[¹²⁵I]‐S36057: a new and highly potent radioligand for the melanin‐concentrating hormone receptor

Abstract

1 Shortened, more stable and weakly hydrophobic analogues of melanin-concentrating hormone (MCH) were searched as candidates for radioiodination. Starting from the dodecapeptide MCH 6 ± 17 , we found that: (1) substitution of Tyr 13 by a Phe residue; (2) addition of a 3-iodo-Tyr residue at the Nterminus; and (3) addition of a hydrophilic spacer 8-amino-3,6-dioxyoctanoyl between the 3-iodo-Tyr and MCH 6 ± 17 (compound S36057), led to an agonist more potent than MCH itself in stimulating

Expression of Receptors for Melanin-Concentrating Hormone (Mch) in Different Tissues and Cell Lines

“…The original method described by Drozdz et al [10] was based on [ 125 I]-[Phe 13 , Tyr 19 ]-MCH as radioligand which was prepared with polymer-bound glucose oxidase= lactoperoxidase and subsequent dual C 18 mini-column and HPLC reversed-phase purification. Modifications of this method included altered ways of radioiodination of the peptide, [20] the introduction of a D-Phe residue at position 13, [9] the use of [ 125 I]-MCH with the natural sequence as radiopeptide, [31] MCH peptide analogs with reduced sequence, e.g., [Tyr 4 , (8-amino-3,6-dioxyoctanoyl) 5 ]-MCH, [4][5][6][7][8][9][10][11][12][13][14][15][16][17]44] and the replacement of intact cells by membrane preparations. It is interesting to note that in contrast to the structural requirements of MCH-R expressed in pigment cells (which does not tolerate an iodinated Tyr 13 ), binding analysis of MCH-R 1 overexpressed in HEK-293 cells was possible with [ 125 I]-MCH.…”

Design and synthesis of orally efficacious benzimidazoles as melanin-concentrating hormone receptor 1 antagonists

“…17,18 The profiles are reported in Table 5. The alkene analogues (6a, 12c, 12d, 12p, and 12t) exhibited very good exposure in rats, indicating the tetra-substituted olefin bonds are metabolically quite stable.…”

Peptide Ligands for the Melanin-Concentrating Hormone (MCH) Receptor 1

“…3), was more active than hMCH in stimulating [ 35 S]-GTP S binding at membranes from HEK293 cells stably expressing the human MCH receptor (IC 50 = 0.59 nM in the cAMP assay, EC 50 = 2.1 nM in the [ 35 S]-GTP S assay.) [38] Its iodinated derivative was a less hydrophobic, more potent and stable radioligand than ( 125 ITyr 13 )-hMCH (3, Fig. 2).…”

“…3) and several other analogs of hMCH(6-17) of various agonist potency prepared by Audinot and coworkers [37][38][39] were used to show that the orexigenic effects of MCH in rats are mediated by the MCH receptor 1 (SLC-1R). First, these compounds were tested in vitro on the rat recombinant SLC-1 receptor (MCH-1R) in cAMP inhibition and [ 125 I]-S36057 binding assays.…”