Amino acid based gallium-68 chelators capable of radiolabeling at neutral pH

Abstract

Gallium-68 (Ga) has been the subject of increasing interest for its potential in the production of radiotracers for diagnosis of diseases. In this work we report the complexation of Ga by the amino acid based tripodal chelate HDpaa, and two bifunctional derivatives, HDpaa.dab and HDpaa.ga, under a range of conditions with particular emphasis on the rapid complexation of Ga at pH 7.4. 100 μM HDpaa achieved a radiochemical yield of 95% at pH 7.4 in 5 minutes at 37 °C. The bifunctional derivatives HDpaa.ga and HDpaa.dab achieved 94% and 84% radiochemical yields, respectively, under the same conditions. The resulting Ga(iii) complexes show thermodynamic stabilities of log K = 18.53, log K = 22.08, log K = 18.36. Unfortunately, the resulting radiolabelled species do not present sufficient serum stability for in vivo application. Herein we show a flexible synthesis for bifunctional chelators based on amino acids that rapidly complex Ga under physiological conditions.

Bn2DT3A, a Chelator for 68Ga Positron Emission Tomography: Hydroxide Coordination Increases Biological Stability of [68Ga][Ga(Bn2DT3A)(OH)]−

“…This may reflect the strain induced by coordination of the central amine to Ga 3+ ; this strain has previously been reported to prevent the coordination of the central amine in tripodal chelates with Ga 3+ . 19,39 The gallium-to-oxygen bond lengths are shorter and lie in the range 1.937(5) to 1.987(5) Å, comparable to those reported for [Ga(DOTA)] − , 36 [Ga-(NOTA)], 37 and [Ga(EDTA)] − . 38 The Ga 3+ complex does not form any classical hydrogen bonds, but within the solidstate structure, there are many C−H•••O interactions.…”

“…As has previously been reported for the [Ga­( Dpaa )­(H 2 O)] system ( Dpaa = 6,6′-{[(carboxymethyl)­azanediyl]­bis­(methylene)}­dipicolinic acid, Figure S1), a deprotonation event occurs in the mildly acidic region (p K a = 5.32, Figure ). , In the case of [Ga­( Dpaa )­(H 2 O)], a coordinated water molecule is the likely site of deprotonation. In the case of [Ga­( Bn 2 DT3A )], there is no evidence for a coordinated water molecule in the neutral species.…”

Chelation in One Fell Swoop: Optimizing Ligands for Smaller Radiometal Ions

“…Ga 3+ is a hard acid ( I A = 7.07) with ionic radius 47–62 pm and a preference for coordination number 4–6 . Many macrocyclic and nonmacrocyclic ligands (examples appear in Chart ) have been reported for their applications in 67/68 Ga based radiopharmaceuticals. − DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) still remains the chelator most widely used by clinicians to radiolabel 68 Ga 3+ , but at elevated temperaturesconditions antithetical to using antibodies as a delivery vehiclebecause of the significant thermodynamic stability and kinetic inertness of the [Ga­(DOTA)] − complex.…”

Evaluation of a Bispidine‐Based Chelator for Gallium‐68 and of the Porphyrin Conjugate as PET/PDT Theranostic Agent

“…[45] The acyclicc helator H 3 Dpaa was able to be readily radiolabeled with 68 Ga when conjugated to ap orphyrin; [46] however,t he resulting complex was insufficiently stable. [46,49] As for bioconjugates, there is an eed of finding a good chelator/porphyrin match in order to optimize both radiolabelinga nd PET imaging properties and PDT efficiency.…”