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The Effect of A Hexanoic Acid Linker Insertion on the Pharmacokinetics and Tumor Targeting Properties of the Melanoma Imaging Agent 99mTc-HYNIC-cycMSH

[ Vol. 17 , Issue. 8 ]

Author(s):

Vania Teixeira, Marcelo Fernández, Natalia Oddone, Xiuli Zhang, Fabio Gallazzi, Hugo Cerecetto, Juan Pablo Gambini, Williams Porcal, Pablo Cabral and Thomas P. Quinn   Pages 1144 - 1152 ( 9 )

Abstract:


Background: Lactam cyclized alpha-melanocyte stimulating hormone (α-MSH) analogues exhibit high stability and affinity for the MC1-R receptors over expressed in melanoma cells. Recently, we reported a novel 99mTc-HYNIC-cycMSH4-13 analogue with the HYNIC chelator directly attached to the lactam cyclized ring.

Objective: In this study we proposed the introduction of a 6-aminohexanoic acid (Ahx) linker between the HYNIC chelator and lactam cyclized peptide cycMSH4-13 to reduce steric hindrance and improve the melanoma targeting and imaging proprieties of the radiolabeled peptide.

Method: HYNIC-Ahx-cycMSH4-13 peptide was synthesized on an automated peptide synthesizer and displayed an IC50 of 0.3 nM using B16/F1 cells. The 99mTc/tricine radiolabeled peptide was examined for radiochemical purity, stability and cell binding. In vivo, biodistribution and planar gamma imaging studies were performed in B16/F1 melanoma tumor bearing C57BK mice.

Results: 99mTc-HYNIC-Ahx-cycMSH4-13 was obtained with a radiochemical purity >95%, was stable up to 24 h at room temperature and exhibited high binding and rapid internalization in B16/F1 cells. In vivo biodistribution studies showed a tumor uptake of 4.92 ± 0.92 % ID/g and 2.78 ± 1.48 % ID/g at 2 h and 4 h post injection, respectively. Whole-body clearance was rapid through urinary excretion. The melanoma tumors were clearly visualized by planar gamma imaging.

Conclusion: 99mTc-HYNIC-Ahx-cycMSH4-13was shown radiochemically stability and exhibited rapid and selective uptake in melanoma cells and tumors. Imaging studies yielded promising preclinical results, warranting further evaluation of 99mTc-HYNIC-cycMSH analogs as melanoma specific imaging agents.

Keywords:

HYNIC, α-MSH, 99mTc, melanoma, Ahx, tumor.

Affiliation:

Departamento de Radiofarmacia, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Mataojo 2055, Montevideo 11400, Departamento de Radiofarmacia, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Mataojo 2055, Montevideo 11400, Laboratorio de Señalización Celular y Nanobiología, Instituto de Investigaciones Biológicas Clemente Estable, Av. Italia 3318, CP 11600, Montevideo, Biochemistry Department, University of Missouri, Research Core Facilities, Univeristy of Missouri, Departamento de Radiofarmacia, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Mataojo 2055, Montevideo 11400, Centro de Medicina Nuclear, Hospital de Clínicas “Dr. Manuel Quintela”, Facultad de Medicina, Universidad de la República. Av. Italia s/n, Montevideo11600, Departamento de Química Orgánica, Facultad de Química, Universidad de la República, Av. General Flores 2124, Montevideo 11800, Departamento de Radiofarmacia, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Mataojo 2055, Montevideo 11400, Biochemistry Department, University of Missouri

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