“Click” chemistry toward bis(DOTA-derived) heterometallic complexes: potential bimodal MRI/PET(SPECT) molecular imaging probes

Abstract

A general synthetic methodology has been developed for the preparation of DOTA-derived heterometallic omplexes as potential bimodal MRI/PET(SPECT) molecular probes. Both alkyne-and azide substituted DOTA-derived chelators have been synthesized and metallated with Gd 3+ (MRI reporter) or ''cold'' isotopes of Cu 2+ , Ga 3+ and In 3+ (potential PET or SPECT reporters). The Cu + -catalyzed Huisgen [3 + 2] cycloaddition has been utilized as a key step in the synthesis of potential bimodal MRI/PET(SPECT) molecular probes. A preliminary optimization of the reaction conditions has been carried out to make the reaction conditions compatible with the radioactive isotopes of Cu 2+ , Ga 3+ and In 3+ possessing short life times. The MRI sensitivity of the potential bimodal MRI/PET(SPECT) molecular probes has been determined and compared to that associated with a clinically used MRI contrast agent.

A Practical Guide on the Synthesis of Metal Chelates for Molecular Imaging and Therapy by Means of Click Chemistry

“…Accordingly,C u II could be quickly and quantitatively removedf rom TRAP derivatives like 7 and 11 after CuAAC functionalization by the addition of excess NOTA and acidification to pH 2-3 or,e ven more conveniently,b y simply adding excessN OTA·3HCl. [48][49][50] Owing to the high thermodynamic stability and pronounced kinetic inertness of Ln III -DOTAc omplexes, [51] transmetalation with Cu II appearsn ot to be an issue here. Because scavengers like NOTAd on ot interfere with virtually any biogenic substrate, the transchelation approachr epresents av aluable alternative to sulfide-mediated demetalation.…”

ChemInform Abstract: A Practical Guide on the Synthesis of Metal Chelates for Molecular Imaging and Therapy by Means of Click Chemistry

“…[47] Notwithstanding this, CuAACc oupling of alkyne-functionalized [Gd III (DOTA)] units to various substrates, for example to the ubiquitous cyclo(RGDfK) peptide (Figure 9), has been performed without complications. [48][49][50] Owing to the high thermodynamic stability and pronounced kinetic inertness of Ln III -DOTAc omplexes, [51] transmetalation with Cu II appearsn ot to be an issue here. Hence, such Gd III chelates are ideal building blocksf or adding an MRI contrast agentf unctionality to any substrate by meanso fc lick chemistry,r endering CuAAC af irstrate reaction in this context.…”

Spectrophotometric determination and removal of unchelated europium ions from solutions containing Eu-diethylenetriaminepentaacetic acid chelate–peptide conjugates

“…In our hands, purification using the commonly employed technique of reversed-phase chromatography [3, 6] did not achieve adequate removal of unchelated metal ion contaminants. Recent literature describes the removal of excess metal ions from DTPA and DOTA chelates by means of “passive” removal techniques, such as size-exclusion chromatography and dialysis [7,8]. Alternatively, “active” removal of excess metal ions has recently been demonstrated using Chelex ® 100 resin for a non-peptide compound that contained a DTPA chelate [9].…”