NOVEL RADIOLABELED POLYDENTATE LIGANDS AS POTENTIAL DIAGNOSTIC PROBES

Muhammad Qadir

Institute of Chemistry, University of the Punjab, Punjab, Pakistan

Abstract

The 99mTc-radiopharmaceuticals have been used for diagnosis of many diseases especially cancer in nuclear medicine for many years ago. Currently, target specific radiopharmaceuticals containing peptides have become more interesting due to increasing the knowledge of receptor binding affinity of specific peptides, as well as ease of chemical modification of peptide sequences. Many chelators have been developed as bifunctional chelators for conjugation to peptides as well as for chelation with 99mTc. Small size chelators are desireable for labeling the small peptides. One of the most important requirements of radiopharmaceuticals is an aqueous phase labeling the biomolecules to 99mTc. These requirements must meet in order to use for nuclear medicine. In this context, Cp- is obviously as a good choice of chelator due to its small size and low molecular weight. The 99mTc radiolabeled peptide comprising Cp (cyclopentadiene) core have not been synthesized in an aqueous phase. Instead, they have been synthesized by double ligand transfer approach in organic solvent using harsh reaction conditions which are still not suitable for routing use. In this study we describe the syntheses of half-sandwich complexes of the type [Cp(CONHR)99mTc(CO)3] in an aqueous phase. The R group represents different tri-peptides which display high binding affinities for oligopeptide transporters PEPT2; the R also represents cyclic RGD peptides which have high binding affinity with integrin family receptor. The desired sequences of number of tripeptides and cyclic RGD peptide were synthesized through solid phase peptide synthesis (SPPS) manually using standard Fmoc-chemistry on 2-chlorotritylchloride resin. We synthesized the Diels-Alder product [(HCpCONHR)2] from Thiele’s acid [(HCp-COOH)2] via double peptide coupling. The 99mTc complexes were prepared directly from [99mTc(OH2)3(CO)3]+ and Diels-Alder dimerized, cyclopentadienyl derivatized peptides in water. This approach corroborates the feasibility of metal-mediated retro Diels-Alder reactions for the preparation of not only small molecules but also of peptides for carrying a [(Cp)99mTc(CO)3] tag. The Re-complexes [(CpCONHR)Re(CO)3] were synthesized by attaching [(Cp-COOH)Re(CO)3] directly to the N-terminus of peptides as prepared from SPPS. The authenticity of the 99mTc-complexes is confirmed by HPLC retention time comparison with the corresponding rhenium complexes, fully characterized by spectroscopic techniques.

Keywords: Radiopharmaceuticals, 99mTC, peptides, Radiolabling, Diagnostic Radio Pharma.