Southwestern In Vivo Cellular and Molecular Imaging Program

Novel Small Animal Imaging Techniques
(Instrumentation)
(Lead Scientist: Peter Antich, Ph.D., D.Sc.)

Dr.Peter Antich (Director Advanced Radiological Sciences) leads a program of instrument development related to medical imaging (PET, SPECT and ultrasound). Most notably this has led to the development of a high resolution small animal imaging PET device.

This core facility will not only provide a resource for the Pre-ICMIC, but continue to develop advanced imaging instrumentation (laboratory and clinical) through industrially supported research. Currently, a three-man development team led by Dr. Edward Tsyganov operates the small animal imaging devices and is engaged in active research (materials science, mechanics, electronics, analysis algorithms) to enhance the equipment. Image coregistration with MR, if necessary for the study, will be done in collaboration with Dr. McColl (Core 7). 

• Small animal PET device (Figure)

• Images of phantom obtained using small animal PET device (Figure)

• Quantitative validation of small animal PET device (Figure)

Small animal SPECT is feasible on clinical systems, which are optimized for high energy ^99mTc. Dr. Antich's small animal instrument incorporates novel technology providing enhanced sensitivity at low energy. Traditional SPECT is associated with high energy isotopes (e.g., ^99mTc, 0.14 MeV; ¹³¹I, 0.35 MeV) making collimation and spatial definition difficult due to Compton scattering and thick shielding requirements. Iodine-125 has been largely neglected since the electron capture decay produces low energy emissions, which are heavily attenuated by tissue. This actually provides a unique opportunity to achieve extremely high resolution by using a multiple pin-hole collimation device requiring little shielding.

Advantages of ¹²⁵I include:

1) Long half-life (t_1/2 ~60 days, vs. 6 h ^99mTc, 8 days ¹³¹I). This places less stringent requirements on speed of synthesis of tagged molecules, increases shelf-life of products, increases feasible imaging time and allows agents to be followed for long-term biodistribution studies.

2) Low-energy (35 keV vs. 350 keV for ¹³¹I) Less stringent shielding requirements for collimation and safety. Photoelectrons are generated at specific location by single photoelectric absorption rather than multiple Compton scatters.

3) Range of labeling. Iodination of proteins is well established and straightforward. There is extensive literature describing labeling procedures for antibodies, blood volume markers etc.

While less satisfactory in large animals, low energy photon emission is well suited for imaging mice, as their low mass and size do not produce excessive attenuation. Given the abundant availability of gene-knock-out mice (models of disease pathology) and SCID mice (implanted with human tumors), this provides a rich array of models for biomedical investigations. Moreover, ready iodination of antibodies, drugs, hormones, and metabolites ensures many significant applications (e.g., tumor detection and antibody delivery). Investigations will be closely integrated with Core 3. All nuclear medicine investigations related to animals will be conducted by Dr. Anca Constantinescu, an expert in radiolabeling, isolation, quality control and animal handling.

Gene Reporters
(Non-Invasive Assays)
(Lead Scientist: Ralph P. Mason, Ph.D.)

Effective non-invasive assays require two components: highly sensitive and specific molecular reporter molecules and highly sensitive detection instrumentation. Based on our background in developing fluorinated physiological reporter molecules, we will pursue novel approaches specifically designed to assess gene transfection and expression. Recently green fluorescent protein (followed by red and blue analogues) has been applied as an expression marker, but relatively transparent or superficial tissues are required for effective in vivo visualization. Some evidence also suggests that GFP expression may interfere with normal cell division, at least for clonogenic capacity of cobblestone area forming cells (CAFCs). As reviewed by Bogdanov and Weissleder several “imaging marker genes” (IMGs) have been demonstrated for PET and SPECT using various ¹⁸F and ¹²⁵I radio labeled ribonucleic acid analogues in conjunction with HSV-tk (herpes simplex virus thymidine kinase). Among other genes cytosine deaminase (CD), tyrosinase and transferrin have been exploited. For NMR it has been shown that conversion of 5-fluorocytosine to 5-fluorouracil induces a 2 ppm chemical shift in the ¹⁹F NMR resonance. Several groups have used this to detect expression of CD in cells in culture and limited studies are reported in vivo. Recently, it has been suggested that a galactopyranose-capped gadolinium chelate reported b-gal expression in developing xenopus laevis (frog) embryos. However, this first generation reporter molecule does not enter cells, requiring intra cellular injection and shows enzyme activity “a few orders of magnitude” less than the usual ONPG used colorimetrically.

While proton contrast agents interact with 55 molar water, a potentially enormous signal, they actually are exploited in terms of induced image contrast changes only, and thus, the critical parameter is contrast to noise. ¹⁹F NMR agents are typically used at millimolar concentration, but there is essentially no competing background signal. We are developing new classes of ¹⁹F reporter molecules.

For Further Information Contact: RALPH  P. MASON, Ph.D.
Page Maintained by: Lan Jiang, M.Sc.
Page Created by: Robert Bollinger II
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