A novel aliphatic 18F-labeled probe for PET imaging of melanoma. 2013

Hongguang Liu, and Shuanglong Liu, and Zheng Miao, and Han Jiang, and Zixin Deng, and Xuechuan Hong, and Zhen Cheng
Molecular Imaging Program at Stanford (MIPS), Bio-X Program, and Department of Radiology, Canary Center at Stanford for Cancer Early Detection, Stanford University , California, 94305-5344, United States.

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.

UI MeSH Term Description Entries
D008545 Melanoma A malignant neoplasm derived from cells that are capable of forming melanin, which may occur in the skin of any part of the body, in the eye, or, rarely, in the mucous membranes of the genitalia, anus, oral cavity, or other sites. It occurs mostly in adults and may originate de novo or from a pigmented nevus or malignant lentigo. Melanomas frequently metastasize widely, and the regional lymph nodes, liver, lungs, and brain are likely to be involved. The incidence of malignant skin melanomas is rising rapidly in all parts of the world. (Stedman, 25th ed; from Rook et al., Textbook of Dermatology, 4th ed, p2445) Malignant Melanoma,Malignant Melanomas,Melanoma, Malignant,Melanomas,Melanomas, Malignant
D008810 Mice, Inbred C57BL One of the first INBRED MOUSE STRAINS to be sequenced. This strain is commonly used as genetic background for transgenic mouse models. Refractory to many tumors, this strain is also preferred model for studying role of genetic variations in development of diseases. Mice, C57BL,Mouse, C57BL,Mouse, Inbred C57BL,C57BL Mice,C57BL Mice, Inbred,C57BL Mouse,C57BL Mouse, Inbred,Inbred C57BL Mice,Inbred C57BL Mouse
D005260 Female Females
D005462 Fluorine Radioisotopes Unstable isotopes of fluorine that decay or disintegrate emitting radiation. F atoms with atomic weights 17, 18, and 20-22 are radioactive fluorine isotopes. Radioisotopes, Fluorine
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D045744 Cell Line, Tumor A cell line derived from cultured tumor cells. Tumor Cell Line,Cell Lines, Tumor,Line, Tumor Cell,Lines, Tumor Cell,Tumor Cell Lines
D049268 Positron-Emission Tomography An imaging technique using compounds labelled with short-lived positron-emitting radionuclides (such as carbon-11, nitrogen-13, oxygen-15 and fluorine-18) to measure cell metabolism. It has been useful in study of soft tissues such as CANCER; CARDIOVASCULAR SYSTEM; and brain. SINGLE-PHOTON EMISSION-COMPUTED TOMOGRAPHY is closely related to positron emission tomography, but uses isotopes with longer half-lives and resolution is lower. PET Imaging,PET Scan,Positron-Emission Tomography Imaging,Tomography, Positron-Emission,Imaging, PET,Imaging, Positron-Emission Tomography,PET Imagings,PET Scans,Positron Emission Tomography,Positron Emission Tomography Imaging,Positron-Emission Tomography Imagings,Scan, PET,Tomography Imaging, Positron-Emission,Tomography, Positron Emission
D051379 Mice The common name for the genus Mus. Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus

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