>London, Ontario, Canada</addr-line></nlm:aff></affiliation></author><author><name sortKey="Such, Mojmir" sort="Such, Mojmir" uniqKey="Such M" first="Mojmír" last="Such">Mojmír Such</name><affiliation><nlm:aff id="au1"><institution>Centre for Functional and Metabolic Mapping, Robarts Research Institute, The University of Western Ontario</institution><addr-line>London, Ontario, Canada</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="au3"><institution>Department of Chemistry, The University of Western Ontario</institution><addr-line>London, Ontario, Canada</addr-line></nlm:aff></affiliation></author><author><name sortKey="Hudson, Robert H E" sort="Hudson, Robert H E" uniqKey="Hudson R" first="Robert H E" last="Hudson">Robert H E. Hudson</name><affiliation><nlm:aff id="au3"><institution>Department of Chemistry, The University of Western Ontario</institution><addr-line>London, Ontario, Canada</addr-line></nlm:aff></affiliation></author><author><name sortKey="Menon, Ravi S" sort="Menon, Ravi S" uniqKey="Menon R" first="Ravi S" last="Menon">Ravi S. Menon</name><affiliation><nlm:aff id="au1"><institution>Centre for Functional and Metabolic Mapping, Robarts Research Institute, The University of Western Ontario</institution><addr-line>London, Ontario, Canada</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="au2"><institution>Department of Medical Biophysics, The University of Western Ontario</institution><addr-line>London, Ontario, Canada</addr-line></nlm:aff></affiliation></author><author><name sortKey="Bartha, Robert" sort="Bartha, Robert" uniqKey="Bartha R" first="Robert" last="Bartha">Robert Bartha</name><affiliation><nlm:aff id="au1"><institution>Centre for Functional and Metabolic Mapping, Robarts Research Institute, The University of Western Ontario</institution><addr-line>London, Ontario, Canada</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="au2"><institution>Department of Medical Biophysics, The University of Western Ontario</institution><addr-line>London, Ontario, Canada</addr-line></nlm:aff></affiliation></author></analytic><series><title level="j">Magnetic Resonance in Medicine</title><idno type="ISSN">0740-3194</idno><idno type="eISSN">1522-2594</idno><imprint><date when="2010">2010</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Several pulse sequences have been used to detect paramagnetic chemical exchange saturation transfer (PARACEST) contrast agents in animals to quantify the uptake over time following a bolus injection. The observed signal change is a combination of relaxation effects and PARACEST contrast. The purpose of the current study was to isolate the PARACEST effect from the changes in bulk water relaxation induced by the PARACEST agent in vivo for the fast low-angle shot pulse sequence. A fast low-angle shot–based pulse sequence was used to acquire continuous images on a 9.4-T MRI of phantoms and the kidneys of mice following PARACEST agent (Tm<sup>3+</sup>-DOTAM-Gly-Lys) injection. A WALTZ-16 pulse was applied before every second image to generate on-resonance paramagnetic chemical exchange effects. Signal intensity changes of up to 50% were observed in the mouse kidney in the control images (without a WALTZ-16 preparation pulse) due to altered bulk water relaxation induced by the PARACEST agent. Despite these changes, a clear on-resonance paramagnetic chemical exchange effect of 4-7% was also observed. A four-pool exchange model was used to describe image signal intensity. This study demonstrates that in vivo on-resonance paramagnetic chemical exchange effect contrast can be isolated from tissue relaxation time constant changes induced by a PARACEST agent that dominate the signal change. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Magn Reson Med</journal-id><journal-id journal-id-type="iso-abbrev">Magn Reson Med</journal-id><journal-id journal-id-type="publisher-id">mrm</journal-id><journal-title-group><journal-title>Magnetic Resonance in Medicine</journal-title></journal-title-group><issn pub-type="ppub">0740-3194</issn><issn pub-type="epub">1522-2594</issn><publisher><publisher-name>Wiley Subscription Services, Inc., A Wiley Company</publisher-name><publisher-loc>Hoboken</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">20432289</article-id><article-id pub-id-type="pmc">3427884</article-id><article-id pub-id-type="doi">10.1002/mrm.22340</article-id><article-categories><subj-group subj-group-type="heading"><subject>Full Papers</subject></subj-group></article-categories><title-group><article-title>In Vivo Detection of PARACEST Agents With Relaxation Correction</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Jones</surname><given-names>Craig K</given-names></name><xref ref-type="aff" rid="au1">1</xref></contrib><contrib contrib-type="author"><name><surname>Li</surname><given-names>Alex X</given-names></name><xref ref-type="aff" rid="au1">1</xref><xref ref-type="aff" rid="au2">2</xref></contrib><contrib contrib-type="author"><name><surname>Suchý</surname><given-names>Mojmír</given-names></name><xref ref-type="aff" rid="au1">1</xref><xref ref-type="aff" rid="au3">3</xref></contrib><contrib contrib-type="author"><name><surname>Hudson</surname><given-names>Robert H E</given-names></name><xref ref-type="aff" rid="au3">3</xref></contrib><contrib contrib-type="author"><name><surname>Menon</surname><given-names>Ravi S</given-names></name><xref ref-type="aff" rid="au1">1</xref><xref ref-type="aff" rid="au2">2</xref></contrib><contrib contrib-type="author"><name><surname>Bartha</surname><given-names>Robert</given-names></name><xref ref-type="aff" rid="au1">1</xref><xref ref-type="aff" rid="au2">2</xref><xref ref-type="corresp" rid="cor1">*</xref></contrib><aff id="au1"><label>1</label><institution>Centre for Functional and Metabolic Mapping, Robarts Research Institute, The University of Western Ontario</institution><addr-line>London, Ontario, Canada</addr-line></aff><aff id="au2"><label>2</label><institution>Department of Medical Biophysics, The University of Western Ontario</institution><addr-line>London, Ontario, Canada</addr-line></aff><aff id="au3"><label>3</label><institution>Department of Chemistry, The University of Western Ontario</institution><addr-line>London, Ontario, Canada</addr-line></aff></contrib-group><author-notes><corresp id="cor1">*Correspondence to: Robert Bartha, Ph.D., Centre for Functional and Metabolic Mapping, Robarts Research Institute, 100 Perth Drive, PO Box 5015, London, ON N6A 5K8, Canada. E-mail: <email>rbartha@imaging.robarts.ca</email></corresp></author-notes><pub-date pub-type="ppub"><month>5</month><year>2010</year></pub-date><pub-date pub-type="epub"><day>23</day><month>4</month><year>2010</year></pub-date><volume>63</volume><issue>5</issue><fpage>1184</fpage><lpage>1192</lpage><history><date date-type="received"><day>17</day><month>6</month><year>2009</year></date><date date-type="rev-recd"><day>03</day><month>11</month><year>2009</year></date><date date-type="accepted"><day>01</day><month>12</month><year>2009</year></date></history><permissions><copyright-statement>Copyright © 2010 Wiley-Liss, Inc.</copyright-statement><copyright-year>2010</copyright-year><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by/2.5/"><license-p>Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.</license-p></license></permissions><abstract><p>Several pulse sequences have been used to detect paramagnetic chemical exchange saturation transfer (PARACEST) contrast agents in animals to quantify the uptake over time following a bolus injection. The observed signal change is a combination of relaxation effects and PARACEST contrast. The purpose of the current study was to isolate the PARACEST effect from the changes in bulk water relaxation induced by the PARACEST agent in vivo for the fast low-angle shot pulse sequence. A fast low-angle shot–based pulse sequence was used to acquire continuous images on a 9.4-T MRI of phantoms and the kidneys of mice following PARACEST agent (Tm<sup>3+</sup>-DOTAM-Gly-Lys) injection. A WALTZ-16 pulse was applied before every second image to generate on-resonance paramagnetic chemical exchange effects. Signal intensity changes of up to 50% were observed in the mouse kidney in the control images (without a WALTZ-16 preparation pulse) due to altered bulk water relaxation induced by the PARACEST agent. Despite these changes, a clear on-resonance paramagnetic chemical exchange effect of 4-7% was also observed. A four-pool exchange model was used to describe image signal intensity. This study demonstrates that in vivo on-resonance paramagnetic chemical exchange effect contrast can be isolated from tissue relaxation time constant changes induced by a PARACEST agent that dominate the signal change. Magn Reson Med 63:1184–1192, 2010. © 2010 Wiley-Liss, Inc.</p></abstract><kwd-group><kwd>PARACEST</kwd><kwd>in-vivo</kwd><kwd>kidney</kwd><kwd>OPARACHEE</kwd><kwd>contrast agent</kwd><kwd>MRI</kwd><kwd>chemical exchange</kwd><kwd>relaxation, mouse</kwd></kwd-group></article-meta></front><body><p>Chemical exchange saturation transfer (<xref ref-type="bibr" rid="b1">1</xref>) can be used to detect endogenous protons (e.g., amide protons (<xref ref-type="bibr" rid="b2">2</xref>)), as well as amide or water protons bound to exogenous diamagnetic (<xref ref-type="bibr" rid="b3">3</xref>) and paramagnetic (<xref ref-type="bibr" rid="b4">4</xref>) agents that exchange with bulk water protons. Paramagnetic chemical exchange saturation transfer (PARACEST) agents have been designed to be sensitive to physiologic parameters such as pH and temperature (<xref ref-type="bibr" rid="b1">1</xref>, <xref ref-type="bibr" rid="b5">5</xref>–<xref ref-type="bibr" rid="b8">8</xref>), metabolites of interest (<xref ref-type="bibr" rid="b4">4</xref>, <xref ref-type="bibr" rid="b9">9</xref>), or proteins such as fibrin (<xref ref-type="bibr" rid="b10">10</xref>). In all cases, exchangeable protons are not directly detected. Rather, they are selectively saturated by the application of a long radiofrequency pulse applied at the resonance frequency (δω) (<xref ref-type="bibr" rid="b11">11</xref>) of the exchangeable proton, provided the slow exchange condition (δω · τ <1, where τ is the lifetime of the protons bound to the PARACEST agent) is satisfied (<xref ref-type="bibr" rid="b1">1</xref>). These saturated protons exchange with bulk water protons, decreasing the detectable bulk water signal. More recently, an alternative approach was introduced (<xref ref-type="bibr" rid="b12">12</xref>) to detect PARACEST agents in the presence of faster exchange. This method involves the on-resonance excitation of bulk water such that spins that do not exchange to off-resonance sites are rotated by a multiple of 360°. Spins that exchange to off-resonance sites do not experience the complete frequency-selective radiofrequency pulse and are incompletely refocused, thereby reducing the bulk water signal. This method has been termed on-resonance paramagnetic chemical exchange effects (OPARACHEE) and is directly related to the agent concentration (<xref ref-type="bibr" rid="b12">12</xref>). The OPARACHEE mechanism has several advantages over off-resonance PARACEST detection, including sensitivity to all bound protons that are exchanging with the bulk water and reduced power requirements (<xref ref-type="bibr" rid="b12">12</xref>). The main disadvantage is that sensitivity to physiologic parameters based on the chemical shift or shape of the bound proton resonance is lost.</p><p>The detection sensitivity of chemical exchange saturation transfer agents depends on many factors, including the chemical shift of the exchangeable proton, the rate of exchange, the saturation power level, and the duration of the saturation pulse (<xref ref-type="bibr" rid="b1">1</xref>, <xref ref-type="bibr" rid="b13">13</xref>). PARACEST agents offer the greatest potential sensitivity due to the large chemical shift of the exchangeable protons, which allows greater exchange rates while satisfying the slow exchange condition (δω · τ <1) for off-resonance detection. Previous studies have estimated the detection sensitivity of PARACECT agents by the OPARACHEE mechanism (<xref ref-type="bibr" rid="b12">12</xref>) or off-resonance saturation (<xref ref-type="bibr" rid="b13">13</xref>) to be in the micromolar range. However, PARACEST agents with exchangeable proton chemical shifts <150 parts per million (ppm) have significantly reduced sensitivity in vivo due to the concomitant magnetization transfer effects from endogenous macromolecules (<xref ref-type="bibr" rid="b15">15</xref>), particularly at the high power levels required for off-resonance saturation or OPARACHEE preparation. Despite the reduced sensitivity, several studies have reported in vivo detection of PARACEST agents (<xref ref-type="bibr" rid="b16">16</xref>, <xref ref-type="bibr" rid="b17">17</xref>) following high-dose (100 μL of 20-50 mM) intravenous injection. These studies identify image signal intensity (SI) changes over time in kidney and liver following injection of thulium-based agents using the OPARACHEE contrast mechanism. In one case, a spin-echo pulse sequence with a pulse repetition time (TR) of 1 sec (<xref ref-type="bibr" rid="b17">17</xref>) was used to detect signal change as a function of time; however, faster imaging schemes based on the true fast imaging with steady state precession (TFISP) pulse sequence have also been used (<xref ref-type="bibr" rid="b16">16</xref>).</p><p>Although previous studies have demonstrated PARACEST contrast agent detection, the observed signal changes included the effects of altered bulk water <italic>T</italic><sub>1</sub> and <italic>T</italic><sub>2</sub> in addition to the PARACEST effect. Signal changes resulting from decreased <italic>T</italic><sub>1</sub>, <italic>T</italic><sub>2</sub>, or <inline-formula><inline-graphic xlink:href="mrm0063-1184-mu1.jpg" mimetype="image"></inline-graphic></inline-formula> (<xref ref-type="bibr" rid="b1">1</xref>) relaxation time constants may enhance agent detection in dynamic studies. Failure to account for these relaxation-based signal changes diminishes one of the primary advantages of PARACEST agents: the ability to turn the contrast on and off at will (<xref ref-type="bibr" rid="b1">1</xref>, <xref ref-type="bibr" rid="b13">13</xref>). Therefore, the purpose of the current study was to characterize the relaxation induced signal changes for thulium-based OPARACHEE contrast agents, to demonstrate that the OPARACHEE effect can be isolated in vivo in the mouse kidney, and to create a model of the PARACEST and relaxation effects that fully describe SI variations in time-course studies acquired using a fast low-angle shot (FLASH) pulse sequence. The FLASH pulse sequence was chosen for this study as it can be used to acquire images rapidly, with minimal artifacts.</p><sec sec-type="materials|methods"><title>MATERIALS AND METHODS</title><sec><title>Bovine Serum Albumin Phantoms</title><p>A PARACEST agent containing a Tm<sup>3+</sup> cation, cyclen ring, CH2C(O) linker, and the Gly-Lys dipeptide sequence as functionalized side chains (Tm<sup>3+</sup>-DOTAM-Gly-Lys) was synthesized as described previously (<xref ref-type="bibr" rid="b18">18</xref>). Phantoms containing 0-, 2-, 6-, and 10-mM Tm<sup>3+</sup>-DOTAM-Gly-Lys (<xref ref-type="bibr" rid="b18">18</xref>) in phosphate buffer solution and 10% cross-linked bovine serum albumin (pH = 7) were created in NMR tubes. <italic>T</italic><sub>1</sub> and <italic>T</italic><sub>2</sub> relaxation time constants were measured on a 9.4-T vertical-bore Varian (Varian Inc., Palo Alto, CA) NMR spectrometer at 37°C using an inversion recovery pulse sequence (inversion time = 0.0125, 0.025, 0.05, 0.1, 0.2, 0.4, 0.8, 1.6, 3.2, 6.4, 12.8, 25.6 sec; TR = 20 sec) and a multiecho spin-echo sequence (echo time = 0.00125, 0.0025, 0.005, 0.01, 0.02, 0.04, 0.08, 0.16, 0.32, 0.64, 1.28, 2.56 sec; TR = 20 sec), respectively. The <italic>T</italic><sub>1</sub> and <italic>T</italic><sub>2</sub> relaxation time constants were quantified by fitting the mean SI in each phantom to the standard relaxation curve using the fmincon optimization algorithm in Matlab (The MathWorks, Natick, MA). The PARACEST effect was isolated from relaxation induced signal changes by taking the difference in the NMR SI between an acquisition preceded by a 240-ms, 6-μT WALTZ-16 preparation pulse and a second acquisition without a preparation pulse. The effect of PARACEST agent concentration (OPARACHEE effect) on the mean NMR SI was quantified using an exponential model.</p><p>The phantoms described above were imaged using a multiecho (eight echoes) gradient echo pulse sequence (TR = 14.9 ms, echo time = 1.4, 3.1, 4.7, 6.4, 8.0, 9.7, 11.3, 13.0 ms) on a horizontal-bore 9.4-T Varian MRI scanner. The proton density (PD) and <inline-formula><inline-graphic xlink:href="mrm0063-1184-mu1.jpg" mimetype="image"></inline-graphic></inline-formula> time constant were calculated for each phantom by fitting to the signal equation:(<xref ref-type="bibr" rid="b20">20</xref>)</p><p><disp-formula id="m1"><graphic xlink:href="mrm0063-1184-m1"></graphic><label>(1)</label></disp-formula></p><p>where SI is the average image SI corresponding to the specified echo-time, <italic>b</italic> is the baseline offset, and the other parameters are described above. The fmincon routine in Matlab was used to minimize the sum of squared errors.</p></sec><sec><title>Mouse Kidney Time Course</title><p>To measure the in vivo OPARACHEE effect, 16-g Balb/C mice (<italic>N</italic> = 4) were imaged using a 9.4-T Varian Inova MRI scanner. This study was approved by the University Council of Animal Care at the University of Western Ontario. Each mouse was placed in an anesthetic induction chamber and anesthetized using 4% isoflurane in oxygen. The mouse was then transferred onto a nose cone and maintained on isoflurane at a rate of 1.5-2.5%, oxygen 2 L/min. A catheter fed by two separate lines was placed in the tail vein. The first line contained saline, while the second line contained contrast agent in saline adjusted to pH 7. The mouse was placed prone in a 30mm millipede coil (Varian) and the abdomen of the mouse was lightly taped to the coil to minimize movement and breathing artifacts. Throughout imaging, the mouse's respiration rate and body temperature were monitored using an MR-compatible physiologic monitoring and gating system (SA Instruments Inc., Stony Brook, NY). With the use of a warm-air feedback system, animals were maintained at 37.5°C. Single-slice FLASH images (TR/echo time = 4.7/2 ms, 128 × 128 centric readout, 30mm field of view, two-dimensional single slice 1mm thick) were acquired continuously for 70 min through the left and right kidneys. Every second image was preceded by a 240-ms, 6-μT WALTZ-16 pulse (<xref ref-type="bibr" rid="b19">19</xref>) to generate OPARACHEE contrast. An interimage delay time of 3 sec allowed time for <italic>T</italic><sub>1</sub> relaxation. Following the first 5 min of continuous imaging, 150 μL of 50-mM Tm<sup>3+</sup>-DOTAM-Gly-Lys (<italic>N</italic> = 2) or 50 μL of 50-mM Gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA) (<italic>N</italic> = 1) was injected.</p><p>Images were two-dimensional motion corrected using an in-house registration algorithm. The superior edge of the kidney was tracked throughout the time series and the position was shifted in the superior-inferior direction so that the superior edge was at the same voxel location. Regions of interest were manually selected in the medulla and cortex of the kidneys, and the average SI was measured as a function of time after normalization to the mean SI at baseline (0-5 min). SI curves were generated separately for the FLASH images (<italic>SI</italic><sub><italic>FLASH</italic></sub>(t)) and for the FLASH images preceded by the WALTZ-16 saturation pulse (<italic>SI</italic><sub><italic>WALTZ</italic>-<italic>FLASH</italic></sub>(t)). OPARACHEE contrast was calculated at each time point using the expression (<italic>SI</italic><sub><italic>FLASH</italic></sub> (t) − <italic>SI</italic><sub><italic>WALTZ</italic>-<italic>FLASH</italic></sub>(t))/<italic>SI</italic><sub><italic>FLASH</italic></sub> (t) × 100 and then subtracting the mean baseline signal (t <1 min).</p><p>The concentration of PARACEST agent observed in vivo was calculated using an exponential relation between OPARACHEE percentage change and concentration calculated for the Tm<sup>3+</sup>-DOTAM-Gly-Lys phantoms described above. This exponential relation was applied to the OPARACHEE contrast observed in the mouse kidney to quantify the concentration of PARACEST agent throughout the time course.</p></sec><sec><title>Mouse Kidney Relaxation Measurement</title><p>To further understand image SI changes generated by the PARACEST agent, tissue <inline-formula><inline-graphic xlink:href="mrm0063-1184-mu1.jpg" mimetype="image"></inline-graphic></inline-formula> time constants and proton densities were measured following agent injection in a fourth 16-g Balb/C mouse. Following animal preparation as described above, a two-dimensional multiecho (eight echoes) gradient echo pulse sequence (TR = 14.9 ms, echo time = 1.4, 3.1, 4.7, 6.4, 8.0, 9.7, 11.3, 13.0 ms) was used to image the kidneys and bladder. All other imaging parameters were as described above. The multiecho acquisition was repeated 900 times (total acquisition time was 70 min); every second acquisition was preceded by a 240-ms, 6-μT WALTZ-16 preparation pulse. The PD and <inline-formula><inline-graphic xlink:href="mrm0063-1184-mu1.jpg" mimetype="image"></inline-graphic></inline-formula> were quantified by fitting to the signal equation (Eq. <xref ref-type="disp-formula" rid="m1">1</xref>). The calculated <inline-formula><inline-graphic xlink:href="mrm0063-1184-mu1.jpg" mimetype="image"></inline-graphic></inline-formula> and PD time courses were median filtered with a kernel width of 5 to remove spike noise.</p></sec><sec><title>Modeling the SI Time Course</title><p>The SI time course of the FLASH-based OPARACHEE contrast following agent injection was modeled using the Bloch equations incorporating the four-pool exchange terms (<xref ref-type="table" rid="tbl1">Table 1</xref>) (<xref ref-type="bibr" rid="b15">15</xref>) and relaxation parameters based on the FLASH signal equation. Two SI time courses, <inline-formula><inline-graphic xlink:href="mrm0063-1184-mu2.jpg" mimetype="image"></inline-graphic></inline-formula> (<italic>t</italic>) and <inline-formula><inline-graphic xlink:href="mrm0063-1184-mu3.jpg" mimetype="image"></inline-graphic></inline-formula> (<italic>t</italic>), were modeled for the kidney following contrast agent injection. The inputs to the model included the WALTZ-16 pulse parameters (amplitude and duration), the imaging pulse sequence parameters (TR, echo time, and flip angle [α]), the relaxation time constants (<italic>T</italic><sub>1</sub>, <italic>T</italic><sub>2</sub>, <inline-formula><inline-graphic xlink:href="mrm0063-1184-mu1.jpg" mimetype="image"></inline-graphic></inline-formula>), and the visible PD. Several of these parameters are time dependent as they vary with agent concentration. The agent concentration as a function of time (uptake curve) was defined using data from the mouse kidney, as were the <inline-formula><inline-graphic xlink:href="mrm0063-1184-mu1.jpg" mimetype="image"></inline-graphic></inline-formula> and PD parameters. The <italic>T</italic><sub>1</sub> and <italic>T</italic><sub>2</sub> relaxation time constants were calculated at each time point using Eqs. <xref ref-type="disp-formula" rid="m4">4</xref> and <xref ref-type="disp-formula" rid="m5">5</xref> below.</p><table-wrap id="tbl1" position="float"><label>Table 1</label><caption><p>Relaxation and Exchange Parameters for the Various Proton Pools Used in the Model<xref ref-type="table-fn" rid="tf1-1">*</xref></p></caption><table frame="hsides" rules="groups"><thead><tr><th align="left" rowspan="1" colspan="1">Pool</th><th align="center" rowspan="1" colspan="1"><italic>T</italic><sub>2</sub> (sec)</th><th align="center" rowspan="1" colspan="1"><italic>T</italic><sub>1</sub> (sec)</th><th align="center" rowspan="1" colspan="1">Chemical shift (ppm)</th><th align="center" rowspan="1" colspan="1">Exchange rate (Hz)</th></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1">Bound</td><td align="center" rowspan="1" colspan="1">0.01</td><td align="center" rowspan="1" colspan="1">1.0</td><td align="center" rowspan="1" colspan="1">500</td><td align="center" rowspan="1" colspan="1">100,000</td></tr><tr><td align="left" rowspan="1" colspan="1">Amide</td><td align="center" rowspan="1" colspan="1">0.01</td><td align="center" rowspan="1" colspan="1">1.0</td><td align="center" rowspan="1" colspan="1">−50</td><td align="center" rowspan="1" colspan="1">295</td></tr><tr><td align="left" rowspan="1" colspan="1">Macromolecular</td><td align="center" rowspan="1" colspan="1">0.000001</td><td align="center" rowspan="1" colspan="1">1.0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">26</td></tr></tbody></table><table-wrap-foot><fn id="tf1-1"><label>*</label><p>The chemical shift is relative to the free water pool and the exchange rate is the exchange of free water protons with the given pool.</p></fn></table-wrap-foot></table-wrap><p>More specifically, the SI <inline-formula><inline-graphic xlink:href="mrm0063-1184-mu2.jpg" mimetype="image"></inline-graphic></inline-formula> (<italic>t</italic>) depends on the pulse sequence parameters (TR = 4.71 ms and flip angle α = 11°) and the tissue relaxation parameters (PD, <italic>T</italic><sub>1</sub>, <inline-formula><inline-graphic xlink:href="mrm0063-1184-mu1.jpg" mimetype="image"></inline-graphic></inline-formula>) and was calculated from the FLASH signal Equation (20):</p><p><disp-formula id="m2"><graphic xlink:href="mrm0063-1184-m2"></graphic><label>(2)</label></disp-formula></p><p>The SI (<inline-formula><inline-graphic xlink:href="mrm0063-1184-mu3.jpg" mimetype="image"></inline-graphic></inline-formula> (<italic>t</italic>)) for the FLASH acquisition preceded by a WALTZ-16 preparation pulse (6-μT amplitude and 240 ms) was also modeled as described above. <inline-formula><inline-graphic xlink:href="mrm0063-1184-mu3.jpg" mimetype="image"></inline-graphic></inline-formula> (<italic>t</italic>)was generated by taking the product of <inline-formula><inline-graphic xlink:href="mrm0063-1184-mu2.jpg" mimetype="image"></inline-graphic></inline-formula> (<italic>t</italic>)and the fractional signal loss generated by the WALTZ-16 pulse (Exchange(t)), calculated based on the four-pool model described previously (<xref ref-type="bibr" rid="b15">15</xref>) and the parameters in <xref ref-type="table" rid="tbl1">Table 1</xref>.</p><p>The model signal intensities (<inline-formula><inline-graphic xlink:href="mrm0063-1184-mu2.jpg" mimetype="image"></inline-graphic></inline-formula> (<italic>t</italic>)and <inline-formula><inline-graphic xlink:href="mrm0063-1184-mu3.jpg" mimetype="image"></inline-graphic></inline-formula> (<italic>t</italic>)) were compared to the measured SI (<italic>SI</italic><sub><italic>FLASH</italic></sub> (<italic>t</italic>) and <italic>SI</italic><sub><italic>WALTZ</italic>-<italic>FLASH</italic></sub> (<italic>t</italic>), respectively) obtained in the kidneys following contrast agent injection. All image analyses and simulations were performed using in-house software written in Matlab (The MathWorks).</p></sec></sec><sec sec-type="results"><title>RESULTS</title><sec><title>Phantom Relaxation Measurements</title><p>The <italic>T</italic><sub>1</sub> and <italic>T</italic><sub>2</sub> relaxation time constants quantified in 10% cross-linked bovine serum albumin phantoms were found to vary substantially as a function of agent concentration (<xref ref-type="table" rid="tbl2">Table 2</xref>). Equations 3 and 4 give the linear relationship with agent concentration found for both transverse and longitudinal relaxation rates (<italic>R</italic><sub>1</sub> = 1/<italic>T</italic><sub>1</sub>, and <italic>R</italic><sub>2</sub> = 1/<italic>T</italic><sub>2</sub>):</p><p><disp-formula id="m3"><graphic xlink:href="mrm0063-1184-m3"></graphic><label>(3)</label></disp-formula></p><p><disp-formula id="m4"><graphic xlink:href="mrm0063-1184-m4"></graphic><label>(4)</label></disp-formula></p><table-wrap id="tbl2" position="float"><label>Table 2</label><caption><p><italic>T</italic><sub>1</sub> and <italic>T</italic><sub>2</sub> Relaxation Time Constants for Tm<sup>3+</sup>-DOTAM-Gly-Lys in 10% Cross-Linked Bovine Serum Albumin</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="center" rowspan="1" colspan="1">Concentration (mM)</th><th align="center" rowspan="1" colspan="1"><italic>T</italic><sub>1</sub> (sec)</th><th align="center" rowspan="1" colspan="1"><italic>T</italic><sub>2</sub> (sec)</th></tr></thead><tbody><tr><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">2.69</td><td align="center" rowspan="1" colspan="1">0.16</td></tr><tr><td align="center" rowspan="1" colspan="1">2</td><td align="center" rowspan="1" colspan="1">2.67</td><td align="center" rowspan="1" colspan="1">0.10</td></tr><tr><td align="center" rowspan="1" colspan="1">6</td><td align="center" rowspan="1" colspan="1">2.35</td><td align="center" rowspan="1" colspan="1">0.06</td></tr><tr><td align="center" rowspan="1" colspan="1">10</td><td align="center" rowspan="1" colspan="1">2.02</td><td align="center" rowspan="1" colspan="1">0.004</td></tr></tbody></table></table-wrap><p>Equations <xref ref-type="disp-formula" rid="m5">5</xref> and <xref ref-type="disp-formula" rid="m6">6</xref> give the relationship with agent concentration for <italic>R</italic><inline-formula><inline-graphic xlink:href="mrm0063-1184-mu4.jpg" mimetype="image"></inline-graphic></inline-formula> and PD:</p><p><disp-formula id="m5"><graphic xlink:href="mrm0063-1184-m5"></graphic><label>(5)</label></disp-formula></p><p><disp-formula id="m6"><graphic xlink:href="mrm0063-1184-m6"></graphic><label>(6)</label></disp-formula></p><p>The OPARACHEE percentage change was calculated and found to be 0, 2.7, 5.1, and 6.7% for the 0−, 2−, 6−, and 10−mM phantoms, respectively. An exponential relation between Tm<sup>3+</sup> concentration and OPARACHEE percentage change was calculated as:</p><p><disp-formula id="m7"><graphic xlink:href="mrm0063-1184-m7"></graphic><label>(7)</label></disp-formula></p></sec><sec><title>Kidney SI Time Course</title><p>Representative in vivo FLASH images and image signal time-courses (<italic>SI</italic><sub><italic>FLASH</italic></sub> and <italic>SI</italic><sub><italic>WALTZ</italic>-<italic>FLASH</italic></sub>) in the cortex and medulla of the kidney are shown for two animals in <xref ref-type="fig" rid="fig01">Fig. 1</xref>. Both <italic>SI</italic><sub><italic>FLASH</italic></sub> and <italic>SI</italic><sub><italic>WALTZ</italic>-<italic>FLASH</italic></sub> in the cortex and medulla dropped rapidly approximately 1 min after agent injection (approximately 6 min into the scan session). <italic>SI</italic><sub><italic>WALTZ</italic>-<italic>FLASH</italic></sub> then increased more slowly than <italic>SI</italic><sub><italic>WALTZ</italic></sub> to the baseline value. The magnitude of the signal change was far greater in the medulla (25–30% of the baseline value) than the cortex (80–90% of the baseline value). The time courses labeled OPARACHEE in <xref ref-type="fig" rid="fig01">Fig. 1</xref> represent the isolated OPARACHEE signal. In the medulla, the OPARACHEE signal increased rapidly after injection, followed by a brief decrease, after which a more gradual increase and then return toward baseline was observed. In contrast, the cortex had a rapid initial increase followed only by a very gradual decline toward baseline at 70 min. To check the robustness of the correction method used to isolate the OPARACHEE signal, a third animal was scanned during an injection of Gd-DTPA. In this case, the <italic>SI</italic><sub><italic>FLASH</italic></sub> curve decreased by 10% following injection of the Gd-DTPA complex (data not shown). However, the correction effectively removed this change and produced a residual OPARACHEE effect of <1%, consistent with our expectations.</p><fig id="fig01" position="float"><label>FIG. 1</label><caption><p>SI time courses shown for the cortex (top row) and medulla (bottom row) regions of the mouse kidney for two different mice. For each set of time courses, there are three plots; the top is the SI measured from the FLASH sequence (no WALTZ-16 pulse) (<italic>SI</italic><sub><italic>FLASH</italic></sub>), the middle is the SI from the FLASH sequence with a WALTZ-16 pulse applied on water resonance (<italic>SI</italic><sub><italic>WALTZ</italic>-<italic>FLASH</italic></sub>), and the bottom is the isolated OPARACHEE effect (i.e., the difference). The data for both the left side (blue) and right side (red) are shown.</p></caption><graphic xlink:href="mrm0063-1184-f1"></graphic></fig><p>The absolute Tm<sup>3+</sup>-DOTAM-Gly-Lys concentration for the left kidney of mouse 2 (<xref ref-type="fig" rid="fig02">Fig. 2</xref>) was calculated based on the OPARACHEE effect using the exponential relation defined in Eq. <xref ref-type="disp-formula" rid="m7">7</xref>.</p><fig id="fig02" position="float"><label>FIG. 2</label><caption><p>Concentration of Tm<sup>3+</sup>-DOTAM-Gly-Lys agent in the medulla region of the mouse kidney throughout the time course.</p></caption><graphic xlink:href="mrm0063-1184-f2"></graphic></fig></sec><sec><title>Kidney Relaxation Measurement Following Agent Injection</title><p>The in vivo tissue <inline-formula><inline-graphic xlink:href="mrm0063-1184-mu1.jpg" mimetype="image"></inline-graphic></inline-formula> time constant was quantified during agent uptake in the cortex and medulla of the left kidney, as shown in <xref ref-type="fig" rid="fig03">Fig. 3</xref>. The image SI associated with the first echo image of the FLASH sequence (<italic>SI</italic><sub><italic>FLASH</italic></sub>) and the FLASH sequence preceded by a WALTZ-16 preparation pulse (<italic>SI</italic><sub><italic>WALTZ</italic>-<italic>FLASH</italic></sub>) is shown as a function of time following agent injection for the left medulla (<xref ref-type="fig" rid="fig03">Fig. 3</xref>a) and left cortex (<xref ref-type="fig" rid="fig03">Fig. 3</xref>d). The associated visible PD (<xref ref-type="fig" rid="fig03">Fig. 3</xref>b and e) and <inline-formula><inline-graphic xlink:href="mrm0063-1184-mu1.jpg" mimetype="image"></inline-graphic></inline-formula> (<xref ref-type="fig" rid="fig03">Fig. 3</xref>c and f) vary substantially following contrast agent injection. For the medulla region (top row), the largest signal changes were associated with a decrease in the visible PD, while there were only small changes in the <inline-formula><inline-graphic xlink:href="mrm0063-1184-mu1.jpg" mimetype="image"></inline-graphic></inline-formula>. The cortex (bottom row) showed a much smaller decrease in visible PD but a greater and more variable decrease in <inline-formula><inline-graphic xlink:href="mrm0063-1184-mu1.jpg" mimetype="image"></inline-graphic></inline-formula> compared to the medulla.</p><fig id="fig03" position="float"><label>FIG. 3</label><caption><p>Altered visible PD and <inline-formula><inline-graphic xlink:href="mrm0063-1184-mu1.jpg" mimetype="image"></inline-graphic></inline-formula> following Tm<sup>3+</sup>-DOTAM-Gly-Lys injection. The top image is the first echo of the first image of the time course and is overlaid with the regions of interest used in the plots below. The plots below represent the normalized SI as a function of time (left column), calculated PD (middle column), and calculated <inline-formula><inline-graphic xlink:href="mrm0063-1184-mu1.jpg" mimetype="image"></inline-graphic></inline-formula> (right column) from the left kidney medulla (top row, which corresponds to the medial region of the kidney) and left kidney cortex (bottom row, which corresponds to the distal region of the kidney).</p></caption><graphic xlink:href="mrm0063-1184-f3"></graphic></fig></sec><sec><title>Model Verification</title><p>Model input parameters were obtained from the medulla of the left kidney of the fourth animal as a function of time for PD (<xref ref-type="fig" rid="fig04">Fig. 4</xref>a) and <inline-formula><inline-graphic xlink:href="mrm0063-1184-mu1.jpg" mimetype="image"></inline-graphic></inline-formula> (<xref ref-type="fig" rid="fig04">Fig. 4</xref>b). Additionally, the input concentration curve as a function of time is shown in <xref ref-type="fig" rid="fig04">Fig. 4</xref>c. The FLASH SI (<italic>SI</italic><sub><italic>FLASH</italic></sub>., black line in <xref ref-type="fig" rid="fig04">Fig. 4</xref>d) and the FLASH SI preceded by the WALTZ-16 pulse (<italic>SI</italic><sub><italic>WALTZ</italic>-<italic>FLASH</italic></sub>, black line in <xref ref-type="fig" rid="fig04">Fig. 4</xref>e) were also measured from the same region of the medulla. The OPARACHEE effect was calculated directly from <italic>SI</italic><sub><italic>FLASH</italic></sub> and <italic>SI</italic><sub><italic>WALTZ-FLASH</italic></sub> and is shown in <xref ref-type="fig" rid="fig04">Fig. 4</xref>f. The simulated signal intensities (<inline-formula><inline-graphic xlink:href="mrm0063-1184-mu2.jpg" mimetype="image"></inline-graphic></inline-formula> (<italic>t</italic>) and <inline-formula><inline-graphic xlink:href="mrm0063-1184-mu3.jpg" mimetype="image"></inline-graphic></inline-formula> (<italic>t</italic>)) are represented by the gray curves in <xref ref-type="fig" rid="fig04">Fig. 4</xref>d and <xref ref-type="fig" rid="fig04">4</xref>e and showed very good agreement to the measured signal intensities. The OPARACHEE curve was calculated (gray curve in <xref ref-type="fig" rid="fig04">Fig. 4</xref>f) from the simulated SI and showed good agreement with the measured OPARACHEE curve (black curve in <xref ref-type="fig" rid="fig04">Fig. 4</xref>f). Therefore, the model, which incorporated information from not only the PARACEST effect but also relaxation effects that change as a function of the concentration of the PARACEST agent, accurately recreated the measured SI time courses both with and without the WALTZ-16 preparation pulse.</p><fig id="fig04" position="float"><label>FIG. 4</label><caption><p>Modeled time-course data for the medulla region of the left mouse kidney. The <bold>(a)</bold> PD, <bold>(b)</bold><inline-formula><inline-graphic xlink:href="mrm0063-1184-mu1.jpg" mimetype="image"></inline-graphic></inline-formula>, and <bold>(c)</bold> uptake curve input functions were calculated from the eight-echo gradient-echo images acquired from mouse 4. The measured (black) and simulated (dashed) signal intensities as shown without WALTZ preparation <bold>(d)</bold> and with WALTZ preparation <bold>(e)</bold>. The measured (black) and simulated (dashed) uptake curves are shown in <bold>(f)</bold>.</p></caption><graphic xlink:href="mrm0063-1184-f4"></graphic></fig></sec></sec><sec sec-type="discussion"><title>DISCUSSION</title><p>The current study demonstrates a significant SI decrease that can be detected in FLASH images acquired at 9.4 T following injection of Tm<sup>3+</sup>-DOTAM-Gly-Lys due to the effect of this compound on bulk water visibility, <italic>T</italic><sub>1</sub>, <italic>T</italic><sub>2</sub>, and <inline-formula><inline-graphic xlink:href="mrm0063-1184-mu1.jpg" mimetype="image"></inline-graphic></inline-formula>. The inclusion of a WALTZ-16 preparation pulse prior to imaging further decreases SI due to the OPARACHEE mechanism. The OPARACHEE effect can be isolated by calculating OPARACHEE(t) = (<italic>SI</italic><sub><italic>FLASH</italic></sub>(<italic>t</italic>) − <italic>SI</italic><sub><italic>WALTZ</italic>-<italic>FLASH</italic></sub>(<italic>t</italic>))/<italic>SI</italic><sub><italic>FLASH</italic></sub> (<italic>t</italic>) × 100. The large decrease in image SI (<italic>SI</italic><sub><italic>FLASH</italic></sub>) observed without the use of the WALTZ-16 preparation pulse highlights the need to obtain appropriate reference images to detect OPARACHEE contrast. Such reference images also provide an inherent control for baseline fluctuations of the acquired signal due to drift of the scanner magnetic field over time, which may be beneficial for very long scans. We present here a method for quantifying the OPARACHEE effect independent of changes in tissue relaxation induced by the paramagnetic agent, by alternating between the acquisition of a control scan and a WALTZ-16 prepared scan throughout a time-course study. The difference between subsequent signal intensities (acquired without and with the WALTZ-16 preparation pulse) provides a measure of the OPARACHEE effect independent of relaxation induced signal changes.</p><sec><title>Phantom Relaxation Measurements</title><p>The bulk water <italic>T</italic><sub>1</sub> and <italic>T</italic><sub>2</sub> relaxation time constants were shown to depend linearly on the thulium concentration in 10% bovine serum albumin. The relationship may vary for different tissues and therefore may require separate calibration in each tissue type (e.g., liver, kidney, brain) and different pathologic states (e.g., normal, cancer, stroke). The observed variation in relaxation parameters with agent concentration suggests that care must be taken when attributing signal change in time-course studies directly to the PARACEST or OPARACHEE effect as SI changes will occur even in the absence of a saturation or preparation pulse.</p></sec><sec><title>Kidney SI Time Courses</title><p>In the mouse kidney, the variation in image SI following agent injection was dependent on the presence or absence of the WALTZ-16 preparation pulse. With the WALTZ-16 pulse present, <italic>SI</italic><sub><italic>WALTZ_FLASH</italic></sub> decreased to 55% of the initial value in the cortex and 30% of the initial value in the medulla and then increased linearly over the following 65 min. In the absence of the WALTZ-16 pulse, <italic>SI</italic><sub><italic>FLASH</italic></sub> had a similar initial decrease but then increased more quickly, returning to the baseline value ∼55 min post injection. Most interesting was the isolated OPARACHEE effect, which showed an initial increase immediately after the injection, then a rapid signal decrease to near baseline around 11 min into the scan, followed by another increase from 12 – 30 min, and finally a gradual decrease over time. The complex nature of the OPARACHEE effect is likely a direct indicator of the concentration of Tm<sup>3+</sup>-DOTAM-Gly-Lys in the kidney as the OPARACHEE effect curve has a similar structure to a renal uptake and excretion time course (<xref ref-type="bibr" rid="b21">21</xref>).</p></sec><sec><title>In Vivo Agent Concentration</title><p>The in vivo agent concentration was quantified based on an exponential relationship between the OPARACHEE percentage change and agent concentration calculated in phantoms. The relationship was assumed to be exponential over the range of concentrations studied; however, a greater concentration range may require more complex models (e.g., superlinear) to provide an accurate representation of OPARACHEE effect as a function of agent concentration. The OPARACHEE signal calculated from the phantoms was isolated from concomitant changes in bulk water relaxation time constants, and therefore the relationship was expected to be maintained in vivo.</p></sec><sec><title>Visible PD</title><p>To further investigate the relaxation mechanisms leading to the decrease in image SI in the absence of the WALTZ-16 preparation pulse, the visible PD and the <inline-formula><inline-graphic xlink:href="mrm0063-1184-mu1.jpg" mimetype="image"></inline-graphic></inline-formula> relaxation time constant were measured following agent injection using a multiecho gradient echo sequence. The visible PD was defined as the y-intercept in the fitted signal decay curve and does not necessarily represent the number of protons in the region. <xref ref-type="fig" rid="fig03">Figure 3</xref>b demonstrates that there can be a very large change in the measured intercept as a function of time following agent injection. One explanation for this change is that bulk water protons may become undetectable in the hydration layers surrounding the lanthanide due to an induced shift of the water resonance frequency. A second possible explanation is a dramatic shortening of the <italic>T</italic><sub>2</sub> of the hydration layer to the microsecond range such that all signal is dephased prior to the first echo time.</p></sec><sec><title>Relaxation Parameters</title><p>The simulations were created based on an input uptake curve and with the relaxation parameters <italic>T</italic><sub>1</sub>, <italic>T</italic><sub>2</sub>, and <inline-formula><inline-graphic xlink:href="mrm0063-1184-mu1.jpg" mimetype="image"></inline-graphic></inline-formula>, as well as the PD dependent on the agent concentration. The resulting simulated signal intensities with and without WALTZ-16 preparation showed good correspondence to signal intensities measured in mouse kidneys. In addition, fixing any of the relaxation parameters (<italic>T</italic><sub>1</sub>, <italic>T</italic><sub>2</sub>, <inline-formula><inline-graphic xlink:href="mrm0063-1184-mu1.jpg" mimetype="image"></inline-graphic></inline-formula>, and PD) to a constant value resulted in modeled signal intensities that deviated significantly from the measured signal intensities (data not shown). Therefore, it was necessary to have knowledge of all four parameters for proper modeling of the decay curve.</p><p>The isolation of the OPARACHEE effect was achieved by taking the ratio of (<italic>SI</italic><sub><italic>FLASH</italic></sub>(<italic>t</italic>) − <italic>SI</italic><sub><italic>WALTZ</italic>-<italic>FLASH</italic></sub>(<italic>t</italic>))/<italic>SI</italic><sub><italic>FLASH</italic></sub> (<italic>t</italic>) × 100. Previous studies have incorporated exchange terms into the differential Bloch equations to build three-pool (<xref ref-type="bibr" rid="b14">14</xref>) and four-pool (<xref ref-type="bibr" rid="b15">15</xref>) models of the PARACEST effect. However, there is currently no analytical solution to this problem. In the Bloch equations, the exchange terms are linearly modeled and therefore the signal change due to the PARACEST effect must be a multiplicative factor applied to the signal equation (Eq. <xref ref-type="disp-formula" rid="m1">1</xref>). Therefore, the proper method to isolate the OPARACHEE effect (or PARACEST effect) from relaxation effects is to calculate (<italic>SI</italic><sub><italic>FLASH</italic></sub>(<italic>t</italic>) − <italic>SI</italic><sub><italic>WALTZ</italic>-<italic>FLASH</italic></sub>(<italic>t</italic>))/<italic>SI</italic><sub><italic>FLASH</italic></sub> (<italic>t</italic>) × 100 for each pair of subsequent time points. However, this approach can only be considered an approximation as there is no analytical solution to the modified Bloch equations.</p></sec><sec><title>Limitations</title><p>This study focused on a Tm<sup>3+</sup>-based compound (Tm<sup>3+</sup>-DOTAM-Gly-Lys) used to generate OPARACHEE contrast. Image SI was found to change following agent injection, even using a conventional FLASH sequence, due to alterations in bulk water visibility and relaxation time constants induced by the Tm<sup>3+</sup> lanthanide. Compounds used for detection of the PARACEST effect by off-resonance excitation (e.g., Eu<sup>3+</sup>) were not discussed, but preliminary results indicate a similar, albeit smaller, effect than the effect noted for the Tm<sup>3+</sup>-based compound used in the current study. This result was expected as it depends on the efficiency of a particular compound to alter bulk water visibility and relaxation time constants. The results obtained in the current study are independent of the endogenous macromolecule magnetization transfer (MT) effect and are applicable to all PARACEST agents.</p><p>Although the simulations utilized <inline-formula><inline-graphic xlink:href="mrm0063-1184-mu1.jpg" mimetype="image"></inline-graphic></inline-formula> and PD values obtained in vivo, the <italic>T</italic><sub>1</sub> and <italic>T</italic><sub>2</sub> time constants used were interpolated from the bovine serum albumin data presented in <xref ref-type="table" rid="tbl1">Table 1</xref>. It would be optimal to acquire the <italic>T</italic><sub>1</sub> and <italic>T</italic><sub>2</sub> data in vivo following injection throughout the time course. However, these measurements were not made in the current study due to the length of time required for each.</p><p>The current study did not include a correction for amplitude of static field inhomogeneities, which could lead to signal variation within the kidneys (<xref ref-type="bibr" rid="b22">22</xref>) and overestimation of the OPARACHEE effect. To minimize such errors, a second-order shim correction was applied to the kidneys, reducing the line width of the bulk water to approximately 150 Hz. In addition, a WALTZ-16 pulse with a bandwidth of ∼400 Hz (2.5-ms subpulse duration) was used for excitation. The WALTZ-16 pulse is inherently insensitive to flip-angle error, and its bandwidth encompassed the range of frequencies found within the kidney, minimizing excitation errors.</p></sec><sec><title>Choice of Imaging Sequence</title><p>The current study utilized a FLASH sequence to increase sensitivity to alterations in bulk water <italic>T</italic><sub>1</sub> and <inline-formula><inline-graphic xlink:href="mrm0063-1184-mu1.jpg" mimetype="image"></inline-graphic></inline-formula>. Pulse sequences that are heavily weighted to relaxation parameters (e.g., FLASH, gradient recalled echo, TFISP) are expected to produce images with large SI variations in the presence of a PARCEST agent, even without the application of a saturation or preparation pulse, and therefore a careful interpretation of signal changes is warranted. The use of fast spin-echo-type sequences can reduce the dependence of image SI on <italic>T</italic><sub>1</sub> and <italic>T</italic><sub>2</sub> relaxation time constants; however, such sequences will not protect against signal loss due to the decreased visibility of the bulk water pool in the presence of a lanthanide-based agent. Therefore, all such experiments should include careful controls to account for such changes.</p></sec><sec><title>Increasing Sensitivity of Detection</title><p>The SI change was shown to be a function of relaxation parameters, and therefore image SI will depend on the type of pulse sequence used for acquisition. The FLASH pulse sequence used in the current study was very sensitive to <italic>T</italic><sub>1</sub> relaxation. However, there are many other possibilities for image acquisition, including TFISP and spin-echo-based sequences. An on-resonance spin-echo pulse sequence with a long TR would have the smallest dependence on relaxation parameters and consequently the cleanest detection of OPARACHEE contrast. However, the acquisition time of such sequences would be relatively long (<xref ref-type="bibr" rid="b16">16</xref>). On the other hand, short TR pulse sequences such as FLASH and TFISP would be more sensitive to relaxation parameters but would be more rapid. The timing parameters of such sequences could potentially be modified to provide optimal in vivo detection sensitivity of the OPARACHEE or PARACEST effect. Such optimization would require knowledge of the relaxation properties of a particular agent. The SI dependence on pulse sequence acquisition and agent properties will be addressed in future work.</p></sec></sec><sec sec-type="conclusions"><title>CONCLUSIONS</title><p>SI time-courses without WALTZ-16 preparation showed large SI changes as a function of time following PARACEST contrast agent injection. This signal variation was attributed to changes in relaxation and bulk water visibility as the agent concentration varied. Despite these effects, on-resonance PARACEST agent detection (OPARACHEE contrast) can be isolated by the acquisition of control images throughout the time course to account for agent-induced signal changes from altered bulk water visibility, <italic>T</italic><sub>1</sub>, <italic>T</italic><sub>2</sub>, and <inline-formula><inline-graphic xlink:href="mrm0063-1184-mu1.jpg" mimetype="image"></inline-graphic></inline-formula> relaxation mechanisms. Failure to account for these signal changes can lead to the significant overestimation of the PARACEST effect. The relationship between OPARACHEE contrast and agent concentration, independent of relaxation parameters, was used to quantify absolute agent concentration changes throughout a time course in a mouse kidney.</p></sec></body><back><ack><p>We thank our animal technician Claire Poppe for her help with the animal setup and injections. 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