Gastrin releasing peptides (GRP) have been shown to be over expressed in small cell lung, prostate, breast, and pancreatic cancers. Of these pancreatic cancer is of great interest for targeting due to its low survival rate. It is estimated that there will be 31,800 deaths due to pancreatic cancer in the US in 2005 alone. The 14 amino acid peptide bombesin (BBN) and analogues have been shown selectively bind GRP receptors. In some cases the altered peptides have been shown to have a higher binding affinity than the native wild strain, which is isolated from the skins of the amphibian Bombina. The 9 amino acid analogue BBN(7-14) has been shown to be a powerful agonist to GRP receptors.
105Rh is a reactor-produced beta-emitting radionuclide with very appealing nuclear properties (t1/2= 35.5 h, Ξ²max= 0.57 MeV, Ξ³ = 319 keV (19%)) for radiotherapy. Its medium beta decay energy has a 1.9 mm maximum range in H2O that will be useful for the homogeneous irradiation of medium sized tumors, while the 35.5 h half-life is sufficient for the production, shipping, labeling and in vivo localization of the labeled drug. The low abundance gamma emission is in the diagnostically useful range, allowing for dosimetry calculations. Rh-105 is readily produced in high specific activity (βΌ10,000Ci/mmol of metal) and "no-carrier added" (NCA) levels by indirect (n,Ξ³) activation of isotopically enriched 104Ru target. The 104Ru forms 105Ru, which beta decays to 105Rh. Alternatively, Rh-105 can be isolated from fission products once Curie quantities are required for clinical trails.
A very important advantage for the utilization of Rh-105 in radiopharmaceuticals is the high kinetic inertness of the low-spin d6 Rh(III) complexes. This property insures the in vivo stability of the complexes, a determining factor that enhances the suitability of the radiotherapeutic agent.
The dithiahydroxymethylphosphine (S2P) bifunctional chelate with different linker lengths (5 C and 8 C) between the metal chelate and the BBN(8-14) peptide were synthesized and characterized. The S2P-BBN(8-14) ligand was radiolabeled with 105Rh(III)-chloride (provided by MURR) in an aqueous ethanol solution by heating at 85oC fir 1 h. Reversed phase HPLC analysis showed the complexes formed with high radiochemical yield. Stability of the Rh-105 labeled S2P complexes was high (<25% degradation over 48 h). Animal studies (CF-1 mice) conducted with the dithiahydroxymethylphosphine 105Rh-S2P-5C-BBN(7-14) complex with the 5 carbon spacer (Figure 1) showed fast urinary clearance (77% ID in 1 hr) and low pancreatic uptake (mice express GRP receptors in the pancreas). The 8 carbon spacer S2P-8C-BBN(7-14) conjugate was synthesized to increase lipophilicity and slow down clearance. The synthesis, characterization, stability studies, IC50 values, and biodistribution data for both complexes in mice will be presented.