Abstract
The majority of solid tumors have hypoxia, or low oxygen levels, which is one of the hallmarks of cancer. Hypoxia was found to relate to cancer metastases and resistance to therapies, therefore, detection of hypoxia plays an important role in the process of cancer prognosis and treatment. Single-photon emission computed tomography (SPECT) is a non-invasive imaging technique using gamma-emitting radiopharmaceuticals to visualize biological activities within the body. SPECT is also applied for the detection of tumor hypoxia with the development of hypoxia-targeting radiopharmaceuticals. Radiopharmaceuticals containing nitroimidazole moieties have received increasing attention due to their bio-reducible characteristics which make the radiopharmaceuticals accumulate in the hypoxia regions. This review summarizes the recent development of 99mTc-labeled radiopharmaceuticals bearing nitroimidazoles for SPECT imaging of tumor hypoxia including the synthetic methods and results of animal studies.
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Introduction
Molecular imaging is a non-invasive imaging method that enables the visualization and quantitative measurement of biological processes at cellular and molecular levels [1,2,3,4,5,6]. Molecular imaging has been applied in disease treatment and diagnosis, as well as in in vitro, animal, and clinical research [7,8,9,10,11,12,13]. Especially, in cancer research and treatment, molecular imaging provides precise and valuable information on tumor position, response to therapy, and cancer staging, making it useful for early detection of cancer [14,15,16,17,18,19]. These days, a number of molecular imaging techniques, including positron-emission tomography (PET) and single photon-emission computed tomography (SPECT), are widely used for the diagnosis and management of various diseases and drug development [20,21,22,23,24,25,26,27,28], many studies reported the labeling methods and synthesis of chelators to improve the effectiveness of PET and SPECT [29,30,31,32].
SPECT scan is a nuclear imaging technique that uses gamma rays to visualize the biological processes in the body by using a small dose of radioactive compounds called radiotracers or radiopharmaceuticals. SPECT uses gamma cameras to capture gamma radiation emitted by radiopharmaceuticals to visualize the uptake of radiopharmaceuticals by different organs or tissues of the body [33]. By combining various images taken by rotating gamma cameras, the SPECT instrument creates three-dimensional images of the body. SPECT is currently applied in the evaluation and diagnosis of numerous diseases including cancers, cardiovascular diseases, and brain disorders [34,35,36].
Technetium-99 m is a gamma ray-emitting radioisotope with a half-life of six hours, which is used for the production of SPECT radiopharmaceuticals. Recently, 99mTc has become common because it can be produced on-site using 99Mo/99mTc generators or kits. Additionally, a wide range of chelates was developed to form many types of complexes with 99mTc [37].
In most solid tumors, hypoxia defined as the lack of oxygen supply, is a common phenomenon due to uncontrolled tumor cell proliferation [38]. Hypoxia is a hallmark of cancer microenvironment and is related to many other hallmarks [39, 40]. Therefore, detection of hypoxia is vital for investigating cancer progression and treatment [41, 42]. Nitroimidazole moieties have been broadly used for developing hypoxia-detection agents due to their selective retention in cells and tissues with low levels of oxygen [43,44,45,46].
In this review, we summarize recent advances in synthetic procedures to produce 99mTc-labeled nitroimidazole derivatives for the detection of hypoxic tumors using SPECT as well as the animal studies on biodistribution and SPECT imaging of these radiopharmaceuticals since 2014.
Development of 99mTc-labeled Complexes Bearing Nitroimidazole
Synthesis of [99mTc(CO)3(L)]
In 2014, a 99mTc(CO)3 complex bearing ligand 2-amine-3-[2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethylthio] propanoic acid (L) was prepared by Rey and co-workers [47]. Compound 2 was prepared from metronidazole 1, triphenylphosphine, and iodine in DCM. A reaction of 2 with cysteine hydrochloride 3 in the presence of triethylamine in THF generated the desired ligand L (4) (Fig. 1). The fac-[99mTc(CO)3(H2O)3]+ precursor complex 5 was produced via the reaction of 99mTc-sodium pertechnetate with carbon monoxide in the presence of Na/K tartrate, Na2CO3, and NaBH4. The 99mTc-Precursor complex 5 could also be prepared from 99mTc-sodium pertechnetate by using an Isolink kit. Substitution reaction of neutralized fac-[99mTc(CO)3(H2O)3]+ complex and ligand L generated the desired 99mTc-labeled complex ([99mTc(CO)3(L)]) with > 90% radiochemical purity (Fig. 2). Biodistribution of radiopharmaceutical [99mTc(CO)3(L)] examined on normal CD1 mice showed moderate to low uptakes in liver, lung, and muscle; the normal tissue uptakes also decreased from 0.5 h to 4.0 h post-injection (p.i.). While on C57BL/6 mice with murine lung cancer, [99mTc(CO)3(L)] expressed the highest tumor uptake of 1.3 ± 0.4%injected dose/g (%ID/g) at 0.5 h p.i. then it reduced to 0.5 ± 0.1%ID/g at 1.0 h p.i., and remained a stable tumor uptake until 4.0 h p.i. Tumor/muscle ratio of [99mTc(CO)3(L)] was also competent at 4.0 h p.i. due to fast muscle clearance.
Synthesis of [99mTc(CO)3(BPA-PEG3-NIM)]+, [99mTc(CO)3(AOPA-PEG3-NIM)] and 99mTc(CO)3(IDA-PEG3-NIM)]–
In 2014, three 99mTc(CO)3-labeled complexes bearing different tridentate ligands connecting to 2-nitroimidazole moiety via PEG linker were developed by Liu and co-workers [48]. The substitution reaction of compound 7 with picolylamine 8 in the presence of Na2CO3 in acetonitrile, followed by a substitution reaction with tert-butyl 2-bromoacetate 9 in the presence of Na2CO3 in acetonitrile generated compound 10. Ligand AOPA-PEG3-NIM was obtained via hydrolysis of 10 with HCl. Substitution of the tosylate of 7 with an azide group by using NaN3 in DMF, followed by conversion of the azide group to an amine group by using PPh3 and water in THF solvent generating compound 12. The reaction of compound 12 with 2-chloromethyl pyridine hydrochloride 13 in the presence of Et3N in acetonitrile produced the desired ligand BPA-PEG3-NIM 14. Substitution reaction of compound 12 with tert-butyl 2-bromoacetate 9 in the presence of Na2CO3 in acetonitrile provided compound 16. Ligand IDA-PEG3-NIM was synthesized in quantitative yield from 15 via hydrolysis with HCl (Fig. 3). The [99mTc(CO)3(H2O)3]+ precursor was produced by using a procedure reported by Alberto and co-workers [49, 50]. The reaction of ligands with [99mTc(CO)3(H2O)3]+ in saline at 100 °C effectively generated the desired 99mTc-labeled complexes with high RCY and > 95% radiochemical purity (Fig. 4). The three 99mTc-labeled complexes were studied for biodistribution in S180 tumor-bearing Kunming mice. The initial tumor uptake at 5 min p.i. of [99mTc(CO)3(BPA-PEG3-NIM)]+ was 0.75 ± 0.08%ID/g, tumor uptake of [99mTc(CO)3(AOPA-PEG3-NIM)] was 0.70 ± 0.01%ID/g, and that of 99mTc(CO)3(IDA-PEG3-NIM)]– was 0.56 ± 0.09%ID/g, indicating the effects of different chelator and the charge of the complex on its tumor uptake. The tumor-to-muscle ratios of [99mTc(CO)3(AOPA-PEG3-NIM)] showed increasing contrast and were the highest among the three complexes, for instance, tumor/muscle ratio of [99mTc(CO)3(AOPA-PEG3-NIM)] reached maximum at 3.01 ± 1.20%ID/g at 2 h p.i.
Synthesis of Tridentate Ligands IDA, DETA and AEG
In 2014, Banerjee and co-workers synthesized nine ligands containing three different nitroimidazoles (2-, 4- and 5-nitroimidazole) and tridentates (iminodiacetic acid (IDA), diethylenetriamine (DETA), and aminoethylglycine (AEG) and radiolabeled with 99mTc by using [99mTc(CO)3(H2O)3]+ [51]. Reactions of 2-, 4-, and 5-nitroimidazole with compound 18 (N,N-bis[(tert-butoxycarbonyl)methyl]-3-bromopropylamine), followed by hydrolysis of ester groups produced IDA ligands 19a-c, respectively [52]. Diethylenetriamine 20 was selectively protected using Boc-ON in THF at 0 °C to afford compound 21. The reaction of 21 with DIEA and 1,3-dibromopropane 22 in acetonitrile under reflux generated compound 23. DETA ligands 24a-b were formed via the reaction of 23 with 2- and 4-nitroimidazoles in the presence of DIEA in acetonitrile under reflux, respectively, followed by a hydrolysis reaction with HCl. DETA ligand 24c was synthesized via the reaction between 1-(3-bromopropyl)-5-nitro-1H-imidazole 25, DIEA, and compound 21 in acetonitrile, followed by hydrolysis of the protecting groups. The reaction of N-Boc-ethylenediamine 26 with DIEA and tert-butyl bromoacetate 27 in acetonitrile, followed by a reaction with DIEA and 1,3-dibromopropane 22 in acetonitrile provided compound 28. Reactions of 28 with 2- and 4-nitroimidazoles and DIEA in acetonitrile under reflux generated the corresponding products, which were then hydrolyzed by HCl to produce the desired AEG ligands 29a-b. Compound 30 was formed via the reaction of N-Boc-ethylenediamine 26 with tert-butyl bromoacetate 27 and DIEA in acetonitrile, followed by the substitution reaction with 25. Hydrolysis of 30 with HCl produced the desired AEG ligand 29c (Fig. 5). Nine ligands (19a-c, 24a-c, and 29a-c) were successfully radiolabeled with [99mTc(CO)3(H2O)3]+ resulting in the desired 99mTc-radiopharmaceuticals in RCY and radiochemical purity over 94%, and specific activities over 104.8 μCi/μmol. Biodistribution of nine 99mTc-labeled radiopharmaceuticals studied on mice bearing fibrosarcoma tumor showed that the three 99mTc-radiopharmaceuticals containing IDA chelators had higher tumor uptake values and also better retention in the tumor with initial tumor uptakes ranging from 0.97 ± 0.06 to 1.33 ± 0.28%ID/g at 30 min p.i., and tumor uptakes ranging from 0.24 ± 0.06 to 0.66 ± 0.07%ID/g at 3 h p.i. Nonetheless, 99mTc-radiopharmaceuticals still expressed lower tumor uptakes compared to [18F]FMISO with tumor uptakes ranging from 4.65 ± 0.86 at 30 min p.i. to 2.04 ± 0.14 at 3 h p.i.
Synthesis of 99mTc-AM and 99mTc-triazole-2NIM
In vivo formation of 99mTc-radiolabeled imaging agent via a cyclooctyne-azide cycloaddition (SPAAC) reaction of 2-nitroimidazole-azide (2NIM-Az) with azadibenzocyclooctyne-MAMA (99mTc-AM) was developed by Chu and Sun in 2015 [53]. Ligand AM was synthesized via the condensation of amino-functional azadibenzocyclooctyne (ADIBO-C6-amine) 31 with monoamine-monoamide-dithiol amino acid (MAMA-AA) 32 in the presence of diisopropylethylamine in DMF (Fig. 6). Deprotection of the trityl group of trityl thioether groups of AM with TFA and triethylsilane in anisole and methanol, followed by reaction with 99mTc-glucoheptonate (99mTc-GH) afforded the desired 99mTc labeled complex (99mTc-AM) with > 95% radiochemical purity. 99mTc-triazole-2NIM was also synthesized via a SPAAC reaction and 99mTc radiolabeling reaction with > 95% radiochemical purity (Fig. 7). Biodistribution of pre-targeting strategy 99mTc-AM and the control radiopharmaceutical 99mTc-triazole-2NIM were tested on Kunming mice bearing S180 tumor. 99mTc-triazole-2NIM showed higher tumor uptakes (0.42 ± 0.05 and 0.54 ± 0.12%ID/g at 1 h and 8 h p.i., respectively) compared to the pre-targeting radiopharmaceutical 99mTc-AM (0.29 ± 0.04 and 0.25 ± 0.03%ID/g at 1 h and 8 h p.i., respectively). However, 99mTc-AM exhibited higher tumor-to-muscle ratios of 3.37 ± 0.40 and 5.01 ± 0.08%ID/g at 8 h p.i. compared to those of 99mTc-triazole-2NIM (1.38 ± 0.13%ID/g at 1 h p.i. and 0.72 ± 0.10%ID/g at 8 h p.i.).
Synthesis of 2-nitroimidazole–DPA–99mTc(CO)3
In 2016, Banerjee and co-workers reported the preparation of a 99mTc(CO)3 complex bearing 2-nitroimidazole–dipicolylamine (DPA) ligand [54]. The substitution reaction of 2-nitroimidazole 38 and 1,3-dibromopropane 39 in the presence of K2CO3 in acetonitrile afforded compound 40, which then underwent a substitution reaction with dipicolylamine in the presence of triethylamine to generate the desired ligand 2-nitroimidazole–DPA (42) (Fig. 8). Radiolabeling of 2-nitroimidazole–DPA ligand with [99mTc(CO)3(H2O)3]+ core in PBS produced 2-nitroimidazole–DPA–99mTc(CO)3 (43) with 96.7 ± 1.5% radiochemical purity and 107.4 ± 1.7 μCi/μmol specific activity (Fig. 9). Biodistribution of 2-nitroimidazole–DPA–99mTc(CO)3 complex was evaluated in fibrosarcoma-bearing Swiss mice and compared to complex 2-nitroimidazole–DETA–99mTc(CO)3. 2-Nitroimidazole–DPA–99mTc(CO)3 exhibited improved tumor uptakes of 0.70 ± 0.16%ID/g at 3 h p.i. in comparison to those of 2-nitroimidazole–DETA–99mTc(CO)3 (0.24 ± 0.06%ID/g at 3 h p.i.). However, tumor-to-background ratios of 2-nitroimidazole–DPA–99mTc(CO)3 and 2-nitroimidazole–DETA–99mTc(CO)3 complexes stayed similar despite modifications of the structures.
Synthesis of 99mTc(CO)3-radiolabeled Triazole derivatives of 2-, 4- and 5-nitroimidazoles
In 2016, three 99mTc-complexes were prepared from [99mTc(CO)3(H2O)3]+ and triazole ligands bearing 2-, 4-, and 5-nitroimidazole by Banerjee and co-workers [55]. The nucleophilic substitution of 2-nitroimidazole with 1,3-dibromopropane in the presence of anhydrous K2CO3 in acetonitrile produced compound 46a. The mixture of compounds 46b and 46c was generated via the substitution reaction of 4-nitroimidazole with 1,3-dibromopropane catalyzed by K2CO3 in acetonitrile. After separation, compounds 46b and 46c were obtained in yields of 75% and 11%, respectively. The 2-, 4-, and 5-nitroimidazole azides (47a-c) were synthesized via the substitution reaction of the bromide group of compounds 46a-c with sodium azide in DMF. Copper-catalyzed alkyne-azide click reactions of nitroimidazole azides 47a-c with L-propargyl glycine 48 were carried out in the presence of CuSO4·2H2O and ascorbic acid in water to produce triazole ligands (49a-c) (Fig. 10). [99mTc(CO)3(H2O)3]+ core was obtained from the reaction between Na99mTcO4, NaBH4, Na2CO3, sodium potassium tartrate, and CO in distilled water. Radiolabeling of triazole ligands (49a-c) via a substitution reaction with [99mTc(CO)3(H2O)3]+ generated desired 99mTc(CO)3 complexes bearing 2-, 4-, and 5-nitroimidazoles with > 90% radiochemical purity and 105.55 ± 1.11, 107.03 ± 0.64 and 107.77 ± 1.11 μCi/μmol specific activities, respectively (Fig. 11). The 99mTc(CO)3 complexes were studied for biodistribution in fibrosarcoma tumor-bearing Swiss mice. Compared to 99mTc(CO)3 complexes bearing 2- and 4- nitroimidazoles, the complexes bearing 5-nitroimidazole exhibited higher tumor uptakes (ranging from 2.03 ± 0.32 to 0.81 ± 0.06%ID/g at 30 min and 3 h p.i.). However, 99mTc(CO)3 complexes bearing 2-, 4- and 5- nitroimidazoles showed comparable tumor-to-background ratios.
Synthesis of 99mTc-5-ntm-asp
In 2016, a 99mTc-labeled complex bearing 3-amino-4-[2-(2-methyl-5-nitro-1H-imidazol)-ethylamino]-4-oxo-butyrate (5-ntm-asp) ligand was produced by Li and co-workers [56]. Alkylation of phthalic diamide 52 with metronidazole 51 in the presence of triphenylphosphine and DIAD in diethylene oxide generated compound 53, which then reacted with HBr under reflux to provide compound 54. The reaction of 54 with Boc-Asp-OBzl in DCM, followed by hydrolysis with triflic acid and TFA afforded ligand 5-nitroimidazole-asparagine (55) (Fig. 12). The target 99mTc-labeled complex (99mTc-5-ntm-asp) was prepared to high radiochemical purity via the reaction of ligand 55 with potassium sodium tartrate and Na[99mTcO4] in the presence of SnCl2 and HCl (Fig. 13). Previously published complexes 99mTc-2-ntm-IDA and 99mTc-5-ntm-IDA, which comprised ligands 2-ntm-IDA and 5-ntm-IDA (Fig. 14) were also synthesized [51]. When applying three complexes in biodistribution studies in BALB/c nude mice bearing A549 lung cancer, 99mTc-5-ntm-asp showed the highest initial tumor uptake of 1.02 ± 0.10 at 30 min p.i. but remained comparable to the two99mTc-complexes bearing IDA at 2 h p.i. and 4 h p.i. However, due to its lower lipophilicity, 99mTc-5-ntm-asp exhibited better pharmacokinetics with comparatively high tumor-to-blood ratios (1.57 ± 0.02%ID/g at 30 min p.i. and 1.55 ± 0.03%ID/g at 4 h p.i.).
Synthesis of [99mTc(NS3)(2NimNC)] and [99mTc(NS3)(MetNC)]
In 2017, by applying ‘4 + 1’ mixed-ligand strategy, Banerjee and co-workers developed two 99mTc-complexes containing isocyanide derivative of 2-nitroimidazole ([99mTc(NS3)(2NimNC)]) and metronidazole ([99mTc(NS3)(MetNC)]) [57]. The synthesis of the isocyanide derivative of 2-nitroimidazole (2NimNC, 62) and the isocyanide derivative of metronidazole (MetNC, 65) was conducted as shown in Fig. 15. The reaction of 2-nitroimidazole and tert-butyl N-(3-bromopropyl)carbamate 58 in the presence of K2CO3 in acetonitrile, followed by hydrolysis with HCl in methanol provided hydrochloride salt 60. The reaction of 60, ethylformate, and triethylamine at reflux generated intermediate 61. The product 2NimNC (62) was afforded via the transformation of the formamide group of 61 into the isocyanide group with phenyldichlorophosphate in the triethylamine/DCM solvent mixture. The metronidazole hydrochloride salt 63 was converted to a formamide derivative of metronidazole 64 via a reaction with ethylformate and triethylamine at reflux. MetNC (65) was prepared from 64 under the same conditions as the synthesis of 2NimNC (62) (Fig. 15). The 99mTc-EDTA precursor complex was obtained via the reaction of Na99mTcO4 and Na2EDTA in the presence of mannitol and SnCl2. Ligand exchanges of hexadentate ligand EDTA with monodentate 2NimNC or MetNC and tetradentate NS3 generated the desired 99mTc-labeled complexes with RCY > 90%, radiochemical purity > 90%, and high specific activities (438.6 ± 1.9 and 443 ± 1.2 μCi/μmol), respectively (Fig. 16). Biodistribution of [99mTc(NS3)(2NimNC)] and [99mTc(NS3)(MetNC)] examined in fibrosarcoma tumor-bearing Swiss mice showed comparable tumor uptakes of the two complexes with initial tumor uptakes of 0.84 ± 0.05 and 0.78 ± 0.08%ID/g at 30 min p.i., respectively and reduced tumor uptakes of 0.34 ± 0.03 and 0.44 ± 0.06%ID/g at 3 h p.i. Both complexes exhibited improved tumor-to-background ratios from 30 min p.i. to 3 h p.i. in which [99mTc(NS3)(2NimNC)] had tumor-to-blood and tumor-to-muscle ratios of 1.24 ± 0.08 and 4.76 ± 1.08%ID/g at 3 h p.i., respectively, and [99mTc(NS3)(MetNC)] had those ratios of 0.89 ± 0.07 and 4.84 ± 1.49%ID/g at 3 h p.i.
Synthesis of 99mTc-2-MBI
In 2020, Zhang and co-workers produced a 99mTc-labeled complex containing 2-mercaptobenzimidazole (2-MBI) ligand for the detection of tumor hypoxia [58]. 2-MBI ligand was prepared via the reaction of o-phenylenediamine 69 with carbon disulfide in the presence of KOH in ethanol/water solvent. After flushing CO into saline solution containing Na2CO3, NaBH4, and potassium sodium tartrate, adding 99mTcO4− and heating the reaction mixture to 75–80 °C produced the [99mTc(CO)3(H2O)3]+ precursor 71. Coordination reaction of [99mTc(CO)3(H2O)3]+ precursor with 2-MBI as a didentate ligand generated the target 99mTc-labeled complex (99mTc-2-MBI) with 96 ± 0.9% radiochemical purity (Fig. 17). Biodistribution study of 99mTc-2-MBI complex conducted in S180 tumor-bearing BALB/c mice indicated high tumor uptake values of 11.17 ± 1.77%ID/g at 30 min p.i. and 12.94 ± 2.09%ID/g at 4 h p.i, and good retention at 24 h p.i. (9.95 ± 1.89%ID/g). 99mTc-2-MBI exhibited maximum tumor-to-muscle ratio of 4.14 ± 0.77%ID/g and tumor-to-blood ratio of 3.91 ± 0.63%ID/g at 24 h p.i. High accumulation of 99mTc-2-MBI was also observed in scintigraphic imaging studies in S180 tumor-bearing BALB/c mice with a tumor-to-non-tumor ratio of 3.39 ± 0.38 (Fig. 18).
Synthesis of 99mTc-tricine-TPPTS-HYNICNM, 99mTc-tricine-TPPMS-HYNICNM, and 99mTc-(tricine)2-HYNICNM
In 2021, Zhang and co-workers developed a 99mTc-complex containing co-ligands 6-hydrazinonicotinamide 2-nitroimidazole derivative (HYNICNM) ligand, triphenylphosphine-3,3′,3′′-trisulfonate (TPPTS) ligand, triphenylphosphine-3-monosulfonate (TPPMS) and tricine [59]. 2-Nitroimidazole reacted with N-(2-bromoethyl)phthalimide 75 to generate compound 76, which then reacted with hydrazine hydrate to produce compound 77. Compound 81 was also prepared via the reaction of 6-chloronicotinic acid 78 with hydrazine hydrate to give 6-hydrazinylnicotinic acid 79, followed by a reaction of 79 with sodium 2-formylbenzenesulfonate 80, then with NHS and DCC. The reaction of compound 81 with 77 in the presence of triethylamine in DMF generated the desired ligand HYNICNM (Fig. 19). Three 99mTc-labeled complexes were prepared via reactions with co-ligands and Na99mTcO4 using SnCl2 as a reducing agent in an acetate buffer solution. In particular, complexes 99mTc-tricine-TPPTS-HYNICNM and 99mTc-tricine-TPPMS-HYNICNM were prepared by the treatment of Na99mTcO4, HYNICNM ligand, tricine, and TPPTS or TPPMS, respectively. Complex 99mTc-(tricine)2-HYNICNM was obtained from Na99mTcO4, HYNICNM ligand, and excess tricine (Fig. 20). Three 99mTc-labeled complexes were synthesized with high RCY (> 95%) and high radiochemical purity (> 95%). In biodistribution studies in S180 tumor-bearing mice, 99mTc-tricine-TPPTS-HYNICNM exhibited the most competent tumor uptake at 2 h p.i. (1.05 ± 0.27%ID/g), and the highest tumor-to-blood and tumor-to-muscle ratios at 2 h p.i. (1.44%ID/g and 5.05%ID/g, respectively) among the three complexes. Therefore, complex 99mTc-tricine-TPPTS-HYNICNM was applied for SPECT/CT imaging studies in S180 tumor-bearing Kunming female mice. 99mTc-tricine-TPPTS-HYNICNM showed the visible accumulation at the tumor site at 2 h p.i. besides high uptakes in kidneys, large intestine, gall bladder, and urinary bladder (Fig. 21).
Synthesis of [99mTc]77a-d
In 2022, four 99mTc(CO)3-complexes containing cyclopentadienyl ligands bearing 2-nitroimidazole were prepared by Su and Chu, in which 2-nitroimidazole moieties were connected to cyclopentadienyl ligands via linkers with different length of carbon chains [60]. Ferrocene was transformed into iron coordinations 88a-c via functionalization of cyclopentadienyl with 4-bromobutyryl chloride 87a-c in the presence of AlCl3 in DCM. Substitution reactions between bromides of complexes 88a-c and 2-nitroimidazole in the presence of K2CO3 in DMF generated complexes 89a-c. Complex 91 was generated from complex 88a in three steps including the substitution reaction of 88a with diethanolamine 90 using triethylamine as a base in DMF, tosylation by TsCl in the presence of NaOH in DCM to generate complex 91, and reaction with 2-nitroimidazole using a similar method as the synthesis of 89a-c (Fig. 22). Radiolabeling reactions of four complexes 89a-c and 92 with 99mTcO4− and Mn(CO)5Br were performed in DMF at 140 °C to give four corresponding 99mTc-labeled complexes Tc-93a-d with >95% radiochemical purity (Fig. 23). The four 99mTc-complexes were studied for biodistribution in S180 tumor-bearing mice. Tc-93b exhibited a higher tumor uptake of 2.23 ± 0.24%ID/g at 2 h p.i. compared to Tc-93a and Tc-93c which also contained one nitroimidazole moiety. Tc-93b also showed a comparable tumor-to-muscle ratio of 1.73 ± 0.29 and tumor-to-blood ratio of 3.56 ± 0.25%ID/g at 2 h p.i. Tc-93d had a better tumor uptake and tumor-to-muscle ratio (3.19 ± 0.77 and 3.47 ± 0.47%ID/g, respectively) at 2 h p.i. compared to Tc-93b due to bearing two nitroimidazole groups. Tc-93b and Tc-93d complexes were used to conduct SPECT imaging of S180 tumor-bearing mice and exhibited observable radioactivity accumulation at tumor regions (Fig. 24).
Development of 99mTc-labeled Complexes Bearing Di-Nitroimidazoles
Synthesis of 99mTc-EC-MISO
In 2015, Chen and co-workers reported the synthetic method and hypoxia-targeting studies of the complex 99mTc-Ethylenedicysteine-bis-misonidazole (99mTc-EC-MISO) [61]. Nucleophilic substitution of 2-nitroimidazole with N-(2,3-epoxypropyl)phthalimide 94 in the presence of K2CO3 in ethanol provided compound 95, and the reaction of 95 with hydrazine in ethanol produced compound 96. EC 97 was activated by EDC-HCl and sulfo-N-hydroxysuccinimide (NHS) and reacted with 96 to afford the precursor EC-MISO. The precursors EC and EC-MISO were radiolabeled with 99mTcO4− in the presence of SnCl2 as a reducing agent and DTT as a protective agent to provide 99mTc-EC and 99mTc-EC-MISO in 90% and 94% radiochemical purities, respectively (Fig. 25). Biodistribution studies of 99mTc-EC-MISO in mice bearing subcutaneous C6 gliomal tumor indicated steady tumor uptakes (1.28 ± 0.22%ID/g at 30 min p.i. and 1.29 ± 0.21%ID/g at 4 h p.i.) and increasing tumor-to-muscle ratios from 2.99%ID/g at 30 min p.i. to 4.68%ID/g at 4 h p.i. Two complexes 99mTc-EC and 99mTc-EC-MISO were applied in SPECT/CT imaging studies in mice bearing tumor. 99mTc-EC-MISO accumulation was observed at the tumor at 30 min and 2 h p.i., which was in accordance with biodistribution studies (Fig. 26). On the other hand, the control complex 99mTc-EC showed no detected radioactivity at the tumor site.
Synthesis of 99mTc-2P2O1, 99mTc-2P2O2, and 99mTc-2P2O4
In 2023, Li and Chu reported the preparation of 99mTc-complexes 99mTc-2P2O1, 99mTc-2P2O2, and 99mTc-2P2O4 [62] by PEG modifying previously reported complex 99mTc-2P2 [63]. Substitution reactions of mono-, di- and tetraethylene glycol with 3,3-dimethylallyl bromide 100 in the presence of KOH in THF, followed by tosylation reaction with TsCl and Et3N produced tosylated PEG derivatives 102a-c. 2-Nitroimidazole reacted with compounds 102a-c in the presence of K2CO3 in acetonitrile to generate nitroimidazole derivatives containing different ethylene glycol units 103a-c. Oxime compounds 105a-c were synthesized via reactions of 103a-c with isoamyl nitrite 104 and hydrochloric acid. Substitution of the chloride in 105a-c with 1,3-propanediamine 106 in the presence of N,N-diisopropylethylamine in acetonitrile afforded the desired ligands 2P2O1, 2P2O2, and 2P2O4, respectively (Fig. 27). The three ligands were radiolabeled with an aqueous solution of 99mTcO4−, sodium tartrate, and stannous chloride as a reducing agent to produce complexes 99mTc-2P2O1, 99mTc-2P2O2, and 99mTc-2P2O4 with good radiochemical purity (> 90%). Biodistribution of the three complexes was examined in mice bearing S180 tumor. 99mTc-2P2O1, 99mTc-2P2O2, and 99mTc-2P2O4 showed comparable tumor uptakes of 0.79 ± 0.20, 1.00 ± 0.26, and 0.71 ± 0.14%ID/g at 4 h p.i., respectively, and also similar to 99mTc-2P2 with tumor uptake of 0.86 ± 0.22%ID/g. Compared to 99mTc-2P2, 99mTc-2P2O1, 99mTc-2P2O2, and 99mTc-2P2O4 exhibited higher tumor-to-blood ratios due to the longer ethylene glycol chain. Among the three complexes, 99mTc-2P2O4 was considered the most effective complex with the highest tumor-to-blood ratio of 2.13 ± 0.19.
Synthesis of 99mTc-EDTA-4-EtNHNM
In 2017, Zhang and co-workers developed the 99mTc-labeled 4-nitroimidazole EDTA derivative 99mTc-EDTA-4-EtNHNM [64]. 4-Nitroimidazole reacted with N-(2-bromoethyl)phthalimide 109 in the presence of K2CO3 in DMF to generate compound 165, which was then transformed into hydrochloride salt 111 via a reaction with hydrazine and HCl [65]. The reaction of 111 with ethylenediaminetetraacetic dianhydride (112) and triethylamine provided the desired ligand EDTA-4-EtNHNM (113) (Fig. 28). EDTA-4-EtNHNM (113) was labeled with 99mTcO4− in the presence of SnCl2 in saline to afford 99mTc-EDTA-4-EtNHNM with high RCY and high radiochemical purity (> 95%). Additionally, 99mTc-EDTA was synthesized using the method described in the study by Cash and co-workers in 1980 [66]. Biodistribution studies of 99mTc-EDTA-4-EtNHNM and 99mTc-EDTA in S180 tumor-bearing mice showed that 99mTc-EDTA-4-EtNHNM had a better tumor uptake (1.38 ± 0.22%ID/g) than 99mTc-EDTA (1.18 ± 0.06%ID/g) at 2 h p.i. 99mTc-EDTA-4-EtNHNM and 99mTc-EDTA were applied in the SPECT imaging studies in the S180 tumor-bearing mice. Accumulation of both 99mTc-complexes at tumor regions was observed, which was according to the results of biodistribution studies (Fig. 29). In particular, the tumor-to-non-tumor regions of interest ratio of 99mTc-EDTA-4-EtNHNM was 3.30 and that of 99mTc-EDTA was 1.62.
Synthesis of 99mTc-EDTA-2-EtNHNM
In 2018, Zhang and co-workers continued to develop a 99mTc-complex bearing EDTA derivative of 2-nitroimidazole [67], to improve the tumor-to-blood ratio of previously reported complex 99mTc-EDTA-4-EtNHNM [64]. Compound 117 was synthesized from 2-nitroimidazole via the reaction of 2-nitroimidazole with N-(2-bromoethyl)phthalimide 115 in the presence of K2CO3 in DMF, followed by treatment with hydrazine. The reaction of 117 with ethylenediaminetetraacetic dianhydride 118 and triethylamine afforded ligand EDTA-2-EtNHNM (119) (Fig. 30) [64]. EDTA-2-EtNHNM was radiolabeled with 99mTcO4− in the presence of reducing agent SnCl2 to produce 99mTc-EDTA-2-EtNHNM with high RCY and radiochemical purity. Biodistribution studies in S180 tumor-bearing mice showed that at 4 h p.i., 99mTc-EDTA-2-EtNHNM and 99mTc-EDTA-4-EtNHNM exhibited comparable tumor uptakes of 1.17 ± 0.23 and 1.04 ± 0.15%ID/g. The tumor-to-muscle and tumor-to-blood ratios of 99mTc-EDTA-2-EtNHNM (6.27 and 2.02%ID/g at 4 h p.i., respectively) were improved when compared to 99mTc-EDTA-4-EtNHNM (4.41 and 0.99%ID/g at 4 h p.i., respectively). SPECT/CT results of 99mTc-EDTA-2-EtNHNM complex were in accordance with the biodistribution studies, in which accumulation of 99mTc-EDTA-2-EtNHNM at the tumor site was clearly observed (Fig. 31). The labeling efficiency, animal models for in vivo experiments, and importantly, the advantages and disadvantages of the mentioned 99mTc-labeled radiotracers are summarized in Table 1.
Conclusion
Hypoxia is found in the majority of solid tumors, thus, the detection of hypoxia plays an important role in diagnosis and treatment of cancer. SPECT is a non-invasive molecular imaging technique with various clinical uses and applications, especially in cancer treatment [68,69,70]. Compared to PET, SPECT is a more affordable and convenient molecular imaging technique. However, the resolution obtained with SPECT imaging is still lower than PET imaging and needs to be improved. Therefore, developing novel radiopharmaceuticals for SPECT imaging of cancers has received increasing interest recently.
Numerous SPECT radiopharmaceuticals are radiolabeled with 99mTc due to the convenience of 99mTc production with generators. Moreover, 99mTc can easily form coordination with many different types of chelating agents, successfully generating varied radiolabeled complexes mostly in good RCY. Notably, the 99mTc-labeled prostate-specific membrane antigen ([99mTc]Tc-PSMA) has been tested and applied in clinical studies for the diagnosis of prostate cancer using SPECT/CT [71,72,73].
The hypoxia-targeting moieties nitroimidazoles can be incorporated into 99mTc-labeled radiotracers by using diverse bifunctional chelating agents. Among the mentioned studies, testing several chelators with the nitro group at different positions on nitroimidazole moiety such as 2-nitroimidazole, 4-nitroimidazole, and 5-nitroimidazole is a common approach to improve hypoxia-targeting efficiency of 99mTc-labeled radiotracers. In addition, some 99mTc-labeled radiotracers containing several nitroimidazole moieties in the structures showed improved tumor uptake, which is also probable to enhance the hypoxia-targeting activity of radiotracers.
Besides the types and number of nitroimidazoles, other factors can also affect the pharmacokinetics and selective accumulation in hypoxic regions of the 99mTc-labeled complexes, namely the hydrophilicity, linkers’ length, and functional groups presenting in the structures. In particular, investigating the effect of different lengths of linkers is an approach to change the hydrophilicity thus might affect tumor uptake and retention, as well as the clearance from blood and non-tumor tissues. It is noteworthy that appropriate pharmacokinetics is important to the efficiency of hypoxia-targeting imaging agents. For example, increasing the hydrophilicity of radiotracers would lead to fast blood clearance, which might result in a better tumor-to-blood contrast, on the other hand, it might reduce the tumor uptake values due to lack of time for diffusion.
With the diversity of chelating agents, novel 99mTc-labeled complexes have been designed and developed with improved pharmacokinetics, tumor accumulation, and tumor-to-background contrast. This review summarizes the recent advances in synthetic methods to produce 99mTc-labeled nitroimidazole derivatives for the detection of hypoxia using the SPECT imaging technique.
Data Availability
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This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (NRF-2021R1A2C1011204).
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Nguyen, A.T., Kim, HK. Recent Progress in Synthesis of 99mTc-labeled Complexes with Nitroimidazoles as SPECT Probes for Targeting Tumor Hypoxia. Nucl Med Mol Imaging 58, 258–278 (2024). https://doi.org/10.1007/s13139-024-00860-7
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DOI: https://doi.org/10.1007/s13139-024-00860-7