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Development and preliminary evaluation of [18F]JHU94620-d8 for PET imaging of cannabinoid receptors type 2
Moldovan, R. P.
The development PET radioligands for imaging of the cannabinoid type 2 receptors (CB2R) has been intensively explored due to their upregulation in various pathological conditions . Recently, we reported the development of [18F]JHU94620 , however, this radioligand suffered from low metabolic stability in vivo. Here, we describe the development of the deuterated analogues [18F]JHU94620-d4 and -d8 as well as their biological evaluation (Figure 1). The precursors for radiofluorination were obtained by coupling 4,5-dimethylthiazol-ylidene-2,2,3,3-tetramethylcyclopropane-1-carboxamide with either d4 or d8 1,4-butanediol-bistosylate and radiofluorinated in the presence of Kryptand K2.2.2. and K2CO3. [18F]JHU94620-d4 and -d8 were obtained in 10% radiochemical yield and >99% radiochemical purity. The fraction of radiometabolites was quantified in mice plasma, brain and spleen of CD1 mice at 30 min p.i. Both [18F]JHU94620-d4 and -d8 demonstrated an improved metabolic stability with 80% intact radioligand detected in the brain vs. 36% for [18F]JHU94620. The CB2 affinity and specificity of [18F]JHU94620-d8 was determined by in vitro binding experiments and a KD(rCB2) of 0.36 nM was determined. Additionally, we evaluated the [18F]JHU94620-d8 uptake by PET-studies into the spleen of healthy rats and in a rat model carrying an adeno-associated viral (AAV2/7) vector expressing hCB2R(D80N) at high densities in the right striatum (hCB2-rs) [3, 4]. Our PET study with [18F]JHU94620-d8 revealed a rCB2 specific uptake into the spleen (AUC0-30min = 33 vs. 17 SUV min after blocking with GW405833). In the hCB2-rs model we could show a target specific uptake of [18F]JHU94620-d8 with a constant SUV of 6.7±0.3 from 6 to 60 min p.i. and an SUVr (right striatum-to-cerebellum) of 43±7at 60 min p.i., as well as a reversible binding in displacement studies. Thus, [18F]JHU94620-d8 is a new PET tracer with improved metabolic stability and excellent ability to image the CB2 receptors in-vivo. Its further evaluation is underway.
Invited lecture (Conferences)
DPhG Annual Meeting 2021 Trends and Perspectives in Pharmaceutical Sciences, 30.09.2021, Leipzig, Germany