Influence of the bifunctional chelator on the pharmacokinetic properties of 99mTc(CO)3-labeled cyclic α-melanocyte stimulating hormone analog

J Med Chem. 2013 Mar 14;56(5):1961-73. doi: 10.1021/jm301647t. Epub 2013 Mar 1.


Aiming at the design of specific melanocortin-1 receptor (MC1R) targeted imaging probes, we report on the effect of different azolyl-ring substitution patterns (carboxylate at the 4-position and/or methyl groups at the 3,5 positions) of pyrazolyl-diamine bifunctional chelators (Pz(2)-Pz(4)) on the pharmacokinetic profile of the (99m)Tc(CO)3-labeled lactam bridge-cyclized α-melanocyte stimulating hormone derivative, βAlaNleCycMSH(hex). Three pyrazolyl-diamine-containing chelators were conjugated to βAlaNleCycMSHhex, with the resulting peptide conjugates displaying subnanomolar MC1R binding affinity. Biodistribution studies in B16F1 melanoma-bearing mice show that all radiopeptides present a good melanoma uptake. The introduction of a carboxylate group in the azolyl-ring leads to a remarkable reduction of the kidney (>89%) and liver (>91%) accumulation for (99m)Tc(CO)3-Pz(3)-βAlaNleCycMSH(hex) and (99m)Tc(CO)3-Pz(4)-βAlaNleCycMSH(hex) when compared to the radiopeptide (99m)Tc(CO)3-Pz(1)-βAlaNleCycMSH(hex), where that group is absent. The good tumor uptake and favorable tumor-to-nontarget-organs ratios of (99m)Tc(CO)3-Pz(3)-βAlaNleCycMSH(hex) and (99m)Tc(CO)3-Pz(4)-βAlaNleCycMSH(hex) highlights the potential of both compounds as melanoma imaging agents.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chelating Agents / chemistry*
  • Drug Stability
  • Humans
  • Melanoma, Experimental / diagnosis
  • Melanoma, Experimental / metabolism
  • Mice
  • Peptides, Cyclic / chemical synthesis
  • Peptides, Cyclic / pharmacokinetics
  • Radiopharmaceuticals* / chemical synthesis
  • Radiopharmaceuticals* / pharmacokinetics
  • Receptor, Melanocortin, Type 1 / chemistry
  • Receptor, Melanocortin, Type 1 / metabolism
  • Technetium / pharmacokinetics
  • alpha-MSH / analogs & derivatives*
  • alpha-MSH / metabolism
  • alpha-MSH / pharmacokinetics


  • Chelating Agents
  • Peptides, Cyclic
  • Radiopharmaceuticals
  • Receptor, Melanocortin, Type 1
  • alpha-MSH
  • Technetium