Open Access

Preliminary evaluation of 18F‑AlF‑NOTA‑MAL‑Cys40‑Exendin‑4 in rodent heart after myocardial ischemia and reperfusion

  • Authors:
    • Xietian Pan
    • Qing Xu
    • Jiangwei Chen
    • Tingting Wang
    • Mingming Zhang
    • Haichang Wang
    • Haokao Gao
  • View Affiliations

  • Published online on: June 27, 2019     https://doi.org/10.3892/mmr.2019.10432
  • Pages: 2276-2284
  • Copyright: © Pan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Glucagon‑like peptide‑1 (GLP‑1) and its receptor (GLP‑1R) exert cardioprotective effects after myocardial ischemia and reperfusion (MI/R) in animal models and human clinical trials. Receptor imaging with positron emission tomography (PET) provides a non‑invasive method for monitoring GLP‑1R expression. In the present study, a fluorine‑18‑labeled aluminum fluoride exendin‑4 analog [18F‑AlF conjugated with 1,4,7‑triazacyclononanetriacetic acid (NOTA)‑maleimide (MAL)‑Cys40‑exendin‑4] was synthesized and evaluated in a rat MI/R model for GLP‑1R imaging. NOTA‑MAL‑Cys40‑exendin‑4 was synthesized by coupling Cys40‑exendin‑4 with NOTA‑MAL. NOTA‑MAL‑Cys40‑exendin‑4 was then conjugated with 18F‑AlF to obtain 18F‑AlF‑NOTA‑MAL‑Cys40‑exendin‑4. The yield of 18F‑AlF‑NOTA‑MAL‑Cys40‑exendin‑4 was 18.5±3.4% (not decay corrected). The process was completed within ~30 min. In rat MI/R models, the tracer exhibited specific binding to GLP‑1R and an appropriate signal‑to‑noise ratio. At 8 h post‑MI/R, tracer uptake reached its peak [0.35±0.053% of injected dose (%ID)/g; n=6] in ischemic myocardium. Localized tracer uptake decreased 1 day (0.20±0.032 %ID/g; n=6) and 3 days (0.16±0.017 %ID/g; n=6) post‑MI/R compared with 8 h post‑MI/R, but still remained higher compared with sham‑operated groups (0.06±0.012 %ID/g; n=6). Pre‑injected unlabeled exendin‑4 effectively blocked tracer accumulation (0.09±0.041 %ID/g; n=6). In conclusion, 18F‑AlF‑NOTA‑MAL‑Cys40‑exendin‑4 demonstrated favorable characteristics for GLP‑1R imaging following MI/R. PET imaging using 18F‑AlF‑NOTA‑MAL‑Cys40‑exendin‑4 in rodent hearts after MI/R revealed a dynamic pattern of GLP‑1R upregulation.

References

1 

Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, de Ferranti SD, Floyd J, Fornage M, Gillespie C, et al: Heart disease and stroke statistics-2017 update: A report from the American Heart Association. Circulation. 135:e146–e603. 2017. View Article : Google Scholar : PubMed/NCBI

2 

Jennings RB, Sommers HM, Smyth GA, Flack HA and Linn H: Myocardial necrosis induced by temporary occlusion of a coronary artery in the dog. Arch Pathol. 70:68–78. 1960.PubMed/NCBI

3 

Jordan JE, Zhao ZQ and Vinten-Johansen J: The role of neutrophils in myocardial ischemia-reperfusion injury. Cardiovasc Res. 43:860–878. 1999. View Article : Google Scholar : PubMed/NCBI

4 

Lesnefsky EJ, Chen Q, Tandler B and Hoppel CL: Mitochondrial dysfunction and myocardial ischemia-reperfusion: Implications for novel therapies. Annu Rev Pharmacol Toxicol. 57:535–565. 2017. View Article : Google Scholar : PubMed/NCBI

5 

Ferdinandy P, Hausenloy DJ, Heusch G, Baxter GF and Schulz R: Interaction of risk factors, comorbidities, and comedications with ischemia/reperfusion injury and cardioprotection by preconditioning, postconditioning, and remote conditioning. Pharmacol Rev. 66:1142–1174. 2014. View Article : Google Scholar : PubMed/NCBI

6 

Drucker DJ: The biology of incretin hormones. Cell Metab. 3:153–165. 2006. View Article : Google Scholar : PubMed/NCBI

7 

Theodorakis MJ, Carlson O, Michopoulos S, Doyle ME, Juhaszova M, Petraki K and Egan JM: Human duodenal enteroendocrine cells: Source of both incretin peptides, GLP-1 and GIP. Am J Physiol Endocrinol Metab. 290:E550–E559. 2006. View Article : Google Scholar : PubMed/NCBI

8 

Holst JJ, Deacon CF, Vilsboll T, Krarup T and Madsbad S: Glucagon-like peptide-1, glucose homeostasis and diabetes. Trends Mol Med. 14:161–168. 2008. View Article : Google Scholar : PubMed/NCBI

9 

Sonne DP, Engstrom T and Treiman M: Protective effects of GLP-1 analogues exendin-4 and GLP-1(9–36) amide against ischemia-reperfusion injury in rat heart. Regul Pept. 146:243–249. 2008. View Article : Google Scholar : PubMed/NCBI

10 

Noyan-Ashraf MH, Momen MA, Ban K, Sadi AM, Zhou YQ, Riazi AM, Baggio LL, Henkelman RM, Husain M and Drucker DJ: GLP-1R agonist liraglutide activates cytoprotective pathways and improves outcomes after experimental myocardial infarction in mice. Diabetes. 58:975–983. 2009. View Article : Google Scholar : PubMed/NCBI

11 

Bose AK, Mocanu MM, Carr RD, Brand CL and Yellon DM: Glucagon-like peptide 1 can directly protect the heart against ischemia/reperfusion injury. Diabetes. 54:146–151. 2005. View Article : Google Scholar : PubMed/NCBI

12 

Deacon CF, Johnsen AH and Holst JJ: Degradation of glucagon-like peptide-1 by human plasma in vitro yields an N-terminally truncated peptide that is a major endogenous metabolite in vivo. J Clin Endocrinol Metab. 80:952–957. 1995. View Article : Google Scholar : PubMed/NCBI

13 

Eng J, Kleinman WA, Singh L, Singh G and Raufman JP: Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma suspectum venom. Further evidence for an exendin receptor on dispersed acini from guinea pig pancreas. J Biol Chem. 267:7402–7405. 1992.PubMed/NCBI

14 

Mikkola K, Yim CB, Fagerholm V, Ishizu T, Elomaa VV, Rajander J, Jurttila J, Saanijoki T, Tolvanen T, Tirri M, et al: 64Cu- and 68Ga-labelled [Nle(14),Lys(40)(Ahx-NODAGA)NH2]-exendin-4 for pancreatic beta cell imaging in rats. Mol Imaging Biol. 16:255–263. 2014. View Article : Google Scholar : PubMed/NCBI

15 

Wild D, Behe M, Wicki A, Storch D, Waser B, Gotthardt M, Keil B, Christofori G, Reubi JC and Mäcke HR: [Lys40(Ahx-DTPA-111In)NH2]exendin-4, a very promising ligand for glucagon-like peptide-1 (GLP-1) receptor targeting. J Nucl Med. 47:2025–2033. 2006.PubMed/NCBI

16 

Sowa-Staszczak A, Pach D, Mikolajczak R, Mäcke H, Jabrocka-Hybel A, Stefańska A, Tomaszuk M, Janota B, Gilis-Januszewska A, Małecki M, et al: Glucagon-like peptide-1 receptor imaging with [Lys40(Ahx-HYNIC-99mTc/EDDA)NH2]-exendin-4 for the detection of insulinoma. Eur J Nucl Med Mol Imaging. 40:524–531. 2013. View Article : Google Scholar : PubMed/NCBI

17 

Kiesewetter DO, Gao H, Ma Y, Niu G, Quan Q, Guo N and Chen X: 18F-radiolabeled analogs of exendin-4 for PET imaging of GLP-1 in insulinoma. Eur J Nucl Med Mol Imaging. 39:463–473. 2012. View Article : Google Scholar : PubMed/NCBI

18 

Gao H, Kiesewetter DO, Zhang X, Huang X, Guo N, Lang L, Hida N, Wang H, Wang H, Cao F, et al: PET of glucagonlike peptide receptor upregulation after myocardial ischemia or reperfusion injury. J Nucl Med. 53:1960–1968. 2012. View Article : Google Scholar : PubMed/NCBI

19 

Kiesewetter DO, Guo N, Guo J, Gao H, Zhu L, Ma Y, Niu G and Chen X: Evaluation of an [(18)F]AlF-NOTA analog of exendin-4 for imaging of GLP-1 receptor in insulinoma. Theranostics. 2:999–1009. 2012. View Article : Google Scholar : PubMed/NCBI

20 

Silverman J, Mark A and Murthy S: The Iacuc Handbook. Iacuc Handbook; 2000

21 

Eltzschig HK and Eckle T: Ischemia and reperfusion-from mechanism to translation. Nat Med. 17:1391–1401. 2011. View Article : Google Scholar : PubMed/NCBI

22 

Timmers L, Henriques JP, de Kleijn DP, Devries JH, Kemperman H, Steendijk P, Verlaan CW, Kerver M, Piek JJ, Doevendans PA, et al: Exenatide reduces infarct size and improves cardiac function in a porcine model of ischemia and reperfusion injury. J Am Coll Cardiol. 53:501–510. 2009. View Article : Google Scholar : PubMed/NCBI

23 

Dawwas GK, Smith SM and Park H: Risk of heart failure hospitalization among users of dipeptidyl peptidase-4 inhibitors compared to glucagon-like peptide-1 receptor agonists. Cardiovasc Diabetol. 17:1022018. View Article : Google Scholar : PubMed/NCBI

24 

Miller PW, Long NJ, Vilar R and Gee AD: Synthesis of 11C, 18F, 15O, and 13N radiolabels for positron emission tomography. Angew Chem Int Ed Engl. 47:8998–9033. 2008. View Article : Google Scholar : PubMed/NCBI

25 

McBride WJ, D'Souza CA, Sharkey RM, Karacay H, Rossi EA, Chang CH and Goldenberg DM: Improved 18F labeling of peptides with a fluoride-aluminum-chelate complex. Bioconjug Chem. 21:1331–1340. 2010. View Article : Google Scholar : PubMed/NCBI

26 

Gao H, Niu G, Yang M, Quan Q, Ma Y, Murage EN, Ahn JM, Kiesewetter DO and Chen X: PET of insulinoma using (1)(8)F-FBEM-EM3106B, a new GLP-1 analogue. Mol Pharm. 8:1775–1782. 2011. View Article : Google Scholar : PubMed/NCBI

27 

Xu Y, Pan D, Xu Q, Zhu C, Wang L, Chen F, Yang R, Luo S and Yang M: Insulinoma imaging with glucagon-like peptide-1 receptor targeting probe (18)F-FBEM-Cys (39)-exendin-4. J Cancer Res Clin Oncol. 140:1479–1488. 2014. View Article : Google Scholar : PubMed/NCBI

28 

Korner M, Stockli M, Waser B and Reubi JC: GLP-1 receptor expression in human tumors and human normal tissues: Potential for in vivo targeting. J Nucl Med. 48:736–743. 2007. View Article : Google Scholar : PubMed/NCBI

29 

Nikolaidis LA, Mankad S, Sokos GG, Miske G, Shah A, Elahi D and Shannon RP: Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion. Circulation. 109:962–965. 2004. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

September 2019
Volume 20 Issue 3

Print ISSN: 1791-2997
Online ISSN:1791-3004

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Pan, X., Xu, Q., Chen, J., Wang, T., Zhang, M., Wang, H., & Gao, H. (2019). Preliminary evaluation of 18F‑AlF‑NOTA‑MAL‑Cys40‑Exendin‑4 in rodent heart after myocardial ischemia and reperfusion. Molecular Medicine Reports, 20, 2276-2284. https://doi.org/10.3892/mmr.2019.10432
MLA
Pan, X., Xu, Q., Chen, J., Wang, T., Zhang, M., Wang, H., Gao, H."Preliminary evaluation of 18F‑AlF‑NOTA‑MAL‑Cys40‑Exendin‑4 in rodent heart after myocardial ischemia and reperfusion". Molecular Medicine Reports 20.3 (2019): 2276-2284.
Chicago
Pan, X., Xu, Q., Chen, J., Wang, T., Zhang, M., Wang, H., Gao, H."Preliminary evaluation of 18F‑AlF‑NOTA‑MAL‑Cys40‑Exendin‑4 in rodent heart after myocardial ischemia and reperfusion". Molecular Medicine Reports 20, no. 3 (2019): 2276-2284. https://doi.org/10.3892/mmr.2019.10432