TABLE 1.

Physicochemical Properties, Pharmacologic Properties, and PET Imaging Parameters in Monkeys of 5 Selected PDE4D Radioligands and Previously Reported (24) PDE4D Ligand [¹¹C]T1650

Radioligand	CNS PET MPO	EC₅₀ (nM)		Selectivity (B/D)	cLogD_7.4	mLogD_7.4	f_p (%)	V_ND	BP_ND
Radioligand	CNS PET MPO	PDE4D	PDE4B	Selectivity (B/D)	cLogD_7.4	mLogD_7.4	f_p (%)	V_ND	BP_ND
[¹¹C]T1650	3.9	3.5	1120	320	3.48	2.89	6.7 ± 0.7	3.58	1.2
[¹¹C]JMJ-81	4.2	2.7 ± 0.5	521 ± 46	193	2.90	3.15	5.7 ± 0.8	3.3, 3.4	1.2, 0.61
[¹¹C]JMJ-129	4.3	1.4 ± 0.01	1070 ± 14	793	2.90	3.28	5.8 ± 0.7	3.5, 4.3	2.4, 1.0
[¹¹C]JMJ-168	4.1	2.1	513	242	3.17	2.73	6.8 ± 0.5	4.0, 5.3	0.69, 0.27
[¹¹C]JMJ-169	4.1	1.1	593	559	3.17	2.82	8.4 ± 0.8	5.2, 3.9	0.57, 2.2
[¹¹C]JMJ-182	3.4	2.0	1340	670	3.28	3.33	2.9 ± 0.2	4.3, 3.7	0.59, 0.44

CNS PET MPO = multiparameter optimization value for central nervous system PET radioligand (estimated as in (26)); EC₅₀ = half-maximal effective concentration; B/D = ratio of EC₅₀ for PDE4B over that for PDE4D; cLogD_7.4 = computed lipophilicity for n-octanol/buffer solution distribution coefficient at pH 7.4; mLogD_7.4 = experimentally measured lipophilicity; f_p = plasma free fraction; PDE4B = PDE4B1–S133D, dimeric isoform of PDE4B that contains UCR1 mutation (S133D) that mimics protein kinase A phosphorylation.
Data for multiparameter optimization for central nervous system PET radioligand scoring (i.e., PDE4D EC₅₀, PDE4B EC₅₀, B/D, and clogD_7.4) are sourced from our previous reports (24,25). Binding assays were repeated (n = 2) for JMJ-81 and JMJ-129. cLogD_7.4 values were calculated with Pallas software; mlogD_7.4 values were measured with radioligands (n = 6). Plasma free fraction was measured and averaged with monkey plasma (n = 4 or greater). V_ND and BP_ND were measured in 2 monkeys except in one monkey for [¹¹C]T1650, in which rolipram was used as blocking agent at 0.5 mg/kg for first monkey studied with [¹¹C]JMJ-81 and at 0.2 mg/kg for all other experiments.