title: The Effect of A Hexanoic Acid Linker Insertion on the Pharmacokinetics and Tumor Targeting Properties of the Melanoma Imaging Agent 99mTc-HYNIC-cycMSH.
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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  99mTc-HYNIC-Ahx-cycMSH4-13 was 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.
authors.affiliation: Departamento de Radiofarmacia, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Mataojo 2055, Montevideo 11400, Uruguay.
authors.forename: Vania
authors.initials: V
authors.lastname: Teixeira
authors.affiliation: Departamento de Radiofarmacia, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Mataojo 2055, Montevideo 11400, Uruguay.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Fernández
authors.affiliation: Laboratorio de Señalización Celular y Nanobiología, Instituto de Investigaciones Biológicas Clemente Estable, Av. Italia 3318, CP 11600, Montevideo, Uruguay.
authors.forename: Natalia
authors.initials: N
authors.lastname: Oddone
authors.affiliation: Biochemistry Department, University of Missouri. Colombia.
authors.forename: Xiuli
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Research Core Facilities, Univeristy of Missouri. Colombia.
authors.forename: Fabio
authors.initials: F
authors.lastname: Gallazzi
authors.affiliation: Departamento de Radiofarmacia, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Mataojo 2055, Montevideo 11400, Uruguay.
authors.forename: Hugo
authors.initials: H
authors.lastname: Cerecetto
authors.affiliation: Centro de Medicina Nuclear, Hospital de Clínicas "Dr. Manuel Quintela", Facultad de Medicina, Universidad de la República. Av. Italia s/n, Montevideo11600, Uruguay.
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: Gambini
authors.affiliation: Departamento de Química Orgánica, Facultad de Química, Universidad de la República, Av. General Flores 2124, Montevideo 11800, Uruguay.
authors.forename: Williams
authors.initials: W
authors.lastname: Porcal
authors.affiliation: Departamento de Radiofarmacia, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Mataojo 2055, Montevideo 11400, Uruguay.
authors.forename: Pablo
authors.initials: P
authors.lastname: Cabral
authors.affiliation: Biochemistry Department, University of Missouri. Colombia.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Quinn
mesh_terms: D000818:Animals; D002208:Caproates / Q000737:chemistry / Q000493:pharmacokinetics*; D051379:Mice; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000175:diagnosis*; D015609:Organotechnetium Compounds / Q000737:chemistry / Q000493:pharmacokinetics*; D010446:Peptide Fragments / Q000737:chemistry / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured; D000521:alpha-MSH / Q000737:chemistry / Q000493:pharmacokinetics*
chemical_list: D002208:Caproates; D015609:Organotechnetium Compounds; D010446:Peptide Fragments; C000622266:technetium 99m HYNIC-Ahx-cycMSH(4-13); C037652:hexanoic acid; D000521:alpha-MSH
keywords: 99mTc; Ahx; HYNIC; melanoma; tumor; α-MSH