Title:The Effect of A Hexanoic Acid Linker Insertion on the Pharmacokinetics and Tumor Targeting Properties of the Melanoma Imaging Agent 99mTc-HYNIC-cycMSH
VOLUME: 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
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
Keywords:HYNIC, α-MSH, 99mTc, melanoma, Ahx, tumor.
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 cycMSH
4-13 to reduce steric hindrance and improve the melanoma
targeting and imaging proprieties of the radiolabeled peptide.
Method: HYNIC-Ahx-cycMSH
4-13 peptide was synthesized on an automated peptide synthesizer and displayed
an IC
50 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-cycMSH
4-13 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-cycMSH
4-13was 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.
