Brain temperature by Biosensor Imaging of Redundant Deviation in Shifts (BIRDS): comparison between TmDOTP5- and TmDOTMA-

Abstract

Chemical shifts of complexes between paramagnetic lanthanide ions and macrocyclic chelates are sensitive to physiological variations (of temperature and/or pH). Here we demonstrate utility of a complex between thulium ion (Tm(3+)) and the macrocyclic chelate 1,4,7,10-tetramethyl 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate (or DOTMA(4-)) for absolute temperature mapping in rat brain. The feasibility of TmDOTMA(-) is compared with that of another Tm(3+)-containing biosensor which is based on the macrocyclic chelate 1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetrakis(methylene phosphonate) (or DOTP(8-)). In general, the in vitro and in vivo results suggest that Biosensor Imaging of Redundant Deviation in Shifts (BIRDS) which originate from these agents (but exclude water) can provide temperature maps with good accuracy. While TmDOTP(5-) emanates three major distinct proton resonances which are differentially sensitive to temperature and pH, TmDOTMA(-) has a dominant pH-insensitive proton resonance from a -CH(3) group to allow higher signal-to-noise ratio (SNR) temperature assessment. Temperature (and pH) sensitivities of these resonances are practically identical at low (4.0T) and high (11.7T) magnetic fields and at nominal repetition times only marginal SNR loss is expected at the lower field. Since these resonances have extremely short relaxation times, high-speed chemical shift imaging (CSI) is needed to detect them. Repeated in vivo CSI scans with BIRDS demonstrate excellent measurement stability. Overall, results with TmDOTP(5-) and TmDOTMA(-) suggest that BIRDS can be reliably applied, either at low or high magnetic fields, for functional studies in rodents.

Figure 1. ¹H spectra and temperature calibration of Tm³⁺ containing complexes

Structures and ¹H spectra of (A) TmDOTP⁵⁻ and (B) TmDOTMA⁻ (at 11.7T, 35 °C, pH 7.4). The inset (in A) compares sensitivity of BIRDS with TmDOTMA⁻ vs. TmDOTP⁵⁻ (spectrum of a sample containing equivalent concentration of each compound). The −CH₃ protons of TmDOTMA⁻ have ~5× higher SNR than the H6 proton of TmDOTP⁵⁻. Temperature and pH dependencies of (C) H6 proton of TmDOTP⁵⁻ (for H2 and H3 protons see ref. (29)) and (D) −CH₃ protons of TmDOTMA⁻. Temperature and/or pH dependencies of proton resonances of Tm³⁺ containing complexes (eq. [1]) are derived from a multi-parametric database (at 11.7T) consisting of chemical shift (δ), temperature (T) and pH and can be suitably portrayed in 3D surface plots. Calibration for TmDOTMA⁻ is simplified by the fact that the resonance of the −CH₃ protons is unaffected by pH (eq. [4]; Supplementary Tab. 1). In contrast, calibration of TmDOTP⁵⁻ has to simultaneously account for relationships between δ vs. T as well as δ vs. pH (29).

Figure 2. SNR effects on BIRDS

(A) Effect of spectral SNR on temperature determination. Temperature standard deviations (σ_T) calculated at various SNR values were used to estimate temperature accuracy. Open and closed symbols, respectively, represent the H6 proton of TmDOTP⁵⁻ and −CH₃ protons of TmDOTMA⁻. See ref. (29) for pH standard deviations (σ_pH) calculated at various SNR values. (B) Sensitivity of BIRDS at different magnetic fields assessed by SNR of the proton resonance from the agent in a capillary tube sample. Squares and circles, respectively, represent data from −CH₃ protons of TmDOTMA⁻ at 4.0T and 11.7T. Similar trends were observed with H6 protons of TmDOTP⁵⁻ (data not shown). Total data acquisition time at each TR was the same. See Tab. 1 (and Supplementary Tab. 1) for temperature (and pH) sensitivities of BIRDS with TmDOTP⁵⁻ and TmDOTMA⁻.

Figure 3. Temperature (and pH) mapping in vitro with BIRDS

The phantom – containing either TmDOTP⁵⁻ (left) or TmDOTMA⁻ (right) – consisted of two parallel glass tubes with different pH (left 7.4, right 7.0) and using a water-heating blanket the temperature was changed in both tubes identically. (A) 2D ¹H CSI datasets with TmDOTP⁵⁻ (left) and TmDOTMA⁻ (right) phantoms. (B) Examples of ¹H spectra from CSI voxels (boxed in A), a pair from the TmDOTP⁵⁻ phantom (left) and another pair from the TmDOTMA⁻ phantom (right), at pH of 7.4 (top) and 7.0 (bottom). (C) Temperature distributions in TmDOTP⁵⁻ (left) and TmDOTMA⁻ (right) phantoms at two different water-bath temperatures, 45 °C (top) and 35 °C (bottom). Note that the TmDOTP⁵⁻ phantom shows similar temperature distributions as with the TmDOTMA⁻ phantom, but in addition it allows accurate distribution of pH.

Figure 4. Temperature (and pH) mapping in vivo with BIRDS

(A) 2D ¹H CSI datasets after infusion of TmDOTP⁵⁻ (left) and TmDOTMA⁻ (right) in the rat. Concentrations of TmDOTP⁵⁻ and TmDOTMA⁻ in the CSI voxel were about 4 and 3 mM, respectively, at infusion doses of 1.0 and 0.5 mmol/kg (Tab. 2). (B) Temperature distributions in cerebral cortex of the rat measured by TmDOTP⁵⁻ (left) and TmDOTMA⁻ (right). (C) Examples of ¹H spectra from CSI voxels (boxed in A), one from the TmDOTP⁵⁻ infused brain (left) and the other from the TmDOTMA⁻ infused brain (right). (D) Temporal stability of temperature (±0.21 and ±0.13 °C, respectively, for TmDOTP⁵⁻ and TmDOTMA⁻) in the CSI voxels (boxed in A), where open and filled symbols represent data from TmDOTP⁵⁻ and TmDOTMA⁻, respectively. See Supplementary Fig. 2 for pH mapping in vivo.