Potential Tumor Imaging Agent Research Articles

Development of a Novel 99mTc-Labeled Folate Derivative Containing Phenyl Isonitrile to Target Folate Receptor with Reduced Renal Uptake.

The folate receptor has attracted much attention in the field of radiolabeled imaging agents due to the significant difference in its expression levels between tumor cells and most normal cells. However, the development of folate-based imaging agents has been limited by their high uptake in the kidney. In this study, to reduce the high renal uptake of radiolabeled folate-based tracers, a phenyl-isonitrile folate derivative (CNMBFA) was designed and labeled with technetium-99m. The complex obtained via the one-step kit labeling method had a high labeling yield (>95%) and high in vitro stability and hydrophilicity (log D7.4 = -1.72 ± 0.13). The results of the in vitro cell uptake and blocking studies and competitive binding experiments revealed that the [[99mTc]Tc-(CNMBFA)6]+ complex was specific for the folate receptor. Biodistribution and inhibition studies in KB tumor-bearing mice revealed moderate uptake and significant inhibition of the complex in tumors, whereas the renal uptake of [[99mTc]Tc-(CNMBFA)6]+ was significantly lower than that of previously reported tracers. Micro-SPECT/CT images further supported its ability to target the folate receptor for tumor imaging. Taken together, these results indicate that [[99mTc]Tc-(CNMBFA)6]+ is a potential tumor imaging agent that has good tumor-targeting properties with minimal radiation damage to the kidney.

Effect of Polar Head Group Modifications on the Tumor Retention of Phospholipid Ether Analogs: Role of the Quaternary Nitrogen.

We have previously described the remarkable capacity of radioiodinated alkyl phospholipids to be sequestered and retained by a variety of tumors in vivo. We have already established the influence of certain structural parameters of iodinated alkyl phospholipids on tumor avidity, such as stereochemistry at the sn-2 carbon of alkylglycerol phosphocholines, meta-or para-position of iodine in the aromatic ring of phenylalkyl phosphocholines, and the length of the alkyl chain in alkyl phospholipids. In order to determine the additional structural requirements for tumor uptake and retention, three new radioiodinated alkylphospholipid analogs, 2-4, were synthesized as potential tumor imaging agents. Polar head groups were modified to determine structure-tumor avidity relationships. The trimethylammonio group in 1 was substituted with a hydrogen atom in 2, an ammonio group in 3 and a tertiary butyl group in 4. All analogs were separately labeled with iodine-125 or iodine-124 and administered to Walker 256 tumor-bearing rats or human PC-3 tumor-bearing SCID mice, respectively. Tumor uptake was assessed by gamma-camera scintigraphy (for [I-125]-labeled compounds) and high-resolution micro-PET scanning (for [I-124]-labeled compounds). It was found that structural modifications in the polar head group of alkyl phospholipids strongly influenced the tumor uptake and tissue distribution of these compounds in tumor-bearing animals. Phosphoethanolamine analog 3 (NM401) displayed a very slight accumulation in tumor as compared with phosphocholine analog 1 (NM346). Analogs 2 (NM400) and 4 (NM402) lacking the positively charged nitrogen atom failed to display any tumor uptake and localized primarily in the liver. This study provided important insights regarding structural requirements for tumor uptake and retention. Replacement of the quaternary nitrogen in the alkyl phospholipid head group with non-polar substituents resulted in loss of tumor avidity.

Radiolabeling and Biological Evaluation of Novel 99mTc-Nitrido and 99mTc-Oxo Complexes with 4-Methoxy-L-Phenylalanine Dithiocarbamate for Tumor Imaging.

To develop novel radiolabeled amino acid tumor imaging agents, 4-methoxy-L-phenylalanine dithiocarbamate (MOPADTC) was synthesized successfully, and two kinds of 99mTc-labeled complexes ([99mTc]TcN-MOPADTC and [99mTc]TcO-MOPADTC) with high radiochemical purities (RCP > 95%) were obtained. The in vitro stability and partition coefficient were determined, and the results show that both of these complexes have good in vitro stability; [99mTc]TcO-MOPADTC is hydrophilic, while [99mTc]TcN-MOPADTC is slightly lipophilic. The biodistribution of [99mTc]TcN-MOPADTC and [99mTc]TcO-MOPADTC in mice bearing S180 tumors shows that the tumor uptake and tumor/muscle ratio of [99mTc]TcO-MOPADTC were higher than the tumor uptake and tumor/muscle ratio of [99mTc]TcN-MOPADTC. In addition, the tumor retention of [99mTc]TcO-MOPADTC is better than the tumor retention of [99mTc]TcN-MOPADTC. A competitive inhibition assay was performed, and the results indicate that [99mTc]TcO-MOPADTC may enter cells primarily via the L-alanine/L-serine/L-cysteine (ASC) system. Single-photon emission computed tomography (SPECT) imaging of [99mTc]TcO-MOPADTC shows obvious accumulation in tumor sites, suggesting that [99mTc]TcO-MOPADTC is a novel potential tumor-imaging agent.

Technetium-99m Labeling of Antineoplaston A10 and Its Bioevaluation as a Potential Tumor Imaging Agent

Technetium-99m Labeling of Antineoplaston A10 and Its Bioevaluation as a Potential Tumor Imaging Agent

Preparation and Evaluation of Novel Folate Isonitrile 99mTc Complexes as Potential Tumor Imaging Agents to Target Folate Receptors

In order to seek novel technetium-99m folate receptor-targeting agents, two folate derivatives (CN5FA and CNPFA) were synthesized and radiolabeled to obtain [99mTc]Tc-CN5FA and [99mTc]Tc-CNPFA complexes, which exhibited high radiochemical purity (>95%) without purification, hydrophilicity, and good stability in vitro. The KB cell competitive binding experiments indicated that [99mTc]Tc-CN5FA and [99mTc]Tc-CNPFA had specificity to folate receptor. Biodistribution studies in KB tumor-bearing mice illustrated that [99mTc]Tc-CN5FA and [99mTc]Tc-CNPFA had specific tumor uptake. Compared with [99mTc]Tc-CN5FA, the tumor/muscle ratios of [99mTc]Tc-CNPFA were higher, resulting in a better SPECT/CT imaging background. According to the results, the two 99mTc complexes have potential as tumor imaging agents to target folate receptors.

99mTc radiolabeling of polyethylenimine capped carbon dots for tumor targeting: synthesis, characterization and biodistribution

Purpose Due to the favorable physicochemical properties and the biocompatibility, carbon dots (CDs) have gained a great attention as a tumor targeting agent. This study investigates polyethylenimine capped CDs (PEI capped CDs) as a prospective nanocarrier of technetium-99m (99mTc) for tumor targeting. Technetium-labeled CDs could be introduced as a promising candidate for single photon emission tomography (SPECT) imaging. Materials and methods Polyethylenimine capped CDs were prepared by hydrothermal method using hyperbranched PEI and citric acid. For a purpose of comparison, citrate capped CDs were also prepared by microwave irradiation. Both types of CDs were characterized and radiolabeled with 99mTc using sodium borohydride (NaBH4) as a reducing agent. Biodistribution and tumor targeting efficiency of the produced radiolabeled CDs have been studied in Earlich ascites tumor mice model. Results Citrate capped CDs and PEI capped CDs have been synthesized successfully and characterized. High radiochemical yield of 99mTc-citrate capped CDs 99mTc-PEI capped CDs was obtained (97 ± 0.7 and 90 ± 0.2, respectively). Biodistribution studies of 99mTc-labeled PEI capped CDs have shown a potential tumor uptake (10 ± 0.5% Radioactivity/gram tumor) with high target to non-target ratio (T/NT) around 7 at 1-h post injection. 99mTc-citrate capped CDs have achieved a lower tumor uptake level (3.8 ± 0.3% Radioactivity/gram tumor 1 h post injection). Conclusion This study introduces PEI capped CDs as a promising nanocarrier of 99mTc for efficient tumor targeting. Technetium-labeled PEI capped CDs could be utilized as a potential SPECT tumor imaging agent.

SP-017 - Novel 99mTc labelled proline isocyanide derivatives as potential tumour imaging agents

SP-017 - Novel 99mTc labelled proline isocyanide derivatives as potential tumour imaging agents

18-F-Fluoroglucosylation of an arginine-arginine-leucine peptide as a potential tumor imaging agent for positron emission tomography

18-F-Fluoroglucosylation of an arginine-arginine-leucine peptide as a potential tumor imaging agent for positron emission tomography

18-F-Fluoroglucosylation of an arginine-arginine-leucine peptide as a potential tumor imaging agent for positron emission tomography

18-F-Fluoroglucosylation of an arginine-arginine-leucine peptide as a potential tumor imaging agent for positron emission tomography

Evaluation and comparison of 99mTc‐labeled d‐glucosamine derivatives with different 99mTc cores as potential tumor imaging agents

Isocyanide is a strong coordination ligand that can coordinate with [99mTc(I)(CO)3]+ core and [99mTc(I)]+ core to produce stable 99mTc complexes, therefore developing a 99mTc‐labeled isocyanide complex for single‐photon emission computed tomography (SPECT) imaging is considered to be of great interest. In order to develop potential tumor imaging agents with satisfied tumor uptake and suitable pharmacokinetic properties in vivo, a novel d‐glucosamine isocyanide derivative, 4‐isocyano‐N‐(2,4,5‐trihydroxy‐6‐(hydroxymethyl)tetrahydro‐2H‐pyran‐3‐yl)butanamide (CN3DG), was synthesized and radiolabeled with [99mTc(I)]+ and [99mTc(CO)3]+ cores to obtain [99mTc(CN3DG)6]+ and [99mTc(CO)3(CN3DG)3]+ in high radiolabeling yields (>95%). Both of the complexes showed good hydrophilicity and great stability in vitro. Cell uptake studies performed in S180 cells demonstrated they were transported into cells by glucose transporters. Biodistribution studies of the two complexes in mice bearing S180 tumor showed they had high tumor uptakes and rapid clearance from muscle and blood so that the tumor/blood and tumor/muscle ratios were high. By comparison, [99mTc(CN3DG)6]+ was superior to [99mTc(CO)3(CN3DG)3]+ in regard to tumor uptake, tumor/blood and tumor/liver ratios. S180 tumors could be seen clearly from the SPECT/CT images with [99mTc(CN3DG)6]+. Considering its favorable properties, [99mTc(CN3DG)6]+ would be a promising tumor imaging agent and needs to be further studied.

Design, synthesis, and biological evaluation of F-18-labelled 2, 4-diaminopyrimidine-type FAK-targeted inhibitors as potential tumour imaging agents

As a type of intracellular nonreceptor tyrosine kinase, focal adhesion kinase (FAK) can be highly expressed in most types of tumours and is thus regarded as a promising antitumour target. In this study, a series of novel 2,4-diaminopyrimidine FAK-targeted inhibitors were designed, synthesized and characterized by 1H NMR, 13C HNMR, and HRMS spectra. These compounds, with an IC50 range of 5.0–205.1 nM, showed superior inhibitory activity against FAK. Two compounds, [18F]Q-2 and [18F]Q-4, with respective IC50 values of 5.0 nM and 21.6 nM, were labelled by 18F, accompanied by evaluation of their biodistributions. For [18F]Q-2, at 30 min post-injection, promising target-to-nontarget ratios were observed, associated with tumour/blood, tumour/muscle, and tumour/bone ratios of 1.17, 2.99 and 2.19, respectively. The results indicated that [18F]Q-2 is a potential PET tracer for tumour diagnosis.

Synthesis and evaluation of Al18F-NODA complex conjugated 2-(4-aminophenyl)benzothiazole as a potential tumor imaging agent

The objective of the study was to prepare and evaluate a 18F-radiolabled tracer (Al18F-5), derivated from the antitumor agent 2-(4-aminophenyl)benzothiazole, as a PET probe for tumor imaging. Al18F-5 was successfully prepared with approx. 40% radiochemical yield in aqueous phase. In in vitro cell uptake experiments and competition assay, Al18F-5 displayed good tumor-binding ability and specificity in HeLa cells (24.7 ± 0.9% ID/106 cells, IC50 = 63.8 ± 13.6 nM) and MCF-7 cells (6.8 ± 0.3% ID/106 cells, IC50 = 331.1 ± 33.7 nM). The nonradioactive compound, Al19F-5, visibly marked HeLa cells and MCF-7 cells but did not stain HEB cells in florescent staining, which further indicated the tumor-binding ability of Al18F-5. In in vivo PET imaging, HeLa and MCF-7 tumors were clearly delineated by specific accumulation of Al18F-5 in model mice. In biodistribution study, Al18F-5 exhibited good tumor uptake (4.66 ± 0.13% ID/g and 3.69 ± 0.56% ID/g, respectively), moderate tumor-to-muscle ratio (3.38 and 2.48, respectively) at 1 h post injection, which were in a good consistency with the results of PET imaging. In conclusion, Al18F-5 might be developed as a candidate PET probe for tumor imaging, though additional optimizations are still needed to improve pharmacokinetics in vivo.

Biological evaluation of histidine and tryptophan labeled with gallium-68 as potential tumor imaging agents

Radiolabeled with gallium-68 amino acids can be interesting and promising probes for tumor imaging using positron emission tomography (PET). Radiolabeled amino acids target the increased amino acid transport in cancer cells compared with normal tissues. In this study we labeled two amino acids histidine and tryptophan with 68Ga, investigated its biodistribution in Wistar rats with subcutaneously transplanted cholangioma RS-1 by gamma counting and compared them with 68GaCl3. The accumulation of 68Ga-histidine in tumor tissue increased approximately 6 fold from 0.11±0.04 %ID/g at 5 min post injection (p.i.) to 0.67±0.07 %ID/g at 3 h p.i. The amount of 68Ga-tryptophan in tumor was also risen 2.4 fold from 0.34±0.18 %ID/g to 0.80±0.06 %ID/g at 5 min and 3 h p.i., respectively. In contrast, the uptake of 68GaCl3 decreased throughout the study from 0.34±0.07 %ID/g to 0.13±0.04 %ID/g. The uptake and retention of 68Ga-histidine and 68Ga-tryptophan in non-target organs, except kidney and femur, were higher than those of 68GaCl3. In conclusion, the obtained results suggest that 68Ga-histidine and 68Ga-tryptophan could serve as potential new PET tracers for tumor imaging.

Synthesis of a Potential Tumor Imaging Agent by Oxidative Radioiodination of Aspirin and Its Preclinical Study

Aspirin, one of nonsteroidal anti-inflammatory analgesic drugs, was labeled with 125I with a labeling yield of 85.5% under the following conditions: pH 9, 100 mg of the substrate, 50 µg of Chloramine-T, 5–15 min, room temperature. The radiochemical yield of 125I-aspirin was determined by paper chromatography and electrophoresis, and the radiochemical purity was determined by HPLC.125I-aspirin was stable for at least 3 h. Biodistribution of 125I-aspirin in normal and tumor-bearing mice was studied. The uptake of 125I-aspirin in tumor sites makes it promising as a new radiopharmaceutical for tumor imaging.

Abstract 4114: Development and application of 18F-labeled Tenascin-C aptamer for cancer imaging

Abstract Aptamers are synthetic single-stranded DNA or RNA that can be held together with complementary sequences by base-pairing. Tenascin-C is an extracellular matrix protein that is overexpressed in cancer tissues. Herein, we investigate the biological characteristics of Tenascin-C aptamer as potential tumor imaging agents. Cy5 or F-18 labeled Tenascin-C aptamers were prepared through hybridization-based labeling method using complementary oligonucleotide platform. Immunoblot analysis was performed on U-251 MG, U-87 MG, C6 and NCI-H460 cell lines to confirm the expression of tenascin-C. In vitro binding specificity of Tenascin-C aptamers was evaluated using confocal microscopy. In vivo biodistribution properties and PET Imaging of the 18F-labeled Tenascin-C were determined in C6 tumor-bearing nude mice. High levels of tenascin-C protein were detected in C6, U-251 MG. and U-87 MG cell lines. However, tenascin-C protein levels were undetectable in NCI-H460 cells. Confocal fluorescence microscopy images showed that Cy5-labeled Tenascin-C aptamer bound specifically to tenascin-C protein expressing cell lines including C6, U-251 MG and U-87 MG, however, not bound to NCI-H460 cells. Tumor uptake of 18F-labeled Tenascin-C aptamer was 1.64 ± 0.36 at 30 min after injection in C6 tumor xenografts. C6 tumors were clearly visualized by microPET imaging in a tumor-bearing mouse at 60 after injection. Tenascin-C aptamer was successfully labeled with F-18 labeled complementary oligonucleotide by base-pair hybridization. In vitro data showed that the cODN platform-hybridized Tenascin-C aptamer was selectively bound to target tumor cells. In addition, C6 tumor xenografts in mice were clearly visualized on microPET imaging. Our study demonstrated that Tenascin-C may be a useful target molecule for the imaging of malignant gliomas. Citation Format: Jun Young Park, Ye Lim Cho, Ju Ri Chae, Ga Eul Chu, Won Gil Cho, Sang Wun Kim, Won Jun Kang. Development and application of 18F-labeled Tenascin-C aptamer for cancer imaging [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4114.

Radiosynthesis and evaluation of novel 99mTc(CO)3-labelled thymidine dithiocarbamate derivatives for tumor imaging with SPECT

A series of novel thymidine dithiocarbamate derivatives (DTC-TdR) were successfully synthesized and then radiolabelled using [99mTc(CO)3]+ core with high yields. The chemical characterizations of 99mTc(CO)3-labelled dithiocarbamate derivatives have been carried out by preparing their corresponding rhenium complexes. The radiotracers were stable in vitro, and the partition coefficient results indicated that they were lipophilic. The cell uptake studies showed the uptakes of these 99mTc(CO)3-labelled thymidine derivatives were mediated by nucleoside transporters. Biodistribution of the complexes in mice bearing tumor showed that they had high tumor uptake and good tumor/muscle ratio. A clear SPECT imaging of the tumor location was obtained in mice bearing S180 tumor with one of radiotracers, suggesting they would be potential tumor imaging agents.

Synthesis of 99mTc-Radiolabeled Uridine as a Potential Tumor Imaging Agent

Uridine, a pyrimidine nucleoside essential for the synthesis of RNA and biomembranes, was radiolabeled with 99mTc to obtain a potential tumor imaging agent. The maximal radiochemical yield of about 96.5%, as determined by paper chromatography and instant thin-layer chromatography, was reached under the following optimum conditions: 1 mg of uridine, 20 μg of SnCl2·2H2O as reducing agent, 20 mg of mannitol as a stabilizer, and pH 8. 99mTc-uridine is stable in vitro at room temperature for up to 6 h post labeling. The biodistrbution study in tumor-bearing mice shows high target-to-nontarget ratio. These results match with the high docking score of the complex on uridine phosphorylase enzyme. 99mTc-uridine shows promise as a tumor imaging agent.

Synthesis, radiolabeling and biological distribution of a new dioxime derivative as a potential tumor imaging agent

A novel dioxime derivative (2E,2′E,3E,3′E)-3,3′-(pyrimidine-4,5-diylbis(azanylylidene))bis(butan-2-one)dioxime was synthesized with a yield of 65%. IR, elemental analysis, mass spectroscopy and 1H-NMR were used to characterize the structure of the synthesized compound. 99mTc-dioxime was radio-synthesized with a high radiochemical yield of 97.8 ± 0.5% and in vitro stability of 6 h under the optimum conditions. The preclinical evaluation of 99mTc-dioxime in solid tumor-bearing mice showed high accumulation in solid tumor cells with a high Target/Non-Target ratio of 5.14 at 30 min post-injection. This study suggests that 99mTc-dioxime derivative is a promising candidate as a new 99mTc-based tumor-imaging agent after further preclinical studies.

Macrocyclic triamine derived glucose analogues for 99mTc(CO)3 labeling: synthesis and biological evaluation as potential tumor‐imaging agents

[99m Tc(CO)3 (H2 O)3 ]+ has attracted great attention among 99m Tc-labeling techniques, due to its ease of preparation, readily substituted water molecules of the precursor fac-[99m Tc(CO)3 (H2 O)3 ]+ by a variety of functional groups, small size and inertness. Bifunctional chelator based on a macrocyclic polyamine framework shows easy complexation with [99m Tc(CO)3 (H2 O)3 ]+ to produce stable complex. In this study, two novel 1, 5, 9-triazacyclododecane derivatives containing a glucose group (6 and 7) were successfully synthesized by reacting different glucose-azides with alkyne-[12]aneN3 via the so-called click chemistry and radiolabeled with [99m Tc(CO)3 (H2 O)3 ]+ to form 99m Tc(CO)3 -6 (C-1-substituted complex) and 99m Tc(CO)3 -7 (C-2-substituted complex) in high yields. The complexes were stable in vitro over 6h when incubated in saline at room temperature and in mouse serum at 37°C. The partition coefficient results showed that they were hydrophilic. The biodistribution studies in Kunming mice bearing S 180 tumor showed both complexes showed accumulation in the tumor. Between them, 99m Tc(CO)3 -7 had the advantages of much higher tumor uptake and tumor/muscle ratio. Compared with other reported 99m Tc-radiolabeled glucose derivatives, 99m Tc(CO)3 -7 also showed a higher tumor uptake and tumor/muscle ratio, suggesting it would be a potential candidate for further development as a tumor-imaging agent.

Synthesis and preliminary biological evaluation of a 99m Tc-chlorambucil derivative as a potential tumor imaging agent.

Technetium-99m-based radiopharmaceuticals have been used widely as diagnostic agents in the nuclear medicine. Chlorambucil (CLB) as one typical alkylating drug exhibits excellent inhibition effects against many human malignancies. To develop and explore a novel potential imaging agent for early diagnosis of tumors, tricarbonyl technetium-99m and rhenium complexes on the basis of the tridentate ligand dipicolylamine (DPA) bound to the chlorambucil pharmacophore were designed and synthesized: 99m Tc-DPA-CLB (3) and Re-DPA-CLB (4). The high performance liquid chromatography analyses showed that the retention time of 3 and 4 was 13.5 and 13.6minutes, respectively. Radiolabeling efficiency of the 99m Tc-DPA-CLB tracer was 97%, and the radiochemical purity was larger than 95% after 6hours stored in phosphate buffered saline or human serum as observed by thin layer chromatography and high performance liquid chromatography. Biodistribution studies in a mouse model of breast cancer showed 99m Tc-DPA-CLB exhibited a favorable tumor affinity. The radiotracer cleared quickly in the first hour via hepatobiliary and renal routes of excretion, resulted in a very low background at 4hours post injection (p.i.). It had moderate uptake ratios of tumor to blood and tumor to muscle. These results suggested 99m Tc-DPA-CLB might be a promising SPECT imaging agent for tumor diagnosis.