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| Chemical name: | Tm-1,4,7,10-Tetraazacyclododecane-N,N',N'',N'''-acetamidoacetic acid |  |
| Abbreviated name: | Tm-DOTA-Gly, Tm-DOTAM-Gly | |
| Synonym: | ||
| Agent category: | Compound | |
| Target: | Non-targeted | |
| Target category: | Non-targeted | |
| Method of detection: | PARACEST magnetic resonance imaging (MRI) | |
| Source of signal\contrast: | Tm3+ | |
| Activation: | No | |
| Studies: |
| Click on the above structure for additional information in PubChem. |
[PubMed]
Chemical Exchange Saturation Transfer (CEST) is a novel magnetic resonance imaging (MRI) contrast mechanism (1) that is an attractive alternative to T1 and T2 contrast mechanisms, particularly at high magnetic fields (2). CEST agents possess a hydrogen proton with a moderate to slow exchange rate with water. Selective saturation of the MR frequency of this proton, followed by exchange with solvent water, reduces the MR signal of the water. PARACEST (PARAmagnetic CEST) agents include a paramagnetic lanthanide ion that shifts the MR frequencies of the exchangeable proton to unique values to facilitate selective detection (3, 4). Endogenous MR contrast may be continually monitored in the presence of PARACEST agents by neglecting to saturate the MR frequency of the exchangeable proton (and assuming that the T1 relaxation of the PARACEST agent is negligible).
The selective saturation is typically applied for two or more seconds to generate a steady-state of saturation (5), which greatly lengthens the time required for in vivo detection of PARACEST MRI contrast agents. However, computer simulations and studies with chemical solutions have shown that more rapid MRI acquisition schemes can be prepended with a selective saturation pulse to accelerate the detection of PARACEST MRI contrast agents (6). The choice of the MRI acquisition scheme is dependent on the T1 relaxation time of the endogenous tissue in the presence of the PARACEST agent. In addition, a second "control" MR image is typically acquired to account for the direct saturation of water by applying selective saturation at a MR frequency with an opposite sign relative to the saturation frequency of the first MR image (7). The need for a second MR image further lengthens the in vivo detection of PARACEST agents. However, a single control MR image can be acquired before injecting the PARACEST agent, which obviates the need to acquire control MR images after injection of the agent and accelerates the temporal detection of PARACEST agents after injection (6). Although dynamic changes in MR image contrast may be caused by faster T2* relaxation or magnetic susceptibilities caused by the agent, these effects are estimated to be much lower than the CEST effect, so that the dynamic changes in MR image contrast are attributed to CEST effect of the agent. These principles were used to detect the accumulation of a PARACEST agent, Tm-DOTA-Gly, within the tumor tissue of a mouse model of MCF-7 human mammary carcinoma (6).
[PubMed]
Tm-DOTA-Gly was synthesized using previously published methods (3, 4). N-(2-Bromoethanoyl) ethyl glycinate was synthesized from bromoethanoyl bromide (0.12 mol) and glycine ethyl ester (0.1 mol). N-(2-Bromoethanoyl) ethyl glycinate (41 mmol) was coupled to cyclen (1,3,5,7-tetraazacyclododecane, 10 mmol) to yield DOTA-Gly-OEt, which was synthesized by exhaustive alkylation of cyclen with N-(2-bromoethanoyl) ethyl glycinate in the presence of K2CO3 (80 mmol) as base (6). The reaction was carried out in acetonitrile by heating at 70°C for 6 h under N2 purging. The solution was cooled to room temperature, and the undissolved materials were removed by filtration. The product was obtained by evaporating the solvent (quantitative yield).
To convert the ethyl ester of DOTA-Gly-OEt (10 mmol) to a carboxylic acid, the hydrolysis reaction was carried out in ethanol/water (1:1) at 60°C by controlling pH with 1N-NaOH solution (pH~11). The reaction was traced with TLC and it was completed after 1h. The reaction mixture was cooled and acidified to pH 3 with 1N-HCl. The solution was lyophilized to produce solids. To purify DOTA-Gly, the solids were dissolved in small amounts of water and separated from the solution by liquid chromatography (yield: 80%). NMR spectroscopy was used to identify the purified product.
DOTA-Gly (1 mmol) was dissolved in water (5 mL) at pH 6.5 and 40 °C, and TmCl3 (1 mmol) in water (3 mL) was added drop by drop for 1 hr and adjusted to pH 7.5 with 0.1-N NaOH solution. The solution was stirred for 12 hrs at 60 °C and adjusted to pH 7.5 whenever the pH dropped below 5. The reaction mixture was cooled to room temperature. The pH was adjusted to 9 and the residual lanthanide-hydroxide white precipitate was removed by filtration. The complete complexation was evaluated with an Arsenazo III color test, which showed negative results for lanthanide free condition. The solution was freeze dried, yielding Tm-DOTA-Gly (yield: 94%). NMR spectroscopy was used to identify the purified product.
[PubMed]
A mouse model with a subcutaneous flank tumor of MCF-7 human mammary carcinoma in athymic NCR nu/nu mouse was successfully applied to a Dynamic Contrast Effect (DCE) CEST MRI study (6). A single mouse was used in this preliminary study. A continuous series of CEST MR images were acquired with selective saturation applied at -51 ppm, which corresponded to the MR chemical shift of the amide protons of Tm-DOTA-Gly. The total acquisition time for one presat-Rapid Acquisition with Relaxation Enhancement (RARE) image was 80 s. A solution of 1 M Tm-DOTA-Gly in 100 μL injection volume (4.0 mmol/kg) was infused within 30 s immediately after the third PARACEST MR image was acquired. After infusing the agent, the CEST MR images of the tumor became increasingly darker relative to the CEST MR images of the tumor prior to infusion. The CEST contrast was quantified at each time point after infusion by comparing the darker CEST MR signal at a particular time point with the brighter average MR signal amplitude during the first 3 CEST MR images acquired before infusion. This procedure avoided an interruption in continuous selective saturation at a single MR frequency. The T1 relaxation time of the flank tumor was measured to be 3.08 s, which was sufficiently long for a presat-RARE sequence with a RARE factor of 16 while still retaining good CEST detection. To achieve a 99% probability that the contrast before and after injection of the agent was different, the contrast-to-noise (CNR) must reach 3√2 (8). The 99% CNR probability threshold was achieved 21 min after injection of the agent, when a 1.97% change in contrast was observed. This change in contrast was attributed to the dynamic increase in the concentration of the agent in the in vivo tumor tissue. Although this dynamic change in contrast may be partly due to a dynamic change in the T2 relaxation rate of water or a dynamic change in magnetic susceptibilities caused by the agent, these effects are estimated to be insufficient to account for this change in image contrast. Therefore the change in image contrast was attributed to the CEST effect of Tm-DOTA-Gly.
R24CA110943
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