Radiofluorination of a Pre‐formed Gallium(III) Aza‐macrocyclic Complex: Towards Next‐Generation Positron Emission Tomography (PET) Imaging Agents

Abstract

As part of a study to investigate the factors influencing the development of new, more effective metal-complex-based positron emission tomography (PET) imaging agents, the distorted octahedral complex, [GaCl(L)]⋅2 H2O has been prepared by reaction of 1-benzyl-1,4,7-triazacyclononane-4,7-dicarboxylic acid hydrochloride (H2L⋅HCl) with Ga(NO3)3⋅9 H2O, which is a convenient source of GaIII for reactions in water. Spectroscopic and crystallographic data for [GaCl(L)]⋅2 H2O are described, together with the crystal structure of [GaCl(L)]⋅MeCN. Fluorination of this complex by Cl−/F− exchange was achieved in high yield by treatment with KF in water at room temperature over 90 minutes, although the reaction was complete in approximately 30 minutes if heated to 80 °C, giving [GaF(L)]⋅2 H2O in good yield. The same complex was obtained by hydrothermal synthesis from GaF3⋅3 H2O and Li2L, and has been characterised by single-crystal X-ray analysis, IR, 1H and 19F{1H} NMR spectroscopy and ESI+ MS.Radiofluorination of the pre-formed [GaCl(L)]⋅2 H2O has been demonstrated on a 210 nanomolar scale in aqueous NaOAc at pH 4 by using carrier-free 18F−, leading to 60–70 % 18F-incorporation after heating to 80 °C for 30 minutes. The resulting radioproduct was purified easily by using a solid-phase extraction (SPE) cartridge, leading to 98–99 % radiochemical purity. The [Ga18F(L)] is stable for at least 90 minutes in 10 % EtOH/NaOAc solution at pH 6, but defluorinates over this time scale at pH of approximately 7.5 in phosphate buffered saline (PBS) or human serum albumin (HSA). The subtle role of the Group 13 metal ion and co-ligand donor set in influencing the pH dependence of this system is discussed in the context of developing potential new imaging agents for PET.

Synthesis of 18F‐radiolabeled diphenyl gallium dithiosemicarbazone using a novel halogen exchange method and in vivo biodistribution

“…This research builds on the use of complexes of group‐13 metals to form high affinity complexes with [ 18 F]fluoride, driven with a goal for the development of lipophilic radiolabeled complexes which may have applications of neuroimaging. Whilst Bhalla et al reported the preparation of the first Ga‐ 18 F complexes, they did not report the properties of their complexes in vivo. This paper describes the first example of in vivo imaging of a Ga‐ 18 F compound.…”

“…These compounds form a square pyramidal structure, raising the possibility of introducing positron emitting isotopes easily using a halogen exchange strategy. Although this method of introducing fluorine‐18 has been explored by McBride et al and Bhalla et al using different metal chelate moieties, the complexes generated by these groups are all hydrophilic. In contrast, gallium‐ 18 F complexes of dithiosemicarbazones will be both lipophilic and neutral.…”

Chemistry for Positron Emission Tomography: Recent Advances in 11C‐, 18F‐, 13N‐, and 15O‐Labeling Reactions

“…[88] Recently,n ew chelators for the formation of 18 F À Al complexes were developed by Bormans and co-workers to address heatsensitive biomolecules.T he new acyclicp olydentate ligands were less rigid than macrocyclic NOTA,w hich substantially reduced the activation energy for AlÀFcomplexation. [194][195][196] Fore xample,[ 18 F]GaF 3 (BnMe 2 -tacn) could be obtained by 19 F/ 18 F exchange in high RCY (81 AE 1%;Scheme 33 D). [192,193] Recently Reid and co-workers developed ac helating strategy for the preparation of as eries of 18 F-labeled Ga compounds through halogen- 18 Fe xchange.…”

Optimization of 18F‐syntheses using 19F‐reagents at tracer‐level concentrations and liquid chromatography/tandem mass spectrometry analysis: Improved synthesis of [18F]MDL100907

“…We propose and demonstrate an approach to optimize radiochemical reactions by tracer‐level (nanomolar) [ 19 F]KF and quantitation using liquid chromatography/tandem mass spectrometry (LC‐MS/MS). Optimizing radiochemical reactions with natural isotope has been a known approach for decades, which helped radiochemists to establish radiolabeling conditions . But to our knowledge, no quantitation method at no‐carrier‐added (NCA) level has been reported, primarily due to the lack of available analytical methods to quantify tracer‐level of product.…”