Journal of Radiopharmaceuticals and Molecular Probes (대한방사성의약품학회지)

Korean Society of Radiopharmaceuticals and Molecular Probes (대한방사성의약품학회)
권호 표지
DOI QR코드

DOI QR Code

Synthesis of 18F-labeled Novel Phosphonium cations as PET Myocardial Perfusion Imaging Agents: Pilot Imaging Studies

  • Ayoung Pyo (College of Pharmacy and Research Institute of Pharmaceutical Science, Gyeongsang National University) ;
  • Jung-Joon Min (Innovation Center for Molecular Probe Development, Department of Nuclear Medicine, Chonnam National University Medical School and Hwasun Hospital) ;
  • Dong-Yeon Kim (College of Pharmacy and Research Institute of Pharmaceutical Science, Gyeongsang National University)
  • Received : 2022.11.30
  • Accepted : 2022.12.12
  • Published : 2022.12.30
Download PDF
⟨ Previous Next ⟩

Abstract

The development of myocardial perfusion imaging (MPI) agents has been motivated because coronary artery disease has been one of the leading causes of death worldwide since the 1960s. Several positron emission tomography (PET) MPI agents were developed, and 18F-labeled phosphonium cations were reported actively among them. In this study, we synthesized novel 18F-labeled phosphonium cations, (5-[18F]fluoropentyl)diphenyl(pyridin-2-yl)phosphonium and (2-(2-[18F]fluoroethoxy)ethyl)diphenyl(pyridin-2-yl)phosphonium, and evaluated potential as MPI agents. Two labeled compounds were synthesized via nucleophilic substitution reactions of 18F-fluoride with the appropriate tosylate precursor in the presence of Kryptofix 2.2.2 and K2CO3. MicroPET studies were performed in normal rats to evaluate in vivo distribution of radiolabeled phosphonium cations for 60 min. The radiolabeled compounds were synthesized with 5%-10% yield. The radiochemical purity of labeled compounds was > 98% by analytical HPLC, and the specific activity was > 11.8 GBq/µmol. The result of microPET studies of these labeled compounds in rats showed intense uptake in the myocardium at 30 and 60 min. The results suggest that these 18F-labeled novel phosphonium cations would have potential as promising candidates for myocardial perfusion imaging.

Keywords

Acknowledgement

이 성과는 정부(과학기술정보통신부)의 재원으로 한국연구재단의 지원(NRF-2020R1C1C1012379 및 NRF-2021-M2E7A3085685)과 산업통상자원부 및 산업기술평가관리원(KEIT) 연구비 지원(2001667)에 의한 연구이며, 다른 상업적 이해관계는 없음

References

  1. Klein R, Celiker-Guler E, Rotstein BH, deKemp RA. PET and SPECT tracers for myocardial perfusion imaging. Semin Nucl Med 2020;50:208-18. https://doi.org/10.1053/j.semnuclmed.2020.02.016
  2. Small GR, Wells RG, Schindler T, Chow BJ, Ruddy TD. Advances in cardiac SPECT and PET imaging: Overcoming the challenges to reduce radiation exposure and improve accuracy. Can J Cardiol 201;29:275-84.
  3. Ohira H, Mc Ardle B, Cocker MS, Dekemp RA, Dasilva JN, Beanlands RS. Current and future clinical applications of cardiac positron emission tomography. Circ J 2013;77:836-48. https://doi.org/10.1253/circj.CJ-13-0213
  4. Gibbons RJ, Valeti US, Araoz PA, Jaffe AS. The quantification of infarct size. J Am Coll Cardiol 2004;44:1533-42. https://doi.org/10.1016/j.jacc.2004.06.071
  5. Knuuti J, Bengel FM. Positron emission tomography and molecular imaging. Heart 2008;94:360-7. https://doi.org/10.1136/hrt.2007.118992
  6. Kim DY, Kim HS, Reder S, Zheng JH, Herz M, Higuchi T, Pyo A, Bom HS, Schwaiger M, Min JJ. Comparison of 18F-labeled fluoroalkylphosphonium cations with 13N-NH3 for PET myocardial perfusion imaging. J Nucl Med 2015;56:1581-6. https://doi.org/10.2967/jnumed.115.156794
  7. Kim DY, Kim HS, Min JJ. Radiosynthesis and evaluation of 18F-labeled aliphatic phosphonium cations as a myocardial imaging agent for positron emission tomography. Nucl Med Commun 2015;36:747-54. https://doi.org/10.1097/MNM.0000000000000315
  8. Kim DY, Kim HS, Le UN, Jiang SN, Kim HJ, Lee KC, Woo SK, Chung J, Bom HS, Yu KH, Min JJ. Evaluation of a mitochondrial voltage sensor, (18F-fluoropentyl)triphenylphosphonium cation, in a rat myocardial infarction model. J Nucl Med 2012;53:1779-85. https://doi.org/10.2967/jnumed.111.102657
  9. Kim DY, Kim HJ, Yu KH, Min JJ. Synthesis of [18F]-labeled (2-(2-fluoroethoxy)ethyl)tris(4-methoxyphenyl)phosphonium cation as a potential agent for positron emission tomography myocardial imaging. Nucl Med Biol 2012;39:1093-8. https://doi.org/10.1016/j.nucmedbio.2012.03.008
  10. Kim DY, Kim HJ, Yu KH, Min JJ. Synthesis of [18F]-labeled (6-fluorohexyl)triphenylphosphonium cation as a potential agent for myocardial imaging using positron emission tomography. Bioconjug Chem 2012;23:431-7. https://doi.org/10.1021/bc2004439
  11. Kim DY, Kim HJ, Yu KH, Min JJ. Synthesis of [18F]-labeled (2-(2-fluoroethoxy)ethyl)triphenylphosphonium cation as a potential agent for myocardial imaging using positron emission tomography. Bioorg Med Chem Lett 2012;22:319-22. https://doi.org/10.1016/j.bmcl.2011.11.005
  12. Madar I, Ravert HT, Du Y, Hilton J, Volokh L, Dannals RF, Frost JJ, Hare JM. Characterization of uptake of the new PET imaging compound 18F-fluorobenzyl triphenyl phosphonium in dog myocardium. J Nucl Med 2006;47:1359-66.
  13. Z C, M S, X C, SS, G. Synthesis of (4-[18F]fluorophenyl)triphenylphosphonium as a potential imaging agent for mitochondrial dysfunction. J Label Compd Radiopharm 2005;48:131-7. https://doi.org/10.1002/jlcr.906
  14. Ravert HT, Madar I, Dannals RF. Radiosynthesis of 3-[18F]fluoropropyl and 4-[18F]fluorobenzyl triarylphosphonium ions. J Label Compd Radiopharm 2004;47:469-76. https://doi.org/10.1002/jlcr.835
  15. Kim DY, Min JJ. Radiolabeled phosphonium salts as mitochondrial voltage sensors for positron emission tomography myocardial imaging agents. Nucl Med Mol Imaging 2016;50:185-95. https://doi.org/10.1007/s13139-016-0397-x
  16. Kim DY, Cho SG, Bom HS. Emerging tracers for nuclear cardiac PET imaging. Nucl Med Mol Imaging 2018;52:266-78. https://doi.org/10.1007/s13139-018-0521-1
  17. Higuchi T, Fukushima K, Rischpler C, Isoda T, Javadi MS, Ravert H, Holt DP, Dannals RF, Madar I, Bengel FM. Stable delineation of the ischemic area by the PET perfusion tracer 18F-fluorobenzyl triphenyl phosphonium after transient coronary occlusion. J Nucl Med 2011;52:965-9. https://doi.org/10.2967/jnumed.110.085993
  18. Madar I, Ravert H, Dipaula A, Du Y, Dannals RF, Becker L. Assessment of severity of coronary artery stenosis in a canine model using the PET agent 18F-fluorobenzyl triphenyl phosphonium: comparison with 99mTc-tetrofosmin. J Nucl Med 2007;48:1021-30. https://doi.org/10.2967/jnumed.106.038778
  19. Min JJ, Biswal S, Deroose C, Gambhir SS. Tetraphenylphosphonium as a novel molecular probe for imaging tumors. J Nucl Med 2004;45:636-43.
  20. Murphy MP. Selective targeting of bioactive compounds to mitochondria. Trends Biotechnol 1997;15:326-30. https://doi.org/10.1016/S0167-7799(97)01068-8
  21. Fukuda H, Syrota A, Charbonneau P, Vallois J, Crouzel M, Prenant C, Sastre J, Crouzel C. Use of 11C-triphenylmethylphosphonium for the evaluation of membrane potential in the heart by positron-emission tomography. Eur J Nucl Med 1986;11:478-83.
  22. Ross MF, Kelso GF, Blaikie FH, James AM, Cocheme HM, Filipovska A, Da Ros T, Hurd TR, Smith RA, Murphy MP. Lipophilic triphenylphosphonium cations as tools in mitochondrial bioenergetics and free radical biology. Biochemistry (Mosc) 2005;70:222-30. https://doi.org/10.1007/s10541-005-0104-5
  23. Kroemer G. Mitochondrial control of apoptosis: an introduction. Biochem Biophys Res Commun 2003;304:433-5. https://doi.org/10.1016/S0006-291X(03)00614-4
  24. Pyo A, Song BR, Kim H, Kim DY. Radiolabeled benzamide derivatives for development of malignant melanoma imaging agents. J Radiopharm Mol Probes 2022;8:25-32.
  25. Yalamanchili P, Wexler E, Hayes M, Yu M, Bozek J, Kagan M, Radeke HS, Azure M, Purohit A, Casebier DS, Robinson SP. Mechanism of uptake and retention of F-18 BMS-747158-02 in cardiomyocytes: a novel PET myocardial imaging agent. J Nucl Cardiol 2007;14:782-8. https://doi.org/10.1016/j.nuclcard.2007.07.009
  26. Marshall RC, Powers-Risius P, Reutter BW, O'Neil JP, La Belle M, Huesman RH, VanBrocklin HF. Kinetic analysis of 18F-fluorodihydrorotenone as a deposited myocardial flow tracer: comparison to 201Tl. J Nucl Med 2004;45:1950-9.
  27. Marshall RC, Powers-Risius P, Reutter BW, Taylor SE, VanBrocklin HF, Huesman RH, Budinger TF. Kinetic analysis of 125I-iodorotenone as a deposited myocardial flow tracer: comparison with 99mTc-sestamibi. J Nucl Med 2001;42:272-81.
  28. Jacobson O, Abourbeh G, Tsvirkun D, Mishani E. Rat imaging and in vivo stability studies using [11C]-dimethyl-diphenyl ammonium, a candidate agent for PET-myocardial perfusion imaging. Nucl Med Biol 2013;40:967-73. https://doi.org/10.1016/j.nucmedbio.2013.07.002
  29. Ilovich O, Billauer H, Dotan S, Freedman NM, Bocher M, Mishani E. Novel and simple carbon-11-labeled ammonium salts as PET agents for myocardial perfusion imaging. Mol Imaging Biol 2011;13:128-39. https://doi.org/10.1007/s11307-010-0336-7
  30. Madar I, Ravert H, Nelkin B, Abro M, Pomper M, Dannals R, Frost JJ. Characterization of membrane potential-dependent uptake of the novel PET tracer 18F-fluorobenzyl triphenylphosphonium cation. Eur J Nucl Med Mol Imaging 2007;34:2057-65. https://doi.org/10.1007/s00259-007-0500-8