Quantitative PET imaging of radioligands with slow kinetics in human brain

Unexpectedly high affinity of a novel histamine H3 receptor antagonist, GSK239512, in vivo in human brain, determined using PET

“…Several possible explanations for the apparent higher in vivo affinity of GSK239512 were considered. Diffusion limitation as a result of a high B max leading to re‐association of both radiotracer and drug could decrease the apparent washout rates from the tissue (Hirvonen et al ., ; Sanabria‐Bohórquez and Van Laere, ), but in this case, it would be expected that the apparent rates of uptake would also be changed to the same extent, and the estimated binding potential refers to an equivalent equilibrium state. Internalization of the H 3 receptor may affect the apparent rate of dissociation of the drug, although no studies on GSK239512 and H 3 receptor internalization have been conducted.…”

Synthetic strategies for radioligands for in vivo imaging of brain cannabinoid type‐1 receptors

“…The radiosynthesis of [ 18 F]-36 and 37 started with alkylation of indole (31) with rac-2-chloromethyl-1-methylpiperidine (32) and in the presence of KOH to form the N-alkylated indole (33). 24 A Friedel-Crafts acetylation reaction was employed for conversion of 33 to the desired compound 35, using acid chloride (34) as an acylating agent.…”

“…[ 18 F]MK9470 has been used extensively both preclinically and clinically by the group of Van Laere for studying the role of the CB1 receptor in various pathologies. 27,[29][30][31][32][33][34] The 11 C analog of 45 was also synthesized (CB-119) from 44 with [ 11 C]CH 3 I and tested in rhesus monkey, but the half-life of carbon-11 was found too short in view of the relatively slow pharmacokinetics of the tracer. 35 Interesting to note here is the fact that MK-0364 (taranabant, Figure 2), a structural analog of MK-9470 that has been evaluated in clinical trials, was synthesized on a multikilogram scale using a modified route compared with the one shown in Scheme 7.…”