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Synthesis and Evaluation of a Series of ^99mTc(CO)₃⁺ Lisinopril Complexes for In Vivo Imaging of Angiotensin-Converting Enzyme Expression

¹ Molecular Insight Pharmaceuticals Inc., Cambridge, Massachusetts; and ² Department of Nuclear Medicine, University of Maryland, Baltimore, Maryland

Correspondence: For correspondence or reprints contact: John W. Babich, Molecular Insight Pharmaceuticals Inc., 160 Second St., Cambridge, MA 02142. E-mail: jbabich{at}molecularinsight.com

In animal models of cardiac disease and in human congestive heart failure, expression of angiotensin-converting enzyme (ACE) is upregulated in the failing heart and has been associated with disease progression leading to cardiac failure and fibrosis. To develop probes for imaging ACE expression, a series of di(2-pyridylmethyl)amine (D) chelates capable of binding M(CO)₃⁺ (M = technetium, rhenium) was conjugated to lisinopril by acylation of the -amine of the lysine residue with a series of di(2-pyridylmethylamino)alkanoic acids where the distance of the chelator from the lisinopril core was investigated by varying the number of methylene spacer groups to produce di(2-pyridylmethyl)amine(C_x)lisinopril analogs: D(C₄)lisinopril, D(C₅)lisinopril, and D(C₈)lisinopril. The inhibitory activity of each rhenium complex was evaluated in vitro against purified rabbit lung ACE and was shown to vary directly with the length of the methylene spacer: Re[D(C₈)lisinopril], inhibitory concentration of 50% (IC₅₀) = 3 nM; Re[D(C₅)lisinopril], IC₅₀ = 144 nM; and Re[D(C₄)lisinopril], IC₅₀ = 1,146 nM, as compared with lisinopril, IC₅₀ = 4 nM. The in vivo specificity for ACE was determined by examining the biodistribution of the ^99mTc-[D(C₈)lisinopril] analog in rats with and without pretreatment with unlabeled lisinopril. Uptake in the lungs, a tissue that constitutively expresses ACE, was 15.2 percentage injected dose per gram at 10 min after injection and was dramatically reduced by pretreatment with lisinopril, supporting ACE-mediated binding in vivo. Planar anterior imaging analysis of ^99mTc-[D(C₈)lisinopril] corroborated these data. Thus, high-affinity ^99mTc-labeled ACE inhibitor has been designed with potency similar to that of lisinopril and has been demonstrated to specifically localize to tissues that express ACE in vivo. This agent may be useful in monitoring ACE as a function of disease progression in relevant diseases such as heart failure.

Key Words: lisinopril • ^99mTc • angiotensin-converting enzyme (ACE) • congestive heart failure • SPECT

COPYRIGHT © 2008 by the Society of Nuclear Medicine, Inc.

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