Iranian Journal of Nuclear Medicine

Iranian Journal of Nuclear Medicine

Development of freeze-dried kit for the preparation of [99mTc]Tc-HYNIC-ALUG: A potential agent for imaging of prostate specific membrane antigen

Document Type : Original Article

Authors
Tanveer Hussain Bokhari 1
Fehmida Bibi 1
Muhammad Irfan 2
Faiz Ahmed 1
Talal Abdul Rahman 3
Shazia Fatima 3
Muhammad Zeeshan 1
Maria Hassan 1
Adam Safi Ullah 1
Muhammad Wasim 2
Nadeem Ahmed Lodhi 2
1 Department of Chemistry, Government College University, Faisalabad, Pakistan
2 Isotope Production Division, Pakistan Institute of Nuclear Science and Technology, Nilore, Islamabad, Pakistan
3 Karachi Institute of Radiotherapy and Nuclear Medicine, Karachi, Pakistan
10.22034/irjnm.2024.129413.1577
Abstract
Introduction: Prostate-specific membrane antigen (PSMA) is increasingly recognized as a viable target for imaging and therapy of Prostate cancer (PCa). In this study, we introduce the freeze-dried kit formulation of [99mTc]Tc-HYNICALUG for easy clinical evaluation of prostate cancer.
Methods: In this work, an in silico modeling of the urea-based PSMA small molecule (HYNIC-ALUG) was performed to check its interaction with human glutamate carboxypeptidase II and compared it with experimental results. The HYNIC-PSMA kit was formulated for easy preparation of [99mTc]Tc-HYNIC-ALUG. The kit contained a freeze-dried mixture of HYNIC-ALUG, coligands SnCl2.2H2O, and antioxidant D-mannitol.
Results: The calculated Ki value (inhibition/dissociation constant) was 4.55 which showed excellent binding affinity of HYNIC-ALUG with PSMA.  miLogP and cLogS values are -4.04 and -3.07 respectively showing its hydrophilic character and predicting its excellent distribution in biological fluids.  Subsequently, the radiochemical purity of the HYNIC-PSMA kit was 99.1 ± 1.32% (n = 6) determined by radio-ITLC and by HPLC as well. In vitro stability in saline and serum was studied up to 4 h and showed high stability (≥ 96%). The distribution of [99mTc]Tc-HYNIC-ALUG was carried out in two patients and SPECT/CT planar images were acquired at 2h and 4h respectively. Bio-physiological distribution of [99mTc]Tc-HYNIC-ALUG was observed normally in lacrimal, salivary glands, liver, spleen, gut, kidneys, and urinary bladder.
Conclusion: The HYNIC-ALUG freeze-dried kit could be used for easy preparation of [99mTc]Tc-HYNIC-ALUG and can be considered as a potential agent for the diagnosis, staging, and restaging of advanced prostate cancer.
Keywords
Prostate cancer
Technetium-99m
HYNIC-ALUG
SPECT imaging
Clinical evaluation
Subjects
  1. Osdzich P, Darr C, Hilser T, Wahl M, Herrmann K, Hadaschik B, Grünwald V. Metastatic prostate cancer-a review of current treatment options and promising new approaches. Cancers (Basel). 2023 Jan 11;15(2):461. 
  2. Xia C, Dong X, Li H, Cao M, Sun D, He S, Yang F, Yan X, Zhang S, Li N, Chen W. Cancer statistics in China and United States, 2022: profiles, trends, and determinants. Chin Med J (Engl). 2022 Feb 9;135(5):584-90.
  3. Center MM, Jemal A, Lortet-Tieulent J, Ward E, Ferlay J, Brawley O, Bray F. International variation in prostate cancer incidence and mortality rates. Eur Urol. 2012 Jun;61(6):1079-92. 
  4. Maurer T, Eiber M, Schwaiger M, Gschwend JE. Current use of PSMA-PET in prostate cancer management. Nat Rev Urol. 2016 Apr;13(4):226-35.
  5. Bryant RJ, Hamdy FC. Screening for prostate cancer: an update. Eur Urol. 2008 Jan;53(1):37-44.
  6. Sharifi M, Yousefnia H, Bahrami-Samani A, Jalilian AR, Zolghadri S, Vaez-Tehrani M, Maus S. Optimized production assessment, compartmental modeling and dosimetric evaluation of 177Lu-PSMA-617 for clinical trials. Int J  Nucl Med Res. 2017;4:45-52.
  7. Santoni M, Scarpelli M, Mazzucchelli R, Lopez-Beltran A, Cheng L, Cascinu S, Montironi R. Targeting prostate-specific membrane antigen for personalized therapies in prostate cancer: morphologic and molecular backgrounds and future promises. J Biol Regul Homeost Agents. 2014 Oct-Dec;28(4):555-63. 
  8. Brunello S, Salvarese N, Carpanese D, Gobbi C, Melendez-Alafort L, Bolzati C. A review on the current state and future perspectives of [99mTc] Tc-housed PSMA-i in prostate cancer. Molecules. 2022;27:2617.
  9. Ferro-Flores G, Luna-Gutiérrez M, Ocampo-García B, Santos-Cuevas C, Azorín-Vega E, Jiménez-Mancilla N, Orocio-Rodríguez E, Davanzo J, García-Pérez FO. Clinical translation of a PSMA inhibitor for 99mTc-based SPECT. Nucl Med Biol. 2017 May;48:36-44.
  10. Garnuszek P, Karczmarczyk U, Maurin M, Sikora A, Zaborniak J, Pijarowska-Kruszyna J, Jaroń A, Wyczółkowska M, Wojdowska W, Pawlak D, Lipiński PFJ, Mikołajczak R. PSMA-D4 radioligand for targeted therapy of prostate cancer: synthesis, characteristics and preliminary assessment of biological properties. Int J Mol Sci. 2021 Mar 8;22(5):2731. 
  11. Xu X, Zhang J, Hu S, He S, Bao X, Ma G, Luo J, Cheng J, Zhang Y. 99mTc-labeling and evaluation of a HYNIC modified small-molecular inhibitor of prostate-specific membrane antigen. Nucl Med Biol. 2017 May;48:69-75.
  12. Werner RA, Derlin T, Lapa C, Sheikbahaei S, Higuchi T, Giesel FL, Behr S, Drzezga A, Kimura H, Buck AK, Bengel FM, Pomper MG, Gorin MA, Rowe SP. 18F-Labeled, PSMA-targeted radiotracers: leveraging the advantages of radiofluorination for prostate cancer molecular imaging. Theranostics. 2020 Jan 1;10(1):1-16.
  13. Jacobson O, Kiesewetter DO, Chen X. Fluorine-18 radiochemistry, labeling strategies and synthetic routes. Bioconjug Chem. 2015 Jan 21;26(1):1-18.
  14. Fendler WP, Calais J, Eiber M, Flavell RR, Mishoe A, Feng FY, Nguyen HG, Reiter RE, Rettig MB, Okamoto S, Emmett L, Zacho HD, Ilhan H, Wetter A, Rischpler C, Schoder H, Burger IA, Gartmann J, Smith R, Small EJ, Slavik R, Carroll PR, Herrmann K, Czernin J, Hope TA. Assessment of 68Ga-PSMA-11 PET accuracy in localizing recurrent prostate cancer: a prospective single-arm clinical trial. JAMA Oncol. 2019 Jun 1;5(6):856-63.
  15. Lawal IO, Ankrah AO, Mokgoro NP, Vorster M, Maes A, Sathekge MM. Diagnostic sensitivity of Tc-99m HYNIC PSMA SPECT/CT in prostate carcinoma: A comparative analysis with Ga-68 PSMA PET/CT. Prostate. 2017 Aug;77(11):1205-12.
  16. Boschi A, Uccelli L, Martini P. A picture of modern Tc-99m radiopharmaceuticals: Production, chemistry, and applications in molecular imaging. Appl Sci. 2019(12);9:2526.
  17. Rezazadeh F, Sadeghzadeh N. Tumor targeting with 99m Tc radiolabeled peptides: Clinical application and recent development. Chem Biol Drug Des. 2019 Mar;93(3):205-21.
  18. Lebowitz E, Richards P. Radionuclide generator systems. Semin Nucl Med. 1974 Jul;4(3):257-68.
  19. Nairne J, Iveson PB, Meijer A. Imaging in drug development. Prog Med Chem. 2015;54:231-80.
  20. Urbán S, Meyer C, Dahlbom M, Farkas I, Sipka G, Besenyi Z, Czernin J, Calais J, Pávics L. Radiation dosimetry of 99mTc-PSMA I&S: a single-center prospective study. J Nucl Med. 2021 Aug 1;62(8):1075-81.
  21. Kim MH, Kim SG, Kim DW. Dual-labeled prostate-specific membrane antigen (PSMA)-targeting agent for preoperative molecular imaging and fluorescence-guided surgery for prostate cancer. J Labelled Comp Radiopharm. 2021 Jan;64(1):4-13.
  22. Rathke H, Afshar-Oromieh A, Giesel FL, Kremer C, Flechsig P, Haufe S, Mier W, Holland-Letz T, De Bucourt M, Armor T, Babich JW, Haberkorn U, Kratochwil C. Intraindividual comparison of 99mTc-methylene diphosphonate and prostate-specific membrane antigen ligand 99mtc-mip-1427 in patients with osseous metastasized prostate cancer. J Nucl Med. 2018 Sep;59(9):1373-9. 
  23. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015 Mar;65(2):87-108. 
  24. Liu C, Zhu Y, Su H, Xu X, Zhang Y, Ye D, Hu S. Relationship between PSA kinetics and Tc-99m HYNIC PSMA SPECT/CT detection rates of biochemical recurrence in patients with prostate cancer after radical prostatectomy. Prostate. 2018 Dec;78(16):1215-21.
  25. Decristoforo C, Mather SJ. The influence of chelator on the pharmacokinetics of 99mTc-labelled peptides. Q J Nucl Med. 2002 Sep;46(3):195-205. 
  26. Shaghaghi Z, Abedi SM, Hosseinimehr SJ. Tricine co-ligand improved the efficacy of 99mTc-HYNIC-(Ser)3-J18 peptide for targeting and imaging of non-small-cell lung cancer. Biomed Pharmacother. 2018 Aug;104:325-31.
  27. Maurer T, Eiber M, Schwaiger M, Gschwend JE. Current use of PSMA-PET in prostate cancer management. Nat Rev Urol. 2016 Apr;13(4):226-35.
  28. Decristoforo C, Mather SJ. 99m-Technetium-labelled peptide-HYNIC conjugates: effects of lipophilicity and stability on biodistribution. Nucl Med Biol. 1999 May;26(4):389-96.
  29. Hubalewska-Dydejczyk A, Fröss-Baron K, Mikołajczak R, Maecke HR, Huszno B, Pach D, Sowa-Staszczak A, Janota B, Szybiński P, Kulig J. 99mTc-EDDA/HYNIC-octreotate scintigraphy, an efficient method for the detection and staging of carcinoid tumours: results of 3 years' experience. Eur J Nucl Med Mol Imaging. 2006 Oct;33(10):1123-33.
  30. King R, Surfraz MB, Finucane C, Biagini SC, Blower PJ, Mather SJ. 99mTc-HYNIC-gastrin peptides: assisted coordination of 99mtc by amino acid side chains results in improved performance both In Vitro and In Vivo. J Nucl Med. 2009 Apr;50(4):591-8. 
  31. Xu X, Zhang J, Hu S, He S, Bao X, Ma G, Luo J, Cheng J, Zhang Y. 99mTc-labeling and evaluation of a HYNIC modified small-molecular inhibitor of prostate-specific membrane antigen. Nucl Med Biol. 2017 May;48:69-75.
  32. Hadisi M, Vosoughi N, Yousefnia H, Bahrami-Samani A, Zolghadri S, Vosoughi S, Alirezapour B. Preclinical evaluation of 188 Re-HYNIC-PSMA as a novel therapeutic agent. J Radioanal Nucl Chem. 2022;2:841-9.
  33. Sharifi M, Yousefnia H, Zolghadri S, Bahrami-Samani A, Naderi M, Jalilian AR, Geramifar P, Beiki D. Preparation and biodistribution assessment of 68 Ga-DKFZ-PSMA-617 for PET prostate cancer imaging. Nucl Sci Tech. 2016;27(6):1-9.
  34. Masteri Farahani A, Maleki F, Sadeghzadeh N, Abediankenari S, Abedi SM, Erfani M. 99m Tc-(EDDA/tricine)-HYNIC-GnRH analogue as a potential imaging probe for diagnosis of prostate cancer. Chem Biol Drug Des. 2020 Aug;96(2):850-60.
  35. Lodhi NA, Park JY, Kim K, Hong MK, Kim YJ, Lee Y-S, Cheon GJ, Kang KW, Jeong JM. Synthesis and evaluation of 99mTc-tricabonyl labeled isonitrile conjugates for prostate-specific membrane antigen (PSMA) Image. Inorganics. 2020; 8(1):5.