Synthesis and Preclinical Evaluation of ¹⁸F-PEG₃-FPN for the Detection of Metastatic Pigmented Melanoma

Abstract

Although F-5-fluoro-N-(2-[diethylamino]ethyl)picolinamide (F-5-FPN) is considered a promising radiopharmaceutical for PET imaging of melanoma, it accumulates at high concentrations in the liver. The aim in this research was to optimize the structure of F-5-FPN with triethylene glycol to reduce liver uptake as well as improve pharmacokinetics, and to evaluate its performance in detection of melanoma liver and lung metastases.F-PEG-FPN was successfully prepared with a high radiolabeling yield (44.68% ± 5.99%) and radiochemical purity (>99%). The uptake of F-PEG-FPN by pigmented B16F10 melanoma cells was significantly higher than that by amelanotic melanoma A375 cells. The binding to B16F10 cells could be blocked by excess F-PEG-FPN. On small animal PET images, B16F10 tumors, but not A375 tumors, were clearly delineated after F-PEG-FPN injection. More importantly, F-PEG-FPN uptake by liver (2.27 ± 0.45 and 1.74 ± 0.35% ID/g, at 1 and 2 h) was significantly lower than that of F-5-FPN, and the lesions in lung and liver could be clearly detected byF-PEG-FPN PET imaging in mouse models of pulmonary or hepatic metastases. Overall, we successfully synthesized F-PEG-FPN, which has higher labeling efficacy and better in vivo pharmacokinetics along with lower liver uptake compared to F-5-FPN. This suggestsF-PEG-FPN as a candidate for pigmented melanoma liver and lung metastasis detection.

Targeted radiotherapy of pigmented melanoma with 131I-5-IPN

“…In theory, a lipophilic compound will be excreted mainly by the hepatobiliary system, while hydrophilic compounds will be excreted mostly through the urinary system. A log P of 0.03 ± 0.03 predicts 131 I-5-IPN is a bit more lipophilic than 18 F-5-FPN (Log P = − 0.17 ± 0.01) [ 23 ], meaning 131 I-5-IPN would distribute more in liver than 18 F-5-FPN. Indeed, 131 I-5-IPN accumulated in liver with 19.81 ± 0.38% ID/g in the inception phase.…”

“…As in our previous method [ 23 ], 131 I-5-IPN (74 kBq, 20 μCi) and human serum (0.2 mL) were incubated at 37 °C for 24 h. The radiochemical purity of 131 I-5-IPN was identified by analytic HPLC.…”

“…Histopathology examination was performed on B16F10 tumors, livers, and kidney according to our previous work [ 23 ]. Stained sections of livers and kidneys were evaluated for necrosis, apoptosis, and inflammatory changes under light microscopy.…”

“…During the past decade, many small benzamide molecules radiolabeled with 18 F [ 15 – 17 ], 11 C [ 18 ], or 131 I [ 19 – 21 ] have been developed for diagnosis or therapy of melanoma. More recently, we reported two promising 18 F-fluoro radiotracers containing 18 F-5-fluoro-N-(2-(diethylamino)ethyl)picolinamide ( 18 F-5-FPN) [ 22 ] and its optimized version ( 18 F-PEG 3 -FPN) [ 23 ], for pigmented melanoma positron-emission tomography (PET) detection. High specificity and affinity as well as rapid elimination from nontarget organs make them potential carriers for TRNT.…”

Multimodality reporter gene imaging: Construction strategies and application

“… Schematic diagram of molecular imaging techniques, including nuclear modalities such as positron emission tomography (PET) 23 , 24 (Adapted with permission from 23 , copyright 2017 ACS Publications) (Adapted with permission from 24 , copyright 2017 Wolters Kluwer Health) and single photon emission computed tomography (SPECT) 25 (Adapted with permission from 25 , copyright 2016 Elsevier), magnetic resonance imaging (MRI) 26 (Adapted with permission from 26 , copyright 2013 Nature Publishing Group), optical imaging (OI) such as bioluminescence imaging (BLI) 27 and fluorescence imaging (FLI) 27 (Adapted with permission from 27 , copyright 2014 Public Library of Science), photoacoustic imaging (PAI) 26 (Adapted with permission from 26 , copyright 2013 Nature Publishing Group), and Cerenkov luminescence imaging (CLI) 28 (Adapted with permission from 28 , copyright 2014 American Association for Cancer Research). …”