Sorbitol as a Polar Pharmacological Modifier to Enhance the Hydrophilicity of Tc-Tricarbonyl-Based Radiopharmaceuticals.

The organometallic technetium-99m tricarbonyl core, [Tc][Tc(CO)(HO)], is a versatile precursor for the development of radiotracers for single photon emission computed tomography (SPECT). A drawback of the Tc-tricarbonyl core is its lipophilicity, which can influence the pharmacokinetic properties of the SPECT imaging probe. Addition of polar pharmacological modifiers to Tc-tricarbonyl conjugates holds the promise to counteract this effect and provide tumor-targeting radiopharmaceuticals with improved hydrophilicities, e.g., resulting in a favorable fast renal excretion in vivo. We applied the "Click-to-Chelate" strategy for the assembly of a novel Tc-tricarbonyl labeled conjugate made of the tumor-targeting, modified bombesin binding sequence [Nle]BBN(7-14) and the carbohydrate sorbitol as a polar modifier. The Tc-radiopeptide was evaluated in vitro with PC-3 cells and in Fox-1 mice bearing PC-3 xenografts including a direct comparison with a reference conjugate lacking the sorbitol moiety. The glycated Tc-tricarbonyl peptide conjugate exhibited an increased hydrophilicity as well as a retained affinity toward the Gastrin releasing peptide receptor and cell internalization properties. However, there was no significant difference in vivo in terms of pharmacokinetic properties. In particular, the rate and route of excretion was unaltered in comparison to the more lipophilic reference compound. This could be attributed to the intrinsic properties of the peptide and/or its metabolites. We report a novel glycated (sorbitol-containing) alkyne substrate for the "Click-to-Chelate" methodology, which is potentially of general applicability for the development of Tc-tricarbonyl based radiotracers displaying an enhanced hydrophilicity.