Published Online
on June 17, 2002

A more recent version of this article appeared on July 9, 2002

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Submitted on March 12, 2002
Revised on May 7, 2002
Accepted on May 7, 2002

Positron Emission Tomography Imaging of Cardiac Reporter Gene Expression in Living Rats

Joseph C. Wu MD, Masayuki Inubushi MD, Gobalakrishnan Sundaresan PhD, Heinrich R. Schelbert MD, and Sanjiv S. Gambhir MD, PhD^*

From Crump Institute for Molecular Imaging (J.C.W., G.S., S.S.G.); Department of Molecular and Medical Pharmacology (J.C.W., M.I., G.S., H.S., S.S.G.); Jonsson Comprehensive Cancer Center (S.S.G.); and Department of Medicine, Division of Cardiology (J.C.W.), UCLA School of Medicine, Los Angeles, Calif.

^* To whom correspondence should be addressed. E-mail: sgambhir{at}mednet.ucla.edu.

Background—Imaging reporter gene expression is useful for noninvasive monitoring of gene therapy. In this study, we imaged cardiac reporter gene expression in living rats using micro positron emission tomography (microPET).

Methods and Results—Rats (n=10) underwent intramyocardial injection with 1x10⁹ pfu of adenovirus carrying cytomegalovirus promoter-driving herpes simplex virus type 1 mutant thymidine kinase (Ad-CMV-HSV1-sr39tk) as PET reporter gene. Control rats (n=4) received 1x10⁹ pfu of adenovirus carrying cytomegalovirus promoter-driving firefly luciferase (Ad-CMV-Fluc). On days 2 to 4, microPET images were obtained after a tail vein injection of nitrogen-13 ammonia ([¹³N]-NH₃) as myocardial perfusion tracer, followed by 9-(4-[¹⁸F]-fluoro-3 hydroxymethylbutyl) guanine ([¹⁸F]-FHBG) to assess HSV1-sr39tk expression. After imaging, hearts were removed for ex vivo [¹⁸F] gamma counting and thymidine kinase enzyme assay. Results show homogenous myocardial distribution of [¹³N]-NH₃ on all microPET images. Rats injected with Ad-CMV-HSV1-sr39tk have significant [¹⁸F]-FHBG uptake in the anterolateral wall compared with background signal in controls. Gamma counting shows 20.0±4.4-fold increase of radioactivity, whereas enzyme assay shows 22.1±6.1-fold increase of thymidine kinase activity in Ad-CMV-HSV1-sr39tk injected rats (P<0.05).

Conclusions—Successful imaging of cardiac HSV1-sr39tk expression was performed in living rats with microPET. The presence of [¹⁸F]-FHBG uptake is confirmed by gamma counting and the presence of HSV1-sr39TK protein by thymidine kinase enzyme assay. Cardiac reporter gene imaging by PET may eventually be applied toward human gene therapy studies.

Key words: gene therapy • viruses • heart diseases • imaging • nuclear medicine

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