Synthesis, gallium-68 radiolabelling and biological evaluation of a series of triarylphosphonium-functionalized DO3A chelators

Abstract

Gallium-68 chelators with tunable lipophilicities were synthesised, and assessed in both in vitro tumour cells and ex vivo isolated hearts.

Synthesis and ex vivo biological evaluation of gallium-68 labelled NODAGA chelates assessing cardiac uptake and retention

“…1). 8,24,25 We confirm this in Fig. 6A, where under baseline conditions, 25.4 ± 1.92 % of an injected [ 99m Tc]Tc-sestaMIBI bolus is retained in the heart 15 minutes post-injection when the mitochondria are polarised, while 0.00 ± 0.53 % is retained when the mitochondria are depolarised by 600 nM CCCP (n = 3).…”

“…Increasing the level of alkyl-functionalisation of the TAP moiety causes an increase Please do not adjust margins Please do not adjust margins in log D7.4 value. This trend was studied and shown previously, 19,24,25 In order to determine whether the tracer exhibited ΔΨmdependent mitochondrial uptake, we employed the Langendorff isolated perfused heart model. This ex vivo model allows accurate and reproducible interventions on intact beating cardiac tissue which would otherwise be lethal to an animal in vivo, whilst also maintaining a high degree of in vivo relevance.…”

“…All three (R)-NODAGA-xy-TAP compounds were radiolabelled and analysed according to the same protocol, a modification of the methodology previously described by Smith et al 24,25 The ligand was dissolved in clinical grade 3.6 M NaOAc to generate a ligand concentration of 500 µM, before adding generatorproduced [ 68 Ga]Ga(III) (in 0.1 M aqueous HCl, 500 µL) and the resulting mixture (pH 5.0) was left at room temperature for 15 minutes. Instant thin-layer chromatography (iTLC) was employed as a quality control (QC) method.…”

“…23 In 2018, Smith et al synthesised a family of DO3A-xy-TAP chelates for gallium-68, functionalised with triphenylphosphonium (TPP), tritolylphosphonium (TTP) and trixylylphosphonium (TXP). 24 These radiotracers were designed with the idea of combining the tuneable lipophilicity afforded by alkyl-functionalisation of the TAP moiety, and the rationale behind the DO3A-xy-TPP chelators used for gallium-67. 23 The most lipophilic tracers of this series, [ 68 Ga]Ga-DO3A-xy-TXP (Fig.…”

“…The pharmacokinetics and sensitivity of the tracers to ΔΨm were then evaluated using the ex vivo Langendorff isolated heart model monitored by our triple -detection system. 24,25,[28][29][30][31]…”