Targeting Translocator Protein (TSPO) with GE-180: Imaging brain inflammation and reactive gliosis

Objectives Traumatic brain injury (TBI) is an increasingly prevalent health issue and one of the leading causes of morbidity and mortality worldwide. In the US alone over 2.5 million TBIs were reported in 2010 (CDC.gov). Neuroinflammation is an important pathological response to brain injury with associated glial cell activation. Translocator protein (TSPO) levels have been shown to increase in the CNS in response to neuronal damage and inflammation. Several TSPO PET tracers, including archetype [¹¹C](R)-PK11195, [¹¹C]PBR28 and [¹⁸F]DPA-714, among others, have highlighted neuroinflammation and reactive gloss associated with traumatic brain injury. The objective of the present study was to demonstrate [¹⁸F]GE-180 ( (4S)-N,N-diethyl-9-(2-fluoroethyl)-5-methoxy-2,3,4,4a,9,9a-hexahydro-1H-carbazole-4-carboxamide; Wadsworth et al., Bioorg Med Chem Lett, 2011), uptake in response to TSPO expression following an experimentally induced focal contusion.

Methods [¹⁸F]GE-180 was prepared in a single step from the corresponding mesylate precursor. The tracer was purified by HPLC, concentrated on a C18 SepPak® and formulated in 5% ethanol/saline for injection. Male Long-Evans rats were anesthetized and a 6 mm craniectomy was produced in the skull (Sham). A controlled cortical impact was produced using a Leica ImpactOne device to induce traumatic brain injury (TBI). Rats were injected with 150-250 μCi of [¹⁸F]GE-180 and imaged 45-75 minutes post-injection using a Siemens InVeon microPET/CT. Control , sham and TBI rats (n=3) were evaluated at 1, 7 and 31 days post injury. Small animal 7T MR was performed to confirm the injury.

Results [¹⁸F]GE-180 was prepared in ~25% radiochemical yield (NDC), with >99% radiochemical and >95% chemical purity and specific activity of 400-800 Ci/mmol. [¹⁸F]GE-180 synthesis has been automated on two commercial systems. There was no CNS accumulation of [¹⁸F]GE-180 in the control or sham animals at all time points. There was a small amount of uptake in the inflamed scar tissue near the craniectomy site in the sham and TBI rats. Uptake and retention of [¹⁸F]GE-180 was clearly visible in the MRI confirmed rat TBI at day 7 and day 31 after injury.

Conclusions [¹⁸F]GE-180 accumulates in rat brain tissue following traumatic injury to the site corroborating an earlier report with [¹⁸F]DPA-714 in a similar model (Wang et al., EJNMMI 2014). This study demonstrates the potential of [¹⁸F]GE-180 as a sensitive imaging agent for TBI and response to therapeutic intervention.

• Download figure
• Open in new tab
• Download powerpoint