N,N-Dimethyl-2-(2-Amino-4-18F-Fluorophenylthio)-Benzylamine (4-18F-ADAM): An Improved PET Radioligand for Serotonin Transporters

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FIGURE 1.
Chemical structures of (+)McN5652, 403U76, IDAM, ADAM, DASB, AFM, DAPA, MADAM, and 4-F-ADAM.
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FIGURE 2.
PET images of 4-¹⁸F-ADAM in baboon brain and MR images of baboon brain at same level as PET images. PET scan displays specific binding of 4-¹⁸F-ADAM to SERT in midbrain region at 90–120 min after radioligand injection. MRI scan reveals anatomic information about midbrain region.
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FIGURE 3.
Time–activity curve of 4-¹⁸F-ADAM in baboon brain. Curve shows that uptake of 4-¹⁸F-ADAM in midbrain region peaks at ∼30–40 min after injection and that defluorination of 4-¹⁸F-ADAM may not occur in baboon.
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FIGURE 4.
Ratio of different brain regions to cerebellum increases with time in baboon brain after injection of 4-¹⁸F-ADAM.

TABLE 1

Selectivity of Ligands for Monoamine Transporters (K_i, nmol/L)

Ligand	SERT	DAT	NET
4-F-ADAM	0.081 ± 0.006*	2,267 ± 188*	117 ± 23*
	(4.8 ± 1.3)^†	(5,358 ± 1,959)^†	(137.2 ± 23.2)^†
(+)McN5652	0.009 ± 0.002*	112 ± 23*	11.3 ± 3.3*
AFM	1.8 ± 0.3^†	2,055 ± 917^†	95.5 ± 33.8^†
ADAM	0.013 ± 0.003*	840 ± 100*	699 ± 80*
DASB	1.10 ± 0.04^‡	1,423 ± 103^‡	1,350 ± 221^‡

TABLE 2

Biodistribution of 4-¹⁸F-ADAM in Rats

Organ	2 min	30 min	60 min	120 min	240 min
Blood	9.52 ± 1.12	3.11 ± 0.12	2.09 ± 0.21	1.05 ± 0.13	0.52 ± 0.07
Heart	1.24 ± 0.05	0.15 ± 0.02	0.08 ± 0.01	0.03 ± 0.01	0.02 ± 0.01
Muscle	14.00 ± 3.69	13.32 ± 1.26	11.29 ± 6.47	3.21 ± 0.46	1.14 ± 0.07
Lung	12.08 ± 1.13	1.35 ± 0.09	0.50 ± 0.05	0.17 ± 0.02	0.07 ± 0.01
Kidney	6.48 ± 0.47	2.77 ± 0.79	1.69 ± 0.15	1.02 ± 0.09	0.48 ± 0.10
Spleen	0.59 ± 0.02	0.38 ± 0.08	0.15 ± 0.01	0.04 ± 0.00	0.02 ± 0.00
Liver	10.86 ± 0.72	7.64 ± 0.65	5.14 ± 0.49	2.71 ± 0.23	1.75 ± 0.17
Skin	4.50 ± 0.14	10.42 ± 5.01	5.19 ± 1.30	2.35 ± 0.19	1.06 ± 0.23
Brain	2.13 ± 0.33	1.90 ± 0.16	0.95 ± 0.13	0.41 ± 0.06	0.08 ± 0.00
Bone	6.48 ± 0.37	13.42 ± 1.68	21.38 ± 0.70	24.78 ± 3.44	24.94 ± 8.88

TABLE 3

Regional Brain Distribution of 4-¹⁸F-ADAM in Rats

Region	2 min	30 min	60 min	120 min	240 min
Cerebellum	0.68 ± 0.11	0.37 ± 0.02	0.13 ± 0.02	0.04 ± 0.00	0.01 ± 0.00
Striatum	0.96 ± 0.22	1.41 ± 0.61	0.60 ± 0.10	0.27 ± 0.04	0.06 ± 0.01
Hippocampus	0.96 ± 0.13	1.03 ± 0.11	0.56 ± 0.08	0.22 ± 0.01	0.03 ± 0.01
Cortex	1.67 ± 0.49	0.87 ± 0.09	0.37 ± 0.08	0.11 ± 0.01	0.02 ± 0.00
Hypothalamus	1.11 ± 0.17	1.34 ± 0.06	0.73 ± 0.13	0.45 ± 0.06	0.08 ± 0.01

TABLE 4

Ratios of Tissue-to-Cerebellum vs. Time After 4-¹⁸F-ADAM Injection in Rats

Region	2 min	30 min	60 min	120 min	240 min
Cerebellum	1.00 ± 0.00	1.00 ± 0.00	1.00 ± 0.00	1.00 ± 0.00	1.00 ± 0.00
Striatum	1.42 ± 0.26	3.74 ± 1.42	4.59 ± 0.12	7.49 ± 0.20	7.03 ± 1.70
Hippocampus	1.41 ± 0.09	2.76 ± 0.28	4.26 ± 0.23	5.97 ± 0.36	3.90 ± 0.57
Cortex	2.48 ± 0.75	2.32 ± 0.17	2.83 ± 0.15	2.95 ± 0.36	2.17 ± 0.59
Hypothalamus	1.63 ± 0.10	3.60 ± 0.33	5.57 ± 0.23	12.49 ± 0.15	9.61 ± 1.64

TABLE 5

Effects of Pretreatment with Monoamine Transporter Inhibitor on Specific Binding of 4-¹⁸F-ADAM in Rats

Region	Control (saline)	(+)McN5652	Methylphenidate	Nisoxetine
Cerebellum	0.04 ± 0.00	0.03 ± 0.01	0.04 ± 0.00	0.04 ± 0.00
Striatum	0.26 ± 0.04	0.04 ± 0.01	0.23 ± 0.02	0.21 ± 0.01
Hippocampus	0.20 ± 0.02	0.05 ± 0.01	0.19 ± 0.02	0.18 ± 0.02
Cortex	0.11 ± 0.00	0.03 ± 0.00	0.13 ± 0.04	0.10 ± 0.02
Hypothalamus	0.43 ± 0.10	0.04 ± 0.01	0.31 ± 0.02	0.28 ± 0.02
Blood	0.05 ± 0.01	0.04 ± 0.00	0.05 ± 0.00	0.05 ± 0.00

(+)McN5652 = serotonin transporter inhibitor; methylphenidate = dopamine transporter inhibitor; nisoxetine = norepinephrine transporter inhibitor.
Data are % dose per gram; average of 3 rats ± SD. Rats were pretreated with drugs (2 mg/kg, 250 μL, intravenously) 5 min before tracer administration (intravenous) and sacrificed 2 h after tracer injection.

TABLE 6

Tissue-to-Cerebellum Ratios After Pretreating Rats with Monoamine Transporter Inhibitors

Region	Control (saline)	(+)McN5652	Methylphenidate	Nisoxetine
Cerebellum	1.00 ± 0.00	1.00 ± 0.00	1.00 ± 0.00	1.00 ± 0.00
Striatum	6.48 ± 1.10	1.42 ± 0.03	5.12 ± 0.31	5.11 ± 0.56
Hippocampus	4.94 ± 0.34	1.77 ± 0.13	4.30 ± 0.15	4.36 ± 0.40
Cortex	2.86 ± 0.24	1.19 ± 0.10	2.82 ± 0.58	2.37 ± 0.45
Hypothalamus	10.66 ± 2.45	1.52 ± 0.39	6.94 ± 0.71	6.93 ± 0.53

(+)McN5652 = serotonin transporter inhibitor; methylphenidate = dopamine transporter inhibitor; nisoxetine = norepinephrine transporter inhibitor.
Data are % dose per gram; average of 3 rats ± SD. Rats were pretreated with drugs (2 mg/kg, 250 μL, intravenously) 5 min before tracer administration (intravenous) and sacrificed 2 h after tracer injection.