Synthesis and stability studies of Ga‐67 labeled phosphonium salts

Abstract

Delocalized lipophilic cations such as tri- and tetra-arylphosphonium are able to diffuse across the mitochondrial membrane, which allows them to selectively accumulate in cells with a high transmembrane potential (ΔΨ ). The mitochondrial membrane potential of cancer cells and cardiomyocytes has been reported to be significantly higher than that of normal epithelial cells. This feature can be exploited for the selective accumulation of phosphonium derivatives for the purposes of molecular imaging using radionuclides. Four structurally related Ga(III)-phosphonium salts were synthesized and fully characterized and found to be modest in toxicity toward T98G human glioblastoma cells (IC > 4 mM). High-activity (100 MBq) analogs containing Ga-67 were also synthesized and their stabilities in phosphate-buffered saline and human serum were determined.

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

“…Synthesis of the DO3A-xy-TAP chelators DO3A-xy-TAP chelators were synthesised as outlined in Scheme 1. The synthesis combined methodologies used by Haslop et al, Wang et al and Kardashinsky et al 27,28,37 Firstly, an alkyl-functionalised aryl bromide was converted into a Grignard reagent before being reacted with phosphorus trichloride to form a triarylphosphine (1). This strategy allowed tuning of the final tracer lipophilicity by altering the alkyl functionalisation, in accordance with the work performed by Haslop et al 27 Whilst anaerobic and anhydrous conditions were maintained as far as possible, some triarylphosphine was found by 31 P{ 1 H}-NMR to be oxidised to its phosphine oxide.…”

“…The methodology was a modification of the procedure described by Kardashinsky et al 37 To a solution of DO3Atriester•HBr (1 eq.) and triarylphosphane-substituted bromoxylene (1 eq.)…”

“…1 H NMR (400 MHz, CDCl 3 ) δ H ( ppm): 7.78 (3H, tt, 3 J HH = 6.9, 4 J HH = 1.7 Hz, p-Ar), 7.74-7.63 (12H, m, o/m-Ar), 7.05-7.04 (4H, m, C 6 H̲ 4 ), 5.33 (2H, broad s, CH̲ 2 P), 3.64 (2H, s, C 6 H 4 CH̲ 2 ), 3.41-2.11 (22H, m, macrocycle H̲ /CH̲ 3 CO 2 ), 1.47 (18H, s, cis-C(CH̲ 3 ) 3 ), 1.43 (9H, s, trans-C(CH̲ 3 ) 3 ). 13 General procedure 3deprotection of tert-butyl protected DO3A-xy-TAP compounds using trifluoroacetic acid (4) The methodology was a modification of the procedure described by Kardashinsky et al 37 tert-butyl protected compounds were dissolved in trifluoroacetic acid (reaction mixture concentration 0.1 g mL −1 ) and stirred at rt under an N 2 atmosphere for 24 h. The acid was removed in vacuo, before the residue was taken up in H 2 O (50 mL) and washed with CHCl 3 (3 × 10 mL). The aqueous solvent was removed under reduced pressure, before the residue was purified via semi-preparative HPLC methods.…”

“…Kardashinsky et al have synthesised DO3A-xy-TAP chelators for gallium-67, in which the TAP groups exhibit methyl and pyridyl functionalisation. [35][36][37] However, no mitochondrial uptake studies have been performed on these chelators, and their utility as gallium-68 based imaging agents has yet to be explored.…”

“…These chelators are designed to combine the rationale behind the DO3A-xy-TPP chelators previously used for copper-64 and gallium-67 chelation, with tunable lipophilicity afforded by alkyl-functionalised triarylphosphonium cations in order to form the novel chelators DO3A-xy-TTP and DO3A-xy-TXP. 27,29,37 After initial synthesis and characterisation of the ligands, their radiolabelling characteristics and log D values were analysed to give an indication of their potential use as mitochondrial imaging agents. The tracers were biologically evaluated in cultured tumour cells and using the ex vivo Langendorff isolated perfused heart model with a unique triple gamma detector system, which has been used previously in our group to assess radiotracer pharmacokinetics.…”