Development and application of a multimodal contrast agent for SPECT/CT hybrid imaging

Abstract

Hybrid or multimodality imaging is often applied in order to take advantage of the unique and complementary strengths of individual imaging modalities. This hybrid noninvasive imaging approach can provide critical information about anatomical structure in combination with physiological function or targeted molecular signals. While recent advances in software image fusion techniques and hybrid imaging systems have enabled efficient multimodal imaging, accessing the full potential of this technique requires development of a new toolbox of multimodal contrast agents that enhance the imaging process. Toward that goal, we report the development of a hybrid probe for both single photon emission computed tomography (SPECT) and X-ray computed tomography (CT) imaging that facilitates high-sensitivity SPECT and high spatial resolution CT imaging. In this work, we report the synthesis and evaluation of a novel intravascular, multimodal dendrimer-based contrast agent for use in preclinical SPECT/CT hybrid imaging systems. This multimodal agent offers a long intravascular residence time (t(1/2) = 43 min) and sufficient contrast-to-noise for effective serial intravascular and blood pool imaging with both SPECT and CT. The colocalization of the dendritic nuclear and X-ray contrasts offers the potential to facilitate image analysis and quantification by enabling correction for SPECT attenuation and partial volume errors at specified times with the higher resolution anatomic information provided by the circulating CT contrast. This may allow absolute quantification of intramyocardial blood volume and blood flow and may enable the ability to visualize active molecular targeting following clearance from the blood.

Figure 1

Schematic of the synthesis of ^99mTc-labeled G4-[[[[Ac]-TIBA]-DTPA]-mPEG₁₂].

Figure 2

¹H NMR characterization of the synthetic route to G4-[[[[Ac]-TIBA]-DTPA]-mPEG₁₂]. ¹H NMR spectra were acquired at 400 MHz for 20 mg/mL solutions of (a) G4-[Ac], (b) G4-[[Ac]-TIBA], (c) G4-[[[Ac]-TIBA]-DTPA], and (d) G4-[[[[Ac]-TIBA]-DTPA]-mPEG₁₂] in D₂O. Peaks are labeled according to the following: (1) 1.91 (COCH₃), (2) 2.28-2.42 (C-CH₂CONH), (3) 2.50-2.61 N-CH₂CH₂NH), (4) 2.68-2.80 (N-CH₂CH₂CO), (5) 3.14-3.36 (CONH-CH₂), (6) 7.49 and 8.21 (TIBA aromatic), (7) 7.18 and 7.27 (DTPA aromatic), and (8) 3.5-3.76 (-OCH₂CH₂).

Figure 3

X-ray attenuation measurements. Phantom images of serial dilutions of G4-[[[[Ac]-TIBA]-DTPA]-mPEG₁₂] in deionized H₂O acquired at 90 kVp. The intensity values obtained in Hounsfield units averaged over 3D-based ROIs were plotted against iodine concentration. Iodine concentrations for G4-[[[[Ac]-TIBA]-DTPA]-mPEG₁₂] were extrapolated from the linear attenuation calibration curve for Omnipaque 350 (Supporting information) and compared to those estimated from ¹H NMR.

Figure 4

Biodistribution of ^99mTc-labeled G4-[[[[Ac]-TIBA]-DTPA]-mPEG₁₂]. The biodistribution of ^99mTc-labeled G4-[[[[Ac]-TIBA]-DTPA]-mPEG₁₂] revealed relatively long blood residence with predominant renal clearance and excretion.

Figure 5

Serial microCT and multimodal microSPECT/CT blood pool imaging. (a) Following acquisition of a pre-contrast image and subsequent intravenous jugular vein injection of 50 mg of G4-[[[[Ac]-TIBA]-DTPA]-mPEG₁₂] dissolved in 0.3 mL sterile 1x PBS (10 minute duration), serial short axis images of the RV/LV blood pool showing significant contrast enhancement were acquired from 0-90 minutes post-injection. Following intravenous jugular vein injection (10 minute duration) of a 440 ± 26 μCi dose of the radiolabeled dendrimer construct (50 mg of ^99mTc-labeled G4-[[[[Ac]-TIBA]-DTPA]-mPEG₁₂] dissolved in 0.3 mL chelation solution), post-mortem microSPECT/CT images of the heart were acquired. The fusion of the (b) microCT and (c) microSPECT coronal images presented in (d) shows significant co-localization of the nuclear and X-ray contrast components.