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Abstract
Malignant melanoma has one of the highest mortality rates of any cancer because of its aggressive nature and high metastatic potential. Clinical staging of the disease at the time of diagnosis is very important for the prognosis and outcome of melanoma treatment. In this study, we designed and synthesized the 18F-labeled pyridine-based benzamide derivatives N-(2-(dimethylamino)ethyl)-5-[18F]fluoropicolinamide ([18F]DMPY2) and N-(2-(dimethylamino)ethyl)-6-[18F]fluoronicotinamide ([18F]DMPY3) to detect primary and metastatic melanoma at an early stage and evaluated their performance in this task. [18F]DMPY2 and [18F]DMPY3 were synthesized by direct radiofluorination of the bromo precursor, and radiochemical yields were ∼15-20%. Cell uptakes of [18F]DMPY2 and [18F]DMPY3 were >103-fold and 18-fold higher, respectively, in B16F10 (mouse melanoma) cells than in negative control cells. Biodistribution studies revealed strong tumor uptake and retention of [18F]DMPY2 (24.8% injected dose per gram of tissue [ID/g] at 60 min) and [18F]DMPY3 (11.7%ID/g at 60 min) in B16F10 xenografts. MicroPET imaging of both agents demonstrated strong tumoral uptake/retention and rapid washout, resulting in excellent tumor-to-background contrast in B16F10 xenografts. In particular, [18F]DMPY2 clearly visualized almost all metastatic lesions in lung and lymph nodes, with excellent image quality. [18F]DMPY2 demonstrated a significantly higher tumor-to-liver ratio than [18F]fluorodeoxyglucose ([18F]FDG) and the previously reported benzamide tracers N-[2-(diethylamino)-ethyl]-5-[18F]fluoropicolinamide ([18F]P3BZA) and N-[2-(diethylamino)-ethyl]-4-[18F]fluorobenzamide ([18F]FBZA) in B16F10-bearing or SK-MEL-3 (human melanoma)-bearing mice. In conclusion, [18F]DMPY2 might have strong potential for the diagnosis of early stage primary and metastatic melanoma using positron emission tomography (PET).

그림 1. (A) 벤즈아마이드의 화학적 구조 및 (B) N-(2-(dimethylamino)ethyl)-5-[18F]fluoropicolinamide ([18F]DMPY2)의 화학적 구조

그림 2. 원발성 및 전이성 흑색종 소동물 모델을 이용한 [18F]DMPY2의 PET 영상평가. (A) 피하이식 흑색종 소동물 모델에서 [18F]DMPY2 정맥주사 후 30, 60분 후의 PET 영상. (B) 폐 전이, (C) 림프절 전이 흑색종 소동물 모델에서 [18F]DMFB 정맥주사 후 60분 후의 PET 영상. (D) 피하이식 흑색종 소동물 모델에서 [18F]DMPY2와 [18F]FDG의 PET 비교 영상

그림 3. (A) 원발성 및 (B) 폐 전이 및 (C) 림프절 전이 흑색종 소동물 모델을 이용한 [18F]DMPY2와 현재 미국에서 임상시험 진행 중인 [18F]P3BZA의 PET 비교 영상

Affiliations

Ayoung Pyo  1   2   3 , Dong-Yeon Kim  4   2   3 , Heejung Kim  5 , Daejin Lim  6 , Seong Young Kwon  1   2   3 , Sae-Ryung Kang  1   2   3 , Hyung-Seok Kim  7 , Hee-Seung Bom  1   2   3 , Jung-Joon Min  4   2   3
1 Department of Nuclear Medicine, Chonnam National University Medical School and Hwasun Hospital, 58128 Hwasun, Korea.
2 Institute for Molecular Imaging and Theranostics, Chonnam National University Medical School, 58128 Hwasun, Korea.
3 Innovation Center for Molecular Probe Development, Chonnam National University Hwasun Hospital, 58128 Hwasun, Korea.
4 Department of Nuclear Medicine, Chonnam National University Medical School and Hwasun Hospital, 58128 Hwasun, Korea; blueburr@gmail.com jjmin@jnu.ac.kr.
5 Korea Drug Development Platform using Radioisotope, Korea Institute of Radiological & Medical Sciences, 01812 Seoul, Korea.
6 Department of Microbiology, Chonnam National University Medical School, 58128 Hwasun, Korea.
7 Department of Forensic Medicine, Chonnam National University Medical School, 58128 Hwasun, Korea.