Ultrasensitive detection of malignant melanoma using PET molecular imaging probes

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 the18F-labeled pyridine-based benzamide derivativesN-(2-(dimethylamino)ethyl)-5-[18F]fluoropicolinamide ([18F]DMPY2) andN-(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 tracersN-[2-(diethylamino)-ethyl]-5-[18F]fluoropicolinamide ([18F]P3BZA) andN-[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).

Increased 68Ga-FAPI Activity in Malignant Melanoma of the Nasal Cavity

“…[5][6][7] The 68 Ga-FAPI uptake in melanoma may be related to the fibrosis associated with melanoma. 8,9 The higher tracer uptake at the thyroiditis site in this case could be due to inflammation-induced fibrosis, in concordance with the recent literature. 10 In addition, our case indicates that 68 Ga-FAPI may also be valuable in the evaluation of patients with primary malignant melanoma of the nasal cavity.…”

Translating Molecules into Imaging—The Development of New PET Tracers for Patients with Melanoma

“…Melanin-targeting tracers have the potential to address current shortcomings in detecting melanoma microlesions and are easy and cost effective to produce on site; in particular, three tracers have demonstrated in vivo imaging performance superior to 18 F-FDG: 18 F-5-FPN, which is also called 18 F-P3BZA [91][92][93][94], 18F-DMPY2 [95], and 18 F-ICF01006, which is also called 18 F-MEL050 [88,[96][97][98]. 18 F-5-FPN ( 18 F-5-fluoro-N-[2-(diethylamino)ethyl] picolinamide) synthesis has been optimized and has shown significantly higher uptake in B16F10 cells than 18 F-FDG (13.29 ± 3.80% ID/g compared to 7.24 ± 1.95%) [91].…”

“…18 F-5-FPN ( 18 F-5-fluoro-N-[2-(diethylamino)ethyl] picolinamide) synthesis has been optimized and has shown significantly higher uptake in B16F10 cells than 18 F-FDG (13.29 ± 3.80% ID/g compared to 7.24 ± 1.95%) [91]. Lung metastases less than 2 mm were better visualized with 18 F-5-FPN than 18 F-FDG, allowing earlier detection of both regional and distant metastases in mice [95,98]. The radiotracer was also tested clinically in a pilot study with healthy volunteers and in patients with pigmented melanoma, who received 18 F-5-FPN with an average dose of 5.72 ± 0.42 mCi.…”

Synthesis and Preclinical Evaluation of a 68Ga-Labeled Pyridine-Based Benzamide Dimer for Malignant Melanoma Imaging

“…The need to image disease-related molecular targets as well as physiological change processes in vivo in clinical diagnostic work has led to increased interest in nuclear medicine imaging modalities such as SPECT or PET, which are (semi-) quantitative and highly sensitive. , Increasing research in melanoma targets has caused more radiopharmaceuticals for diagnosis and treatment to be developed including iodoamphetamine, monoclonal antibodies, , melanocortin type 1 receptor (MC1R), − α-melanocyte-stimulating hormone and analogs, ,, benzamide (BZA), and BZA derivatives. − The marked increase of melanin in malignant melanoma is due to a high elevation of tyrosinase activity, which plays a rate-limiting role in melanogenesis. BZA is a small molecule that can freely crosses cell membranes and bind to melanin.…”

“…The structural analogs of BZA exhibit efficient uptake in tumors and lower accumulation in healthy tissues such as muscles. In recent years, 18 F/ 123 I/ 99m Tc-labeled BZA derivatives have been developed for melanoma detection. − …”