In vivo three‐dimensional molecular imaging with Biosensor Imaging of Redundant Deviation in Shifts (BIRDS) at high spatiotemporal resolution

Abstract

Spectroscopic signals which emanate from complexes between paramagnetic lanthanide III ions (e.g., Tm3+) and macrocyclic chelates (e.g., 1,4,7,10-tetramethyl 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate, or DOTMA4−) are sensitive to physiology (e.g., temperature and/or pH). Because non-exchanging protons from these lanthanide-based macrocyclic agents have relaxation times on the order of a few milliseconds, rapid data acquisition is possible with chemical shift imaging (CSI). Thus Biosensor Imaging of Redundant Deviation in Shifts (BIRDS) which originate from non-exchanging protons of these paramagnetic agents, but exclude water proton detection, can allow molecular imaging. Previous 2D CSI experiments with such lanthanide-based macrocyclics allowed acquisition from ~12 µL voxels in rat brain within 5 minutes using rectangular encoding of k-space. Because cubical encoding of k-space in 3D for whole brain coverage increases CSI acquisition time to several tens of minutes or more, a faster CSI technique is required for BIRDS to be of practical use. Here we demonstrate a CSI acquisition method to improve 3D molecular imaging capabilities with lanthanide-based macrocyclics. Using TmDOTMA−, we show datasets from a 20×20×20 mm3 field-of-view with voxels of ~1 µL effective volume acquired within 5 minutes (at 11.7T) for temperature mapping. By employing reduced spherical encoding with Gaussian weighting (RESEGAW) instead of cubical encoding of k-space, a significant increase in CSI signal is obtained. In vitro and in vivo 3D CSI data with TmDOTMA−, and presumably similar lanthanide-based macrocyclics, suggest that acquisition using RESEGAW can be used for high spatiotemporal molecular mapping with BIRDS.

Characterization of a lanthanide complex encapsulated with MRI contrast agents into liposomes for biosensor imaging of redundant deviation in shifts (BIRDS)

“…In comparison, the √(T 2 /T 1 ) ratio for diamagnetic proton signals is in the range of 0.01-0.1 (31). Thus high spatial resolution CSI is possible with BIRDS (3-5). Signal averaging is enhanced without cost of additional acquisition time because T 1 of paramagnetically shifted protons is usually a few ms.…”

“…The excitation of H2, H3 and H6 protons was achieved using a single-banded refocused 90° Shinnar-Le Roux (SLR) RF pulse of 30 kHz bandwidth and 300 μs duration. The CSI datasets were acquired using reduced spherical encoding with uniform sampling of k-space with 1743 encoding steps (5) with a recycle time (TR) of 8 ms, 32 averages per encoding step, 2048 points per FID, and a field of view (FOV) of 32×32×32 mm 3 . The phase encode gradient duration was 136 μs and the spectral window was 192 kHz.…”

“…In other words, the BIRDS approach bypasses the need to detect relaxation of abundant water protons, but instead focuses on the chemical shift of dilute non-exchangeable protons on lanthanide complexes like TmDOTP 5− and TmDOTMA − . Moderately high resolution BIRDS data are possible with optimally designed probes and/or improved chemical shift imaging (CSI) schemes (5), because the magnetic resonance properties of the non-exchangeable protons on paramagnetic probes like TmDOTP 5− and TmDOTMA − are quite unusual (e.g., ultra-short relaxation times, highly broadened peaks, hyperfine shifted peaks, etc. ).…”

“…It should be noted, however, that the best CSI resolution of 1 μL for 3 dimensional (i.e., 3D) imaging with BIRDS of the whole rat brain in merely a few minutes that has been achieved with 0.5 mmol/kg of TmDOTMA − (5) can be further improved using faster imaging (e.g., shorter recycle time, faster gradient switching to higher amplitudes, etc) and increased signal-to-noise ratio (SNR). To improve BIRDS sensitivity further with liposomal encapsulation of the lanthanide monomer (i.e., for improved monitoring of disease status with BIRDS) and considering the possibility of combining BIRDS with other T 1 and T 2 agents typically used for MRI (i.e., to generate superior contrast for disease diagnosis with MRI), we postulated that BIRDS would stand resilient in the presence of large perturbing paramagnetic fields generated by strong T 1 and T 2 contrast agents like Magnevist and Molday ION respectively, especially in nanocarriers like liposomes.…”

Dendrimer-Based Responsive MRI Contrast Agents (G1–G4) for Biosensor Imaging of Redundant Deviation in Shifts (BIRDS)

“…While short T 2 values can be problematic for conventional NMR detection because the SNR of a Lorentzian line decreases, the short T 2 values for the resonances in dendrimers are useable for molecular imaging because of ultra-high-speed CSI needed for BIRDS. 17 Future improvements in scanner digitizers in conjunction with pulse sequence and coil designs would further facilitate the detection of short T 2 resonances such as in the higher generation dendrimers. For example, ultrashort TE chemical shift imaging could be integrated to improve SNR in BIRDS of paramagnetic dendrimers further.…”