Table II.

Development of PET and SPECT Radioligands for the 5-HT System Designed for Use in Human Subjects

Target	Type	Radioligand	Rodent	Nonhuman primate	Human	Ongoing studies	Reason for failure	Known problems
5-HT1A	SPECT	[123I]p-MPPI	✔	✔	×	–	No specific 5-HT1A binding Rapid metabolism Possible brain exclusion via efflux transporter	–
	PET	[11C]WAY-100635	✔	✔	✔	✔	–	Fast systemic metabolism; difficult kinetic modelling with arterial input function, reference tissue models complicated by radiometabolites in plasma
		[11C]CPC-222	✔	ND	✔	ND		Lower signal-to-background ratio than [11C]WAY-100635
		[11C](R)-RWAY	×	✔	×	–	Possible influx of lipophilic radiometabolite	P-gp substrate in rodent
		[11C]DWAY	✔	✔	✔	ND		Unreliable radiolabelling technique; low radioactive yield
		[18F]6FPWAY	ND	✔	×	–	Moderate uptake	–
		[18F]MPPF	✔	✔	✔	✔	–	P-gp substrate; fast brain clearance and low uptake
		[18F]FCWAY	✔	✔	✔	✔	–	Defluorination of parent compound; sub-optimal imaging
		[18F]MefWAY	ND	✔	ND	–
		[11C]NAD-299	ND	✔	ND	–
		[11C]CUMI-101	✔	✔	✔		–	Partial, not full agonist
5-HT1B	PET	[11C]AZ10419369	ND	✔	✔		–
		[11C]P943	ND	✔	✔	✔	–
5-HT2A	SPECT	[123I]DOI	×	×	–	–	Low target-to-background ratio	Non-selective (5-HT2C)
		[123I]MSP	✔	ND	ND	ND
		[123I]-R91150	✔	✔	✔	✔	–	Lower target-to-background ratio than equivalent PET tracers
		[123I]-3-I-CO	×	ND	–	–	–	Low target-to-background ratio, possible P-gp substrate
	PET	[11C]Ketanserin	ND	ND	×	–	Low target-to-background ratio, fast metabolism	Non-selective (α1, H1, 5-HT2C)
		[11C]NMSP	ND	ND	✔	–	–	Non-selective (D2)
		[11C]MBL	ND	✔	✔	–		Non-selective (some D2, α1, 5-HT1 and 5-HT2C)
		[18F]setoperone	✔	✔	✔	✔	–	Non-selective (D2)
		[18F]altanserin	✔	✔	✔	✔	–	Need for bolus-infusion due to radiometabolites requiring complex modelling using other methods. Possible mixed pharmacology
		[18F]deuteroaltanserin	ND	✔	✔	✔	–
		[18F]RP62203	✔	ND	–	–		Multi-step radiosynthesis
		[11C]MDL100907	✔	✔	✔	✔	–	Arterial input function needed
		[18F]MH.MZ	×	ND	ND	–	Extensive first-pass metabolism, slow washout	-
		(R)-[18F]MH.MZ	✔	ND	ND
		[11C]Cimbi-5 and 36	✔	✔ (pig)	ND	ND
5-HT3	PET	[11C]MDL 72222	×	×	–	–	Lack of specific binding, high lipophilicity	Low 5-HT3 brain density
		[11C]YM060, [11C]Y-25130	×	–	–	–	Low brain uptake, low lipophilicity, ionisation of tertiary amide
		[11C]KF17643	×	–	–	–	No specific binding
		[11C]S21007	×	×	–	–	No specific binding
		[18F]MR18445	×	×	–	–	No specific binding
		[11C]NMQ	×	×	–	–	Rapid kinetics, high non-specific binding
5-HT4	SPECT	[123I]SB207710	×	✔	ND	–	–
	PET	[11C]SB207145	✔	✔ (pig)	✔	✔	–	Slow kinetics
5-HT6	PET	[18F]12ST05	×	–	–	–	No specific binding	–
		[11C]GSK215083	ND	✔ (pig)	✔
		[11C]GSK224558	ND	(pig only)	ND	–		Inferior ligand compared with [11C]GSK215083
5-HT7	PET	[11C]DR4446	ND	×	–	–	Minimal specific binding	–
SERT	SPECT	β-[123I]CIT, nor-β-[123I]CIT	✔	✔	✔	✔	–	Non-selective (DAT, NET)
		[123I]ADAM	✔	✔	✔	✔	–	Lower resolution than equivalent PET tracers. Ratio method of quantification over-estimates specific binding
	PET	[11C]McN5652	✔	✔	✔	✔	–	Slow brain uptake, irreversible kinetics complicate quantification
		[11C]DASB	✔	✔	✔	✔	–
		[11C]MADAM	ND	✔	✔	✔	–
		[18F]ADAM	✔	✔	ND	–	–
5-HT synthesis		[11C]-AMT	✔	✔	✔	✔	–	Low target-to-background ratio, analysis complicated by possible blood-brain barrier exchange and additional metabolic pathways
		[11C]-HTP	✔	✔	✔	✔	–	Lack of correlation with [11C]-AMT in direct comparison suggests further validation is necessary

✔ indicates that ex vivo, PET, or SPECT studies were performed and the ligand was considered successful in the species identified. In certain instances, radioligands were tested in pig brain either in addition to, or instead of nonhuman primate. × indicates that ex vivo, PET, or SPECT studies were performed but the ligand was not considered successful in the species indicated. “Ongoing studies” indicate that the ligand is still being used for research or clinical purposes in humans. ND indicates not yet determined, i.e. experiments have not been published in the species indicated. Missing data are either not applicable (−) or not available/not known (blank cells).