Journal of Nuclear Medicine | |
Synthesis and Evaluation of a Series of 99mTc(CO)3+ Lisinopril Complexes for In Vivo Imaging of Angiotensin-Converting Enzyme Expression | |
John W. Babich1  John L. Joyal1  Frank J. Femia1  Kevin P. Maresca1  Omer Aras1  Shawn M. Hillier1  John A. Barrett1  William C. Eckelman1  Craig N. Zimmerman1  Vasken Dilsizian1  | |
关键词: lisinopril; 99mTc; angiotensin-converting enzyme (ACE); congestive heart failure; SPECT; | |
DOI : 10.2967/jnumed.107.049064 | |
学科分类:医学(综合) | |
来源: Society of Nuclear Medicine | |
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【 摘 要 】
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 ε-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(Cx)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.
【 授权许可】
Unknown
【 预 览 】
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