We recently developed a novel cannabinoid subtype-1 (CB₁) receptor radioligand ¹¹C-SD5024 for brain imaging. This study aimed to evaluate ¹¹C-SD5024 both in vitro and in vivo and compare it with the other CB₁ receptor ligands previously used in humans, i.e., ¹¹C-MePPEP, ¹¹C-OMAR, ¹⁸F-MK-9470, and ¹⁸F-FMPEP-d₂. In vitro experiments were performed to measure dissociation constant (K_i) in human brain and to measure the lipophilicity of five CB₁receptor ligands listed above. In vivo specific binding in monkeys was measured by comparing total distribution volume (V_T) at baseline and after full receptor blockade. The kinetics of ¹¹C-SD5024 in humans were evaluated in seven healthy subjects with compartmental modeling. SD5024 showed K_i=0.47 nM, which was at an intermediate level among the five CB₁ receptor ligands. Lipophilicity (LogD_7.4) was 3.79, which is appropriate for brain imaging. Monkey scans showed high proportion of specific binding: ~80% of V_T. In humans, ¹¹C-SD5024 showed peak brain uptake of 1.5-3 standardized uptake value, which was slightly higher than those of ¹¹C-OMAR and ¹⁸F-MK-9470. One-compartment model showed good fitting, consistent with the vast majority of brain uptake being specific binding found in the monkey. Regional V_T values were consistent with known distribution of CB₁ receptors. V_T calculated from 80 and 120min of scan data were strongly correlated (R²=0.97), indicating that 80min provided adequate information for quantitation and that the influence of radiometabolites was low. Intersubject variability for V_T of ¹¹C-SD5024 was 22%, which was low among the five radioligands and indicated precise measurement. In conclusion,¹¹C-SD5024 has appropriate affinity and lipophilicity, high specific binding, moderate brain uptake, and provides good precision to measure the binding. The results suggest that ¹¹C-SD5024 is slightly better than or equivalent to ¹¹C-OMAR and that both are suitable for clinical studies, especially those that involve two scans in one day.
© 2013.

PMID:

 

24076222

 

[PubMed – as supplied by publisher]