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Development of 18F-labeled picolinamide probes for PET imaging of malignant melanoma.

ABSTRACT: Melanoma is an aggressive skin cancer with worldwide increasing incidence. Development of positron emission tomography (PET) probes for early detection of melanoma is critical for improving the survival rate of melanoma patients. In this research, (18)F-picolinamide-based PET probes were prepared by direct radiofluorination of the bromopicolinamide precursors using no-carrier-added (18)F-fluoride. The resulting probes, (18)F-1, (18)F-2 and (18)F-3, were then evaluated in vivo by small animal PET imaging and biodistribution studies in C57BL/6 mice bearing B16F10 murine melanoma tumors. Noninvasive small animal PET studies demonstrated excellent tumor imaging contrasts for all probes, while (18)F-2 showed higher tumor to muscle ratios than (18)F-1 and (18)F-3. Furthermore, (18)F-2 demonstrated good in vivo stability as evidenced by the low bone uptake in biodistribution studies. Collectively, these findings suggest (18)F-2 as a highly promising PET probe for translation into clinical detection of melanoma.

SUBMITTER: Liu H

PROVIDER: S-EPMC3586277 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Development of 18F-labeled picolinamide probes for PET imaging of malignant melanoma.

Liu Hongguang H Liu Shuanglong S Miao Zheng Z Deng Zixin Z Shen Baozhong B Hong Xuechuan X Cheng Zhen Z

Journal of medicinal chemistry 20130118 3

Melanoma is an aggressive skin cancer with worldwide increasing incidence. Development of positron emission tomography (PET) probes for early detection of melanoma is critical for improving the survival rate of melanoma patients. In this research, (18)F-picolinamide-based PET probes were prepared by direct radiofluorination of the bromopicolinamide precursors using no-carrier-added (18)F-fluoride. The resulting probes, (18)F-1, (18)F-2 and (18)F-3, were then evaluated in vivo by small animal PET ...[more]

PMID: 23301672

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Project description:Radiofluorinated benzamide and nicotinamide analogues are promising molecular probes for the positron emission tomography (PET) imaging of melanoma. Compounds containing aromatic (benzene or pyridine) and N,N-diethylethylenediamine groups have been successfully used for development of melanin targeted PET and single-photon emission computed tomography (SPECT) imaging agents for melanoma. The objective of this study was to determine the feasibility of using aliphatic compounds as a molecular platform for the development of a new generation of PET probes for melanoma detection. An aliphatic N,N-diethylethylenediamine precursor was directly coupled to a radiofluorination synthon, p-nitrophenyl 2-(18)F-fluoropropionate ((18)F-NFP), to produce the probe N-(2-(diethylamino)ethyl)-2-(18)F-fluoropropanamide ((18)F-FPDA). The melanoma-targeting ability of (18)F-FPDA was further evaluated both in vitro and in vivo through cell uptake assays, biodistribution studies, and small animal PET imaging in C57BL/6 mice bearing B16F10 murine melanoma tumors. Beginning with the precursor (18)F-NFP, the total preparation time for (18)F-FPDA, including the final high-performance liquid chromatography purification step, was approximately 30 min, with a decay-corrected radiochemical yield of 79.8%. The melanin-targeting specificity of (18)F-FPDA was demonstrated by significantly different uptake rates in tyrosine-treated and untreated B16F10 cells in vitro. The tumor uptake of (18)F-FPDA in vivo reached 2.65 ± 0.48 %ID/g at 2 h postinjection (p.i.) in pigment-enriched B16F10 xenografts, whereas the tumor uptake of (18)F-FPDA was close to the background levels, with rates of only 0.37 ± 0.07 %ID/g at 2 h p.i. in the nonpigmented U87MG tumor mouse model. Furthermore, small animal PET imaging studies revealed that (18)F-FPDA specifically targeted the melanotic B16F10 tumor, yielding a tumor-to-muscle ratio of approximately 4:1 at 1 h p.i. and 7:1 at 2 h p.i. In summary, we report the development of a novel (18)F-labeled aliphatic compound for melanoma imaging that can be easily synthesized in high yields using the radiosynthon (18)F-NFP. The PET probe (18)F-FPDA exhibits high B16F10 tumor-targeting efficacy and favorable in vivo pharmacokinetics. Our study demonstrates that aliphatic compounds can be used as a new generation molecular platform for the development of novel melanoma targeting agents. Further evaluation and optimization of (18)F-FPDA for melanin targeted molecular imaging are therefore warranted.

Project description:Integrin ?v?6 is a cell surface receptor minimally expressed by healthy tissue but elevated in lung, colon, skin, ovarian, cervical, and pancreatic cancers. A molecular PET agent for integrin ?v?6 could provide significant clinical utility by facilitating both cancer staging and treatment monitoring to more rapidly identify an effective therapeutic approach.Here, we evaluated 2 cystine knot peptides, R01 and S02, previously engineered with a 3-6 nM affinity for integrin ?v?6, for (18)F radiolabeling and PET imaging of BxPC3 pancreatic adenocarcinoma xenografts in mice. Cystine knot peptides were labeled with N-succinimidyl-4-(18)F-fluorobenzoate and evaluated for binding affinity and serum stability. Peptides conjugated with (18)F-fluorobenzoate (2-3 MBq) were injected via the tail vein into nude mice xenografted with BxPC3 (integrin ?v?6-positive) or 293 (integrin ?v?6-negative) tumors. Small-animal PET scans were acquired at 0.5, 1, and 2 h after injection. Ex vivo ?-counting of dissected tissues was performed at 0.5 and 2 h.(18)F-fluorobenzoate peptides were produced in 93% ((18)F-fluorobenzoate-R01) and 99% ((18)F-fluorobenzoate-S02) purity. (18)F-fluorobenzoate-R01 and (18)F-fluorobenzoate-S02 had affinities of 1.1 ± 0.2 and 0.7 ± 0.4 nM, respectively, and were 87% and 94%, respectively, stable in human serum at 37°C for 2 h. (18)F-fluorobenzoate-R01 and (18)F-fluorobenzoate-S02 exhibited 2.3 ± 0.6 and 1.3 ± 0.4 percentage injected dose per gram (%ID/g), respectively, in BxPC3 xenografted tumors at 0.5 h (n = 4-5). Target specificity was confirmed by low tumor uptake in integrin ?v?6-negative 293 tumors (1.4 ± 0.6 and 0.5 ± 0.2 %ID/g, respectively, for (18)F-fluorobenzoate-R01 and (18)F-fluorobenzoate-S02; both P < 0.05; n = 3-4) and low muscle uptake (3.1 ± 1.0 and 2.7 ± 0.4 tumor to muscle for (18)F-fluorobenzoate-R01 and (18)F-fluorobenzoate-S02, respectively). Small-animal PET data were corroborated by ex vivo ?-counting of dissected tissues, which demonstrated low uptake in nontarget tissues with only modest kidney uptake (9.2 ± 3.3 and 1.9 ± 1.2 %ID/g, respectively, at 2 h for (18)F-fluorobenzoate-R01 and (18)F-fluorobenzoate-S02; n = 8). Uptake in healthy pancreas was low (0.3% ± 0.1% for (18)F-fluorobenzoate-R01 and 0.03% ± 0.01% for (18)F-fluorobenzoate-S02; n = 8).These cystine knot peptide tracers, in particular (18)F-fluorobenzoate-R01, show translational promise for molecular imaging of integrin ?v?6 overexpression in pancreatic and other cancers.

Dataset Information

Development of 18F-labeled picolinamide probes for PET imaging of malignant melanoma.

Publications

Development of 18F-labeled picolinamide probes for PET imaging of malignant melanoma.

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