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Imaging hNET Reporter Gene Expression with ¹²⁴I-MIBG

¹ Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York; ² Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, New York; ³ Cyclotron and Radiochemistry Core Facility, Memorial Sloan-Kettering Cancer Center, New York, New York; ⁴ Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, New York; and ⁵ Memorial Hospital Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, New York

Correspondence: For correspondence or reprints contact: Ronald G. Blasberg, MD, Departments of Neurology and Radiology, MH (Box 52), Molecular Pharmacology and Chemistry Program, SKI, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, New York 10021. E-mail: blasberg{at}neuro1.mskcc.org

The norepinephrine transporter (NET) has recently been suggested as a useful reporter gene. We have extended this effort by constructing an internal ribosomal entry site (IRES)-linked hNET-green fluorescent protein (GFP) hybrid reporter gene for both nuclear and optical imaging. Methods: A retroviral vector pQCXhNET-IRES-GFP was constructed and used to generate several reporter cell lines and xenografts. Transduced cells were sorted by fluorescence-activated cell sorting based on GFP expression and used for both in vitro and in vivo imaging studies. Results: The transduced reporter cells accumulated ¹²³I- or ¹²⁴I-labeled metaiodobenzylguanidine (MIBG) to high levels compared with the wild-type parent cell lines. Differences in MIBG accumulation between cell lines were primarily due to differences in influx (K₁) rather than efflux (k₂). The estimated MIBG distribution volumes (V_d) for transduced Jurkat, C6, and COS-7 cells were 572 ± 13, 754 ± 25, and 1,556 ± 38 mL/g, respectively. A correlation between radiotracer accumulation (K₁) and GFP fluorescence intensity was also demonstrated. Sequential imaging studies of mice bearing pQCXhNET-IRES-GFP transduced and wild-type C6 xenografts demonstrated several advantages of ¹²⁴I-MIBG small-animal PET compared with ¹²³I-MIBG -camera/SPECT. This was primarily due to the longer half-life of ¹²⁴I and to the retention and slow clearance (half-time, 63 ± 6 h) of MIBG from transduced xenografts compared with that from wild-type xenografts (half-time, 12 ± 1 h) and other organs (half-time, 2.6–21 h). Very high radioactivity ratios were observed at later imaging times; at 73 h after ¹²⁴I-MIBG injection, the C6/hNET-IRES-GFP xenograft-to-muscle ratio was 293 ± 48 whereas the C6 xenograft-to-muscle ratio was 0.71 ± 0.19. Conclusion: These studies demonstrate the potential for a wider application of hNET reporter imaging and the future translation to patient studies using radiopharmaceuticals that are currently available for both SPECT and PET.

Key Words: human norepinephrine transporter • ¹²⁴I-MIBG • ¹²³I-MIBG • PET • -camera • SPECT • molecular imaging • reporter gene

^* Contributed equally to this work.

COPYRIGHT © 2007 by the Society of Nuclear Medicine, Inc.

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