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DOI: 10.1055/s-0045-1809921
A New Labeling Method of 99mTc-PSMA-HBED-CC
Abstract
Objective
68Ga-PSMA-HBED-CC (68Ga-PSMA-11) was approved by the U.S. Food and Drug Administration as the first prostate-specific membrane antigen (PSMA)-targeted positron emission tomography (PET) imaging drug for patients with prostate cancer. However, the utility of 68Ga-PSMA-HBED-CC may be limited due to PET/CT or PET/MR accessibility and 68GaCl3 availability produced from 68Ge/68Ga generator or cyclotron. Thus, in-house preparation of 99mTc-PSMA-HBED-CC was developed as an alternative to 68Ga-PSMA-HBED-CC to be ubiquitous and affordable in the worldwide population.
Methods
A solution of 99mTc-pertechnetate was added to PSMA-HBED-CC and 4% SnCl2·2H2O in a 10-mL sterile vial. The mixture was heated at 100°C for 15 minutes and then allowed to cool to room temperature. Labeling conditions were optimized to maximize the radiochemical yield of 99mTc-PSMA-HBED-CC. The chelation completeness was monitored using instant thin layer chromatography, and the stability of 99mTc-PSMA-HBED-CC was subsequently evaluated.
Results
The radiolabeling of 99mTc-PSMA-HBED-CC was successful using the appropriate amount of 10 µg PSMA-HBED-CC 3 µg SnCl2·2H2O and 99mTc-pertechnetate 370 MBq at 100°C for 15 minutes, yielded the best result in high radiochemical yield (71.49 ± 2.42%), radiochemical purity (98.29 ± 2.65%), and specific activity of 37.84 ± 1.47 GBq/µmol. 99mTc-PSMA-HBED-CC is stable with radiochemical purity of more than 95% within 4 hours at room temperature.
Conclusion
A new labeling method of 99mTc-PSMA-HBED-CC was developed. Quality control parameters of 99mTc-PSMA-HBED-CC met the criteria in accordance with the European Pharmacopoeia.
Introduction
Prostate cancer is the most common malignancy found in men and the second leading cause of cancer death worldwide.[1] Over the past two decades, the initial diagnosis and follow-up have been serum prostate-specific antigen levels, digital rectal examination, and some conventional imaging techniques including ultrasound, computed tomography, magnetic resonance imaging, and bone scintigraphy, but none provides highly specific and sensitive detection. Although transrectal ultrasound-guided prostate biopsy is currently accepted as the gold standard to provide the histopathological diagnosis of prostate cancer,[2] it is an invasive procedure that resulted in a risk of side effects and the accuracy of diagnosis. The accurate definition of tumor burden and its staging is particularly important for effective treatment selection. Therefore, molecular imaging, a noninvasive method, has been employed to visualize the tumor in both soft tissue and bone with higher specific and sensitive detection, monitored response to therapy to improve management of prostate cancer, clinical outcome, and patient's quality of life.
The Food and Drug Administration (FDA) approved 68Ga-PSMA-HBED-CC (68Ga-PSMA-11, previous name: 68Ga-DKFZ-PSMA-11, generic name: 68Ga-Gazetotide) as the first prostate-specific membrane antigen (PSMA)-targeted positron emission tomography (PET) imaging drug for men with prostate cancer.[3] The development of 68Ga-PSMA-HBED-CC, which targets PSMA, has offered new perspectives for prostate cancer diagnosis and evaluation of therapeutic response.[4] PSMA is a cell surface transmembrane protein with 750 amino acids type II glycoprotein that primarily expresses in normal prostate epithelium and is overexpressed in prostate cancer cells including bone metastasis.[5] X-ray crystal structure analysis of PSMA, also known as N-acetylated L-aspartyl-L-glutamate peptidase (NAALADase I), has identified the critical interaction of potent inhibitors within the hydrophobic active site of the enzyme.[6] Consequently, several classes of NAALADase I inhibitors had been exploited for structure-based design platforms, leading to the novel synthesis of PSMA-HBED-CC.[7] [8] [9] To date, 68Ga-PSMA-HBED-CC has explicitly demonstrated superior detection of PSMA-positive prostate cancer lesions in recurrent and metastatic sites over conventional imaging methods[10] [11] and two other FDA-approved PET tracers, 18F-fluciclovine and 11C-choline that are used in patients with suspected cancer recurrence.[12] Recently, the FDA also approved 18F-piflufolastat as the second PSMA-targeted PET imaging drug with prostate cancer.
Besides 68Ga-PSMA-HBED-CC, the preferential use of 99mTc-labeled urea-based PSMA inhibitor has received interest as an alternative option to widespread the advantages of PSMA imaging due to a number of prostate cancer patients who are scheduled on PSMA imaging. The hybrid modality of single-photon emission CT (SPECT)/CT offers a wide range of workhorses in nuclear medicine with lower financial access, especially the remote medical center in which PET/CT facility is not available. Although the spatial resolution of 99mTc is not as good as that of 68Ga, 99mTc provides a sufficiently long half-life of 6 hours in both preparation and accumulation in the target site. Moreover, the decay range of 99mTc is short enough to minimize radiation exposure to patients and medical staff.
While some 99mTc-labeled PSMA tracers have been previously reported using various PSMA ligands with several forms of complexation, for example, [99mTc(CO)3(L)3]+,[13] [14] [15] MAG3-based 99mTc-PSMA-I&S,[16] 99mTc-MIP,[17] [18] [19] [20] 99mTc-HYNIC-PSMA,[21] [22] peptide-chelator-based 99mTc-DUPA,[23] 99mTc-PSMA-T4,[24] 99m Tc-PSMA-tricarbonyl-HBED-CC,[25] and 99mTc-PSMA-HBED-CC,[26] it challenges to develop a convenient labeling method in a single step without coligand for 99mTc-complexation. According to our experience in theranostics, we adapted the routine standard labeling procedure of 68Ga-PSMA-HBED-CC with the rationale that HBED-CC would serve as a suitable chelator in a mimic manner to diethylenetriamine pentaacetic acid (DTPA) as shown in [Fig. 1]. Our attention focused on optimizing the labeling parameters to improve the radiosynthesis of 99mTc-PSMA-HBED-CC.


Material and Methods
PSMA-HBED-CC was purchased from ABX advanced biochemical compounds (GmbH, Germany). Sodium 99mTc-pertechnetate was purchased from Global Medical Solution (Thailand). Stannous chloride dihydrate and hydrochloric acid were purchased from Sigma-Aldrich (Germany). The stock solution of 4% stannous chloride was freshly prepared and kept in a refrigerator. All chemicals and solvents were used without further purification unless otherwise noted. The C18 cartridge (Sep-Pak Light, lot no. 045732200A) was purchased from Waters (United States). The TLC scanner Raytest model MiniGita was used.
Preparation of 4% Stannous Chloride Stock Solution
SnCl2·2H2O 0.144 mg was added to 37% HCl 0.75 mL, followed by heating at 100°C for 5 minutes. After cooling down to room temperature, 6 N HCl 2.25 mL was added to 4% SnCl2·2H2O, which should be freshly prepared before labeling.
Labeling of PSMA-HBED-CC with Tc-99m
To a mixture of 4% SnCl2·2H2O solution calculated as an amount of SnCl2 and an aliquot of PSMA-HBED-CC (10 µg in H2O 100 µL) in 10 mL sterile vial, 99mTc-pertechnetate 370 MBq was added. The labeling was performed at 100°C for 15 minutes in a heating block, followed by a 10-minute cool down to reach room temperature. The crude product was passed through a C18 cartridge. 99mTc-PSMA-HBED-CC was slowly purged from a C18 cartridge using EtOH:H2O (1:1) 2 mL to the final product vial.
Quality Control
Radiochemical purity (RCP) analyses were performed using instant thin-layer chromatography (iTLC) on silica paper strips as a stationary phase with two different mobile phases. The free form of 99mTcO4 − was determined using 0.9% normal saline, whereas 99mTc-colloid formation was determined using acetone as the mobile phase. The radioactivity distribution on iTLC strips was also determined on a TLC scanner. Subsequently, radiochemical yield (RCY) was calculated. The pH of the final product was determined using a pH indicator.
Stability Test
The chemical stability of 99mTc-PSMA-HBED-CC was carried out by incubating the final product radioactivity in samples range 10.22 ± 0.40 mCi at room temperature for 6 hours and monitored by iTLC every hour. The radioconcentration used for the stability test was 2.04 mCi/mL. No stabilizer was added.
Results
Labeling of 99mTc-PSMA-HBED-CC
The labeling parameters were investigated to achieve the highest possible RCY. The quantity of PSMA-HBED-CC used in each experiment remained constant at 10 µg (0.011 µmol). In accordance with the DTPA cold kit formulation, the appropriate radioactivity of 99mTc-pertechnetate was determined in direct correlation with approximate 370 MBq (10 mCi), while maintaining the solution's pH at 5.0, as indicated in [Table 1].
Abbreviation: RCY, radiochemical yield.
In the preliminary experiment, 10.02 mCi of 99mTcO4 − was combined with 0.5 µg of SnCl2 at room temperature for 15 minutes that resulted in a RCY of 0.25%, with 99.58% of 99mTcO4 − remaining unbound. Subsequently, the reaction temperature was increased to 100°C for 15 minutes, in alignment with the standard procedure for labeling 68Ga-PSMA-HBED-CC. This adjustment resulted in a RCY of 11.11%, affirming the choice to set the reaction conditions at 100°C for 15 minutes. In iterations 3 to 8, the amount of SnCl2 was progressively adjusted to enhance the RCY. By increasing the SnCl2 quantity by 0.5 µg in each iteration, the highest RCY of 65.91% was achieved in the sixth iteration. However, when the amount of SnCl2 exceeded 3.5 µg, complete chelation occurred between PSMA-HBED-CC and 99mTcO4 −, which also led to a significant rise in the formation of hydrolyzed species, ultimately diminishing the RCY. Total radioactivities of the final product recovered after labeling are 10.12 ± 0.58 mCi.
Chemical Stability of 99mTc-PSMA-HBED-CC
The chemical stability of 99mTc-PSMA-HBED-CC was evaluated using the optimized labeling method in the 6th iteration that produced the highest RCY. The compound was incubated at room temperature for 6 hours, and RCP was checked hourly through iTLC ([Fig. 2]). The findings are shown in [Fig. 3]. In general, the RCP of Tc-99m radiopharmaceuticals should meet or exceed 95%. This study demonstrated that the RCP of 99mTc-PSMA-HBED-CC remained above 95% for up to 4 hours after labeling, and stayed above 90% at the 5th and 6th hours.




Discussion
Since the identification of PSMA as an antigen and the discovery of the specific antibody 7E11-C5 (capromab) for both normal and malignant prostate epithelium, as reported by Horoszewicz et al,[27] PSMA has emerged as a crucial target for prostate cancer cells.[28] [29] [30] In 2012, Eder et al developed the urea-based PET tracer 68Ga-PSMA-HBED-CC (formerly 68Ga-DKFZ-PSMA-11) to address the limitations of the lead antibody J591.[31] The U.S. FDA approved 68Ga-PSMA-HBED-CC as the first PET imaging agent for PSMA-positive lesions in men with prostate cancer in December 2020[3] and 18F-piflufolastat as the second PET imaging agent for PSMA-positive lesions in men with prostate cancer in May 2021.[3] Inspired by this breakthrough, our study aimed to develop 99mTc-PSMA-HBED-CC as a SPECT imaging analog to increase accessibility for prostate cancer diagnosis.
PSMA-HBED-CC was chosen for this study due to its widespread clinical use and commercial availability. The dose of PSMA-HBED-CC was standardized at 10 μg. To optimize the manual labeling of 99mTc-PSMA-HBED-CC, various labeling conditions and amounts of calculated SnCl2 were assessed. The results, presented in [Table 1], indicate that 99mTc-PSMA-HBED-CC is a thermodynamically favorable product. Using 2.5 to 4.0 μg of SnCl2 resulted in a RCY exceeding 50%. When the SnCl2 amount exceeded 3.5 μg, no uncomplexed Tc-99m was detected, indicating effective reduction of TcO4 −. However, higher amounts of SnCl2 also increased colloid formation. Optimal quantitative radiolabelling of 10 μg of PSMA-HBED-CC was achieved with 3.0 μg of SnCl2. To prevent colloid formation, both SnCl2 and PSMA-HBED-CC must be present in the reaction mixture before adding TcO4 − to form the desired complex.
The chemical stability of 99mTc-PSMA-HBED-CC was evaluated by incubating it at room temperature. As shown in [Fig. 2], it retained RCP above 95% for up to 4 hours. After this period, free Tc-99m increased. Therefore, it is recommended to use 99mTc-PSMA-HBED-CC within 4 hours of preparation or store it in a refrigerator to maintain stability.
Vats et al[26] previously reported the preparation of 99mTc-PSMA-HBED-CC using 50 mg of PSMA-HBED-CC, 40 mg of SnCl2, and TcO4 − 740 MBq at pH 5, yielding a RCY of 60 ± 5%, a RCP greater than 98%, and specific activity of 15 ± 5 GBq/µmol. However, they did not conduct stability tests. Economically, our study used 10 µg of PSMA-HBED-CC, 3 µg of SnCl2, and 370 MBq of 99mTc-pertechnetate at 100°C for 15 minutes, achieving a higher RCY (71.49 ± 2.42%), RCP (98.29 ± 2.65%), and specific activity (37.84 ± 1.47 GBq/µmol). This method is more cost-effective and easier to manipulate.
Conclusion
To optimize the labeling of PSMA-HBED-CC with 99mTc-pertechnetate for prostate cancer imaging, the labeling procedure should be carried out at 100°C for 15 minutes using 3 µg of SnCl2, minimizing the presence of free 99mTc-pertechnetate and colloid formation. Purification with a C18 cartridge is required to achieve RCP that complies with the European Pharmacopoeia standards. The stability of 99mTc-PSMA-HBED-CC remains robust for up to 4 hours at room temperature, with RCP exceeding 95%. It is recommended to use the labeled product within 4 hours of preparation.
Conflict of Interest
None declared.
Authors' Contributions
B.P. and S.S. contributed to the conceptualization, methodology, formulation, formal analysis, and visualization. B.P. performed the kit manufacturing. S.S. managed funding and acquisition. S.S. was a major contributor in writing the manuscript. All authors have read and agreed to the final version.
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References
- 1 Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68 (06) 394-424
- 2 Moe A, Hayne D. Transrectal ultrasound biopsy of the prostate: does it still have a role in prostate cancer diagnosis?. Transl Androl Urol 2020; 9 (06) 3018-3024
- 3 Hennrich U, Eder M. [68Ga] Ga-PSMA-11: the first FDA-approved 68Ga-radiopharmaceutical for PET imaging of prostate cancer. Pharmaceuticals 2021; 14 (08) 713-725
- 4 Afshar-Oromieh A, Haberkorn U, Eder M, Eisenhut M, Zechmann CM. [68Ga]Gallium-labelled PSMA ligand as superior PET tracer for the diagnosis of prostate cancer: comparison with 18F-FECH. Eur J Nucl Med Mol Imaging 2012; 39 (06) 1085-1086
- 5 Silver DA, Pellicer I, Fair WR, Heston WD, Cordon-Cardo C. Prostate-specific membrane antigen expression in normal and malignant human tissues. Clin Cancer Res 1997; 3 (01) 81-85
- 6 Davis MI, Bennett MJ, Thomas LM, Bjorkman PJ. Crystal structure of prostate-specific membrane antigen, a tumor marker and peptidase. Proc Natl Acad Sci U S A 2005; 102 (17) 5981-5986
- 7 Mesters JR, Henning K, Hilgenfeld R. Human glutamate carboxypeptidase II inhibition: structures of GCPII in complex with two potent inhibitors, quisqualate and 2-PMPA. Acta Crystallogr D Biol Crystallogr 2007; 63 (Pt 4): 508-513
- 8 Lundmark F, Olanders G, Rinne SS, Abouzayed A, Orlova A, Rosenström U. Design, synthesis, and evaluation of linker-optimised PSMA-targeting radioligands. Pharmaceutics 2022; 14 (05) 1098-1117
- 9 Barinka C, Byun Y, Dusich CL. et al. Interactions between human glutamate carboxypeptidase II and urea-based inhibitors: structural characterization. J Med Chem 2008; 51 (24) 7737-7743
- 10 Maurer T, Eiber M, Schwaiger M, Gschwend JE. Current use of PSMA-PET in prostate cancer management. Nat Rev Urol 2016; 13 (04) 226-235
- 11 Virgolini I, Decristoforo C, Haug A, Fanti S, Uprimny C. Current status of theranostics in prostate cancer. Eur J Nucl Med Mol Imaging 2018; 45 (03) 471-495
- 12 Li M, Zelchan R, Orlova A. The performance of FDA-approved PET imaging agents in the detection of prostate cancer. Biomedicines 2022; 10 (10) 2533-2556
- 13 Banerjee SR, Foss CA, Castanares M. et al. Synthesis and evaluation of technetium-99m- and rhenium-labeled inhibitors of the prostate-specific membrane antigen (PSMA). J Med Chem 2008; 51 (15) 4504-4517
- 14 Maresca KP, Hillier SM, Lu G. et al. Small molecule inhibitors of PSMA incorporating technetium-99m for imaging prostate cancer: effects of chelate design on pharmacokinetics. Inorg Chim Acta 2012; 389: 168-175
- 15 Lu G, Maresca KP, Hillier SM. et al. Synthesis and SAR of 99mTc/Re-labeled small molecule prostate specific membrane antigen inhibitors with novel polar chelates. Bioorg Med Chem Lett 2013; 23 (05) 1557-1563
- 16 Robu S, Schottelius M, Eiber M. et al. Preclinical evaluation and first patient application of 99mTc-PSMA-I&S for SPECT imaging and radioguided surgery in prostate cancer. J Nucl Med 2017; 58 (02) 235-242
- 17 Hillier SM, Maresca KP, Lu G. et al. 99mTc-labeled small-molecule inhibitors of prostate-specific membrane antigen for molecular imaging of prostate cancer. J Nucl Med 2013; 54 (08) 1369-1376
- 18 Vallabhajosula S, Nikolopoulou A, Babich JW. et al. 99mTc-labeled small-molecule inhibitors of prostate-specific membrane antigen: pharmacokinetics and biodistribution studies in healthy subjects and patients with metastatic prostate cancer. J Nucl Med 2014; 55 (11) 1791-1798
- 19 Reinfelder J, Kuwert T, Beck M. et al. First experience with SPECT/CT using a 99mTc-labeled inhibitor for prostate-specific membrane antigen in patients with biochemical recurrence of prostate cancer. Clin Nucl Med 2017; 42 (01) 26-33
- 20 Schmidkonz C, Goetz TI, Kuwert T. et al. PSMA SPECT/CT with 99mTc-MIP-1404 in biochemical recurrence of prostate cancer: predictive factors and efficacy for the detection of PSMA-positive lesions at low and very-low PSA levels. Ann Nucl Med 2019; 33 (12) 891-898
- 21 Zhang J, Zhang J, Xu X. et al. Evaluation of radiation dosimetry of 99mTc-HYNIC-PSMA and imaging in prostate cancer. Sci Rep 2020; 10 (01) 4179-4187
- 22 Xu X, Zhang J, Hu S. et al. 99mTc-labeling and evaluation of a HYNIC modified small-molecular inhibitor of prostate-specific membrane antigen. Nucl Med Biol 2017; 48: 69-75
- 23 Kularatne SA, Zhou Z, Yang J, Post CB, Low PS. Design, synthesis, and preclinical evaluation of prostate-specific membrane antigen targeted (99m)Tc-radioimaging agents. Mol Pharm 2009; 6 (03) 790-800
- 24 Sergieva S, Mangaldgiev R, Dimcheva M, Nedev K, Zahariev Z, Robev B. SPECT-CT imaging with [99mTc] PSMA-T4 in patients with recurrent prostate cancer. Nucl Med Rev 2021; 24 (02) 70-81
- 25 Shi S, Yao L, Li L. et al. Synthesis of novel technetium-99m tricarbonyl-HBED-CC complexes and structural prediction in solution by density functional theory calculation. R Soc Open Sci 2019; 6 (11) 191247-191260
- 26 Vats K, Agrawal K, Sharma R, Sarma HD, Satpati D, Dash A. Preparation and clinical translation of 99mTc-PSMA-11 for SPECT imaging of prostate cancer. Med Chem Commun 2019; 10 (12) 2111-2117
- 27 Horoszewicz JS, Kawinski E, Murphy GP. Monoclonal antibodies to a new antigenic marker in epithelial prostatic cells and serum of prostatic cancer patients. Anticancer Res 1987; 7 (5B): 927-935
- 28 Lopes AD, Davis WL, Rosenstraus MJ, Uveges AJ, Gilman SC. Immunohistochemical and pharmacokinetic characterization of the site-specific immunoconjugate CYT-356 derived from antiprostate monoclonal antibody 7E11-C5. Cancer Res 1990; 50 (19) 6423-6429
- 29 Kahn D, Williams RD, Seldin DW. et al. Radioimmunoscintigraphy with 111indium labeled CYT-356 for the detection of occult prostate cancer recurrence. J Urol 1994; 152 (5 Pt 1): 1490-1495
- 30 Wynant GE, Murphy GP, Horoszewicz JS. et al. Immunoscintigraphy of prostatic cancer: preliminary results with 111In-labeled monoclonal antibody 7E11-C5.3 (CYT-356). Prostate 1991; 18 (03) 229-241
- 31 Eder M, Schäfer M, Bauder-Wüst U. et al. 68Ga-complex lipophilicity and the targeting property of a urea-based PSMA inhibitor for PET imaging. Bioconjug Chem 2012; 23 (04) 688-697
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26. Juni 2025
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References
- 1 Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68 (06) 394-424
- 2 Moe A, Hayne D. Transrectal ultrasound biopsy of the prostate: does it still have a role in prostate cancer diagnosis?. Transl Androl Urol 2020; 9 (06) 3018-3024
- 3 Hennrich U, Eder M. [68Ga] Ga-PSMA-11: the first FDA-approved 68Ga-radiopharmaceutical for PET imaging of prostate cancer. Pharmaceuticals 2021; 14 (08) 713-725
- 4 Afshar-Oromieh A, Haberkorn U, Eder M, Eisenhut M, Zechmann CM. [68Ga]Gallium-labelled PSMA ligand as superior PET tracer for the diagnosis of prostate cancer: comparison with 18F-FECH. Eur J Nucl Med Mol Imaging 2012; 39 (06) 1085-1086
- 5 Silver DA, Pellicer I, Fair WR, Heston WD, Cordon-Cardo C. Prostate-specific membrane antigen expression in normal and malignant human tissues. Clin Cancer Res 1997; 3 (01) 81-85
- 6 Davis MI, Bennett MJ, Thomas LM, Bjorkman PJ. Crystal structure of prostate-specific membrane antigen, a tumor marker and peptidase. Proc Natl Acad Sci U S A 2005; 102 (17) 5981-5986
- 7 Mesters JR, Henning K, Hilgenfeld R. Human glutamate carboxypeptidase II inhibition: structures of GCPII in complex with two potent inhibitors, quisqualate and 2-PMPA. Acta Crystallogr D Biol Crystallogr 2007; 63 (Pt 4): 508-513
- 8 Lundmark F, Olanders G, Rinne SS, Abouzayed A, Orlova A, Rosenström U. Design, synthesis, and evaluation of linker-optimised PSMA-targeting radioligands. Pharmaceutics 2022; 14 (05) 1098-1117
- 9 Barinka C, Byun Y, Dusich CL. et al. Interactions between human glutamate carboxypeptidase II and urea-based inhibitors: structural characterization. J Med Chem 2008; 51 (24) 7737-7743
- 10 Maurer T, Eiber M, Schwaiger M, Gschwend JE. Current use of PSMA-PET in prostate cancer management. Nat Rev Urol 2016; 13 (04) 226-235
- 11 Virgolini I, Decristoforo C, Haug A, Fanti S, Uprimny C. Current status of theranostics in prostate cancer. Eur J Nucl Med Mol Imaging 2018; 45 (03) 471-495
- 12 Li M, Zelchan R, Orlova A. The performance of FDA-approved PET imaging agents in the detection of prostate cancer. Biomedicines 2022; 10 (10) 2533-2556
- 13 Banerjee SR, Foss CA, Castanares M. et al. Synthesis and evaluation of technetium-99m- and rhenium-labeled inhibitors of the prostate-specific membrane antigen (PSMA). J Med Chem 2008; 51 (15) 4504-4517
- 14 Maresca KP, Hillier SM, Lu G. et al. Small molecule inhibitors of PSMA incorporating technetium-99m for imaging prostate cancer: effects of chelate design on pharmacokinetics. Inorg Chim Acta 2012; 389: 168-175
- 15 Lu G, Maresca KP, Hillier SM. et al. Synthesis and SAR of 99mTc/Re-labeled small molecule prostate specific membrane antigen inhibitors with novel polar chelates. Bioorg Med Chem Lett 2013; 23 (05) 1557-1563
- 16 Robu S, Schottelius M, Eiber M. et al. Preclinical evaluation and first patient application of 99mTc-PSMA-I&S for SPECT imaging and radioguided surgery in prostate cancer. J Nucl Med 2017; 58 (02) 235-242
- 17 Hillier SM, Maresca KP, Lu G. et al. 99mTc-labeled small-molecule inhibitors of prostate-specific membrane antigen for molecular imaging of prostate cancer. J Nucl Med 2013; 54 (08) 1369-1376
- 18 Vallabhajosula S, Nikolopoulou A, Babich JW. et al. 99mTc-labeled small-molecule inhibitors of prostate-specific membrane antigen: pharmacokinetics and biodistribution studies in healthy subjects and patients with metastatic prostate cancer. J Nucl Med 2014; 55 (11) 1791-1798
- 19 Reinfelder J, Kuwert T, Beck M. et al. First experience with SPECT/CT using a 99mTc-labeled inhibitor for prostate-specific membrane antigen in patients with biochemical recurrence of prostate cancer. Clin Nucl Med 2017; 42 (01) 26-33
- 20 Schmidkonz C, Goetz TI, Kuwert T. et al. PSMA SPECT/CT with 99mTc-MIP-1404 in biochemical recurrence of prostate cancer: predictive factors and efficacy for the detection of PSMA-positive lesions at low and very-low PSA levels. Ann Nucl Med 2019; 33 (12) 891-898
- 21 Zhang J, Zhang J, Xu X. et al. Evaluation of radiation dosimetry of 99mTc-HYNIC-PSMA and imaging in prostate cancer. Sci Rep 2020; 10 (01) 4179-4187
- 22 Xu X, Zhang J, Hu S. et al. 99mTc-labeling and evaluation of a HYNIC modified small-molecular inhibitor of prostate-specific membrane antigen. Nucl Med Biol 2017; 48: 69-75
- 23 Kularatne SA, Zhou Z, Yang J, Post CB, Low PS. Design, synthesis, and preclinical evaluation of prostate-specific membrane antigen targeted (99m)Tc-radioimaging agents. Mol Pharm 2009; 6 (03) 790-800
- 24 Sergieva S, Mangaldgiev R, Dimcheva M, Nedev K, Zahariev Z, Robev B. SPECT-CT imaging with [99mTc] PSMA-T4 in patients with recurrent prostate cancer. Nucl Med Rev 2021; 24 (02) 70-81
- 25 Shi S, Yao L, Li L. et al. Synthesis of novel technetium-99m tricarbonyl-HBED-CC complexes and structural prediction in solution by density functional theory calculation. R Soc Open Sci 2019; 6 (11) 191247-191260
- 26 Vats K, Agrawal K, Sharma R, Sarma HD, Satpati D, Dash A. Preparation and clinical translation of 99mTc-PSMA-11 for SPECT imaging of prostate cancer. Med Chem Commun 2019; 10 (12) 2111-2117
- 27 Horoszewicz JS, Kawinski E, Murphy GP. Monoclonal antibodies to a new antigenic marker in epithelial prostatic cells and serum of prostatic cancer patients. Anticancer Res 1987; 7 (5B): 927-935
- 28 Lopes AD, Davis WL, Rosenstraus MJ, Uveges AJ, Gilman SC. Immunohistochemical and pharmacokinetic characterization of the site-specific immunoconjugate CYT-356 derived from antiprostate monoclonal antibody 7E11-C5. Cancer Res 1990; 50 (19) 6423-6429
- 29 Kahn D, Williams RD, Seldin DW. et al. Radioimmunoscintigraphy with 111indium labeled CYT-356 for the detection of occult prostate cancer recurrence. J Urol 1994; 152 (5 Pt 1): 1490-1495
- 30 Wynant GE, Murphy GP, Horoszewicz JS. et al. Immunoscintigraphy of prostatic cancer: preliminary results with 111In-labeled monoclonal antibody 7E11-C5.3 (CYT-356). Prostate 1991; 18 (03) 229-241
- 31 Eder M, Schäfer M, Bauder-Wüst U. et al. 68Ga-complex lipophilicity and the targeting property of a urea-based PSMA inhibitor for PET imaging. Bioconjug Chem 2012; 23 (04) 688-697





