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(Circulation. 2003;107:326.)
© 2003 American Heart Association, Inc.

Basic Science Reports

Positron-Emission Tomography Reporter Gene Expression Imaging in Rat Myocardium

Masayuki Inubushi, MD; Joseph C. Wu, MD; Sanjiv S. Gambhir, MD, PhD; Gobalakrishnan Sundaresan, PhD; Nagichettiar Satyamurthy, PhD; Mohammad Namavari, PhD; Simon Yee, PhD; Jorge R. Barrio, PhD; David Stout, PhD; Arion F. Chatziioannou, PhD; Lily Wu, MD; Heinrich R. Schelbert, MD, PhD

From the Department of Molecular and Medical Pharmacology, The Crump Institute for Molecular Imaging, and Department of Urology, University of California, Los Angeles.

Correspondence to Heinrich R. Schelbert, MD, PhD, Department of Molecular and Medical Pharmacology, UCLA School of Medicine, B2-086J CHS, Box 951735, Los Angeles, CA 90095-1735. E-mail hschelbert{at}mednet.ucla.edu

Background— This study examines the quantitative accuracy, detection sensitivity, and time course of imaging the expression of a mutant herpes simplex type-1 virus thymidine kinase (HSV1-sr39tk) PET reporter gene in rat myocardium by using the PET reporter probe 9-(4-[¹⁸F]-Fluoro-3-Hydroxymethylbutyl)-Guanine ([¹⁸F]-FHBG) and a small-animal PET (microPET).

Methods and Results— In 40 rats, adenovirus expressing HSV1-sr39tk driven by a cytomegalovirus promoter (Ad-CMV-HSV1-sr39tk, 1x10⁶ to 1x10⁹ pfu) was injected through a thoracotomy directly into the left ventricular myocardium. After 3 days, myocardial perfusion was imaged with [¹³N]-ammonia for delineating the left ventricular myocardium, followed by imaging the expression of the reporter gene with intravenous [¹⁸F]-FHBG. The total myocardial [¹⁸F]-FHBG accumulation was quantified in percent of injected dose (%ID). Immunohistochemistry and autoradiography demonstrated HSV1-sr39tk enzyme (HSV1-sr39TK) and accumulation of [¹⁸F]-FHBG in the inoculated myocardium in 3 rats each. In 24 rats with various viral titers, the %ID was correlated with ex vivo well counting (r²=0.981, P<0.0001) and myocardial HSV1-sr39TK activity by tissue enzyme activity assay (r²=0.790, P<0.0001). Myocardial [¹⁸F]-FHBG accumulation was identified at viral titers down to 1x10⁷ pfu. In 6 rats serially imaged up to day 17, myocardial [¹⁸F]-FHBG accumulation on microPET peaked on days 3 to 5 and was no longer identified on days 10 to 17.

Conclusions— HSV1-sr39tk reporter gene expression can be monitored with [¹⁸F]-FHBG and microPET in rat myocardium quantitatively and serially with high detection sensitivity. Cardiac PET reporter gene imaging offers the potential of monitoring the expression of therapeutic genes in cardiac gene therapy.

Key Words: nuclear medicine • imaging • genes • myocardium • gene therapy

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