期刊
MOLECULAR PHARMACEUTICS
卷 10, 期 9, 页码 3384-3391出版社
AMER CHEMICAL SOC
DOI: 10.1021/mp400225s
关键词
melanoma imaging; PET; melanin; F-18; benzamide
资金
- Melanoma Research Alliance
- NCI In Vivo Cellular Molecular Imaging Center (ICMIC) [P50 CA114747]
- Ministry of Science and Technology of China [2012ZX10004801-003-011]
- Chinese Ministry of Education [313040]
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-F-18-fluoropropionate (F-18-NFP), to produce the probe N-(2-(diethylamino)ethyl)-2-F-18-fluoropropanamide (F-18-FPDA). The melanoma-targeting ability of F-18-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 F-18-NFP, the total preparation time for F-18-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 F-18-FPDA was demonstrated by significantly different Uptake rates in tyrosine treated and untreated B16F10 cells in vitro. The tumor uptake of F-18-FPDA in vivo reached 2.65 +/- 0.48 %ID/g. at 2 h postinjection (p.i.) in pigment-eniiched B16F10 xenografts, whereas the tumor uptake of F-18-FPDA was close to the background levels, with rates of only 037 +/- 0.07:%ID/g at 2.h p.i. in the nonpigmented U87MG tumor mouse model. Furthermore, small animal PET imaging studies revealed that F-18-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 F-18 labeled aliphatic compound for melanoma imaging that can be easily synthesized in high yields using the radiosynthon F-18-NFP the PET probe F-18-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 F-18-FPDA for melanin targeted molecular imaging are therefore warranted.
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