Expedient Multi-Step Synthesis of Organometallic Complexes of Tc and Re in High Effective Specific Activity. A New Platform for the Production of Molecular Imaging and Therapy Agents

Abstract

For over thirty years, instant labeling kits which involve no purification steps have been the only method used to prepare (99m)Tc radiopharmaceuticals for clinical studies. To address the limitations imposed by instant kits, which is hindering the development of molecularly targeted Tc- and Re-based imaging and therapy agents, a new strategy for the rapid multistep synthesis and purification of organometallic technetium-based molecular probes and corresponding rhenium-based therapeutic analogues was developed. Beginning with MO4(-) (M = (99m)Tc, (186/188)Re), the carbonyl precursor [M(CO)3(H2O)3](+) was synthesized in 3 min in quantitative yield in a microwave reactor. A dipicolyl ligand was added and the chelate complex was formed in high yield in 2 min using microwave heating at 150 degrees C. This was followed by a new purification strategy to remove unlabeled ligand which entailed using a copper resin/C18 solid phase extraction protocol giving the desired product in greater than 78% decay corrected yield (dcy). Conversion to the corresponding succinimidyl active ester was achieved following a 5 min microwave irradiation at 120 degrees C and C18 solid phase extraction purification in 60% dcy. A series of amides were prepared subsequently by microwave heating at 120 degrees C for 5 min producing the desired targets in greater than 86% dcy. The reported method represents a move away from traditional instant kits toward more versatile platform synthesis and purification technologies that are better suited for producing modern molecular imaging and therapy agents.

Preparation, 99mTc-labeling and biodistribution studies of a PNA oligomer containing a new ligand derivative of 2,2′-dipicolylamine

“…Furthermore, this ligand needed to contain a functional group to allow its coupling to a PNA oligomer. Our attention rapidly turned to 2,2′-Dipicolylamine (Dpa) derivatives, which have already been intensively used in nuclear chemistry and which can be furthermore easily functionalized [53][54][55][56][57][58][59][60][61][62][63][64][65][66]. Thus, the ligand 2-azido-N,N-bis((pyridin-2-yl)methyl)ethanamine (Dpa-N 3 , Scheme 1) was prepared in a one-step synthesis starting from the known compound 2-(bis(pyridin-2-ylmethyl)amino)ethanol [51] (Dpa-OH) with triphenyl phosphine, diisopropyl azodicarboxylate and diphenylphosphoryl azide in THF (Scheme 1).…”

Coordination Modes of Multidentate Ligands infac-[Re(CO)3(polyaminocarboxylate)] Analogues of99mTc Radiopharmaceuticals. Dependence on Aqueous Solution Reaction Conditions

“…In particular, the fac -{M I (CO) 3 } + core (M = Re, 99m Tc) has been assessed because of its small size, its low-spin d6 electronic configuration, and the high chemical and kinetic stability of its complexes 30. These useful properties of the fac -{M I (CO) 3 } + core allow the labeling of low-molecular-weight biomolecules attached through the three remaining facial sites available for substitution to produce agents having high specific activities 30,33-38. A convenient kit described by Alberto and colleagues for generating solutions of the fac -[ 99m Tc(CO) 3 (H 2 O) 3 ] + cation is now commercially available 39,40.…”

Preparation of technetium‐99m bifunctional chelate complexes using a microfluidic reactor: a comparative study with conventional and microwave labeling methods

“…For the exploration of the feasibility of using microfluidic reactors to produce technetium‐based molecular imaging agents, key reaction parameters were investigated for the reaction of [ 99m Tc(CO) 3 (OH 2 ) 3 ] + and the bifunctional chelate dithiazole valeric acid (DTV) (Scheme ). The microfluidic reactor was found to outperform identical reactions carried out using either conventional batch techniques or a microwave reactor, which has previously been shown in our group to enhance the reaction between the technetium tricarbonyl core and bifunctional chelates . The study was also designed to provide insight into the benefits and challenges of using microfluidics to optimize the labeling of new lead candidates prior to preclinical assessment.…”