[¹⁸F]PRIMATX, a New Positron Emission Tomography Tracer for Imaging of Autotaxin in Lung Tissue and Tumor‐Bearing Mice

Abstract

Autotaxin (ATX) is a secreted enzyme with tissue levels associated with tissue injury, which increase during wound healing and chronic fibrotic diseases. We selected [18F](R,E)‐3‐(4‐chloro‐2‐((5‐methyl‐2H‐tetrazol‐2‐yl)methyl)phenyl)‐1‐(4‐((5‐(2‐fluoroethoxy)pyridin‐2‐yl)methyl)‐2‐methylpiperazin‐1‐yl)prop‐2‐en‐1‐one ([18F]PRIMATX, [18F]2), a tracer for positron emission tomography, to image ATX expression in vivo. It successfully differentiates expression levels in lung tissue samples from idiopathic pulmonary fibrosis patients, and allows the detection of ATX‐expressing tumors in living mice, confirming its potential for development as a clinical imaging agent.

Positron Emission Tomography Imaging of Autotaxin in Thyroid and Breast Cancer Models Using [18F]PRIMATX

“…and Echelon Biosciences introduced ATX-red-2 as the first and, to date, the only ATX fluorescence imaging probe. This compound was used for the quantification of ATX activity in a murine melanoma model after treatment with different concentrations of carbamoylphosphonates. , In 2019, Briard et al presented the first 18 F-labeled radiotracer for the PET imaging of ATX, [ 18 F]­PRIMATX . This compound was optimized from a high-throughput lead structure and developed as an 18 F-radiotracer with a high potency against ATX as determined with an IC 50 value of 5 nM.…”

“…Potassium Kryptofix (K 2 CO 3 /K 222 ) was used to elute no-carrier-added [ 18 F]­fluoride off a QMA (Waters Sep-Pak QMA plus light) cartridge into a drying vial, which was dried under nitrogen gas at 95 °C. Dried [ 18 F]­fluoride was resuspended in acetonitrile (∼0.3 mL) and was transferred to a new reaction vial containing ( R , E )-2-((6-((4-(3-(4-chloro-2-((5-methyl-2 H -tetrazol-2-yl)­methyl)­phenyl)­acryloyl)-3-methylpiperazin-1-yl)­methyl)­pyridin-3-yl)­oxy)­ethyl-4-methylbenzenesulfonate 1 (3 mg, 4.5 μmol; provided by Novartis Institutes for BioMedical Research, Basel, Switzerland and synthesized according to Briard et al). The whole mixture was reacted at 85 °C for 5 min under nitrogen to produce the [ 18 F]­PRIMATX, [ 18 F]­2 .…”

“…In contrast, properties like high stability in vivo become more important. ,, An ideal molecular imaging probe for ATX should be stable in vivo throughout the time course of the ATX imaging experiment, and it should possess adequate lipophilicity to make transient associations with biomolecules during the biodistribution and targeting process. Most importantly, the radiotracer should demonstrate a high level of specificity in binding to its target. − …”

“…Recent efforts have resulted in the development and initial testing of [ 18 F]­PRIMATX, an 18 F-labeled derivative based on a benzyl-methyl-tetrazole ATX inhibitor that binds tightly to ATX. , …”

Establishment of a guided, in vivo, multi-channel, abdominal, tissue imaging approach

“…This longitudinal study design enables a reduction in animal experiments, as not as many animals have to be sacrificed than for endpoint based analysis methods as, for instance, for histologic analyses. Imaging methods applied in animal research include micro-computed tomography 1 , magnetic resonance imaging 2 , positron emission tomography 3 , ultrasound 4 , and optical imaging. Optical imaging has two significant advantages: Firstly, in combination with fluorescence, variety of different fluorophores such as dyes, antibodies, or fusion proteins are available 5,6 .…”