N-(2-(Dimethylamino)Ethyl)-4-¹⁸F-Fluorobenzamide: A Novel Molecular Probe for High-Contrast PET Imaging of Malignant Melanoma

Abstract

Malignant melanoma is an aggressive and serious form of skin cancer, with prognosis and treatment outcome depending heavily on the clinical stage of the disease at the time of diagnosis. Here, we synthesized a novel 18 F-labeled benzamide derivative to target melanoma and then evaluated its biologic characteristics in small-animal models. Methods: N-(2-(dimethylamino)ethyl)-4-18 F-fluorobenzamide ( 18 F-DMFB) was synthesized by reaction of N-succinimidyl 4-18 Ffluorobenzoate with N,N-dimethylethylenediamine. The binding affinity of 18 F-DMFB was measured in B16F10 (mouse melanoma) cells with or without L-tyrosine. Small-animal PET imaging with 18 F-DMFB was performed on B16F10 xenograft and metastasis mouse models. Results: The overall non-decay-corrected radiochemical yield of 18 F-DMFB was approximately 10%-15%. Uptake of 18 F-DMFB was melanin-specific, as cellular uptake in B16F10 increased more than 18-fold in the presence of L-tyrosine. Biodistribution studies revealed that 18 F-DMFB accumulated, and was retained, in B16F10 xenografts for 120 min (10, 30, 60, and 120 min: 9.24, 10.80, 13.0, and 10.59 percentage injected dose/g, respectively) after radiotracer injection. Liver uptake of 18 F-DMFB decreased from 10 to 120 min and showed fast clearance (10, 30, 60, and 120 min: 11.19, 5.7, 2.47, and 0.4 percentage injected dose/g). Furthermore, 18 F-DMFB allowed visualization of metastatic lesions immediately after injection and was retained in lesions for over 60 min, with a high tumor-to-background ratio. Conclusion: 18 F-DMFB demonstrated a high melanin-targeting ability and tumor-specific tumor uptake in both primary and metastatic lesions in animal models bearing malignant melanoma. 18 F-DMFB may be a potential PET imaging agent for melanoma.

Ultrasensitive detection of malignant melanoma using PET molecular imaging probes

“…Benzamide derivatives such as [ 18 F]FBZA have a diethyl amine residue, and some such compounds with an alkyl (number of carbon: > 3), cycloalkyl, or pyridyl structure in the amine residue showed melanoma uptake of less than 9.0%ID/g at 60 min in B16F10 xenografts. We recently reported [ 18 F]DMFB with an amine residue modified from diethyl to dimethyl, which revealed higher tumor uptake than the unmodified tracer (39). Second, in the present study, we substituted pyridine for benzene in the [ 18 F]DMFB structure, and this modification further increased the tumor uptake up to 24%ID/g in B16F10 xenografts.…”

“…In this regard, we recently reported on the novel benzamide derivative N-(2-(dimethylamino)ethyl)-4-[ 18 F]fluorobenzamide ([ 18 F]DMFB), which has a carbon chain amine residue in the benzamide derivative shortened from diethyl to dimethyl. [ 18 F]DMFB has improved in vivo performance for the detection of melanoma and its metastases (39).…”

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

“…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. − …”

“…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.…”