Facile synthesis of MDTPA and BMDTPA: Design and synthesis of novel DTPA-peptide conjugates for radiolabelling

Aim: In-111 radiolabelling of monoclonal antibodies was achieved by using 3,6-bis(carboxymethyl)-9-{[(2-maleimidoethyl)carbamoyl]-methyl}-3,6,9-triazaundecanedioic acid (MDTPA), synthesised in 12 steps. 1.We designed and investigated a new synthetic route of MDTPA to investigate In-radiolabelling of a cysteine derivatised nanogastrin peptide. We also targeted the synthesis of 1,9-bis{[(2-maleimidoethyl)-carbamoyl]methyl}-3,6,9-tris(carboxymethyl)-3,6,9-triaza-undecanoic acid (BMDTPA) from which the corresponding DTPA-N,N”-bis(amide) peptide conjugate can potentially chelate Gd(III), Y(III), Cu(II) and Zn(II) and therefore open avenues towards novel peptide/antibody based MRI and PET contrasting agents.

2.Methods: 2-aminoethylmaleimide, synthesised in 3 steps, was reacted with DTPA anhydride to obtain MDTPA and/or BMDTPA. Then nanogastrin peptide was treated separately with both MDTPA and BMDTPA and cold Indium labelling of the corresponding peptide conjugates were characterised by RP HPLC-MS. Results: The coupling of 2-aminoethylmaleimide, synthesised in 3 steps (70% overall yield) with DTPA anhydride afforded both MDTPA and BMDTPA in 5% and 72% yield respectively after RP HPLC purification. Nanogastrin-MDTPA coupling afforded the corresponding peptide conjugate, which successfully labelled with Indium (analysed by HPLC-MS). Application of BMDTPA as a spacer in the synthesis of a bis-HYNICnanogastrin conjugate followed by Tc-99m radiolabelling will also be presented.

Conclusions:The novel 4-step short synthesis of both MDTPA and BMDTPA was accomplished thus making both compounds more accessible to functionalise peptides and antibodies of interest for a wide range of applications.