Development of a rhodium tetrathioether bombesin analogue and investigation of cyclic and acyclic ligand systems for 105Rh(III)

Rhodium-105 is an attractive nuclide for radiotherapeutic applications due to its nuclear properties (566 keV , 319 keV [19%], 306 keV [5%]) and the kinetic stability of Rhodium (III) complexes with soft sulfur donor atoms. Extension of previous research involving tetrathioether chelate systems to include a targeting molecule may have implications for prostate cancer therapy. This work reports on the synthesis and evaluation of a new bombesin peptide targeted Rh (III) tetrathioether analogue, [Rh-S48Aoc-BBN(7-14)NH2] + , which shows high affinity for the BB2r receptor on PC-3 cancer cells (IC50 = 2.2 ± 0.3 nM). However, multiple 105 Rh labeled species were obtained under the radiolabeling conditions investigated. To better understand the results observed for [ 105 Rh-8Aoc-BBN(7-14)NH2] + , the chemistries of previously investigated [Rh-S4-Diol] + and [Rh-S4-(COOH)2] + were reevaluated using more recently available techniques. A quantitative evaluation of the [RhS4-Diol] + and [Rh-S4-(COOH)2] + systems using NMR, ESI-MS and HPLC reveals formation of multiple species resulting from both exchange of the coordinated chlorides at the metal center and esterification of pendant carboxylate groups. While a predominate trans-chloro Rh(III)-S4 species may be favored by addition of excess NaCl, both ethanol and acid are required for radiolabeling. Thus, ligand systems utilizing pendant carboxylate groups are not compatible with traditional 105 Rh radiolabeling techniques. Future studies involving a 105 Rh tetrathioether bombesin analogue without pendant carboxylate groups are recommended.