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WAY-100635 Binds to 5-HT1A Receptors and Provides a Higher Radioactive Signal Than [Carbonyl-11C]WAY-100635 in the Human Brain

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WAY-100635 Binds to 5-HT1A Receptors and Provides a Higher Radioactive Signal Than [Carbonyl-11C]WAY-100635 in the Human Brain The PET Radioligand [carbonyl-11C]Desmethyl- WAY-100635 Binds to 5-HT1A Receptors and Provides a Higher Radioactive Signal Than [carbonyl-11C]WAY-100635 in the Human Brain Bengt Andre´e, MD, PhD1; Christer Halldin, PhD1; Victor W. Pike, PhD2; Roger N. Gunn, PhD2; Hans Olsson, MD1; and Lars Farde, MD, PhD1 1Psychiatry Section, Department of Clinical Neuroscience, Karolinska Hospital, Karolinska Institutet, Stockholm, Sweden; and 2MRC Cyclotron Unit, Hammersmith Hospital, Imperial College School of Medicine, London, United Kingdom nents. For 11C-WAY, small amounts of an additional labeled metabolite comigrated with reference desmethyl-WAY- 5-Hydroxytryptamine (serotonin)-1A (5-HT1A) receptors are of key interest in research on the pathophysiology and treat- 100635. Conclusion: The advantages of 11C-DWAY over 11C- ment of psychiatric disorders. The PET radioligand [carbonyl- WAY for research on central 5-HT1A receptors is supported by 11C]WAY-100635 (11C-WAY), where WAY-100635 is 3H-(N-(2- a significantly higher radioactivity signal at equipotent doses, (1-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridyl) providing improved imaging statistics and advantages in bio- cyclohexane-carboxamide, is commonly used for quantita- mathematic modeling and the preclusion of 11C-DWAY as a tion of 5-HT1A receptors in the human brain. The aim of this metabolite interfering with PET measurements. PET study was to compare 11C-WAY with the putative me- Key Words: brain; human; PET; 5-hydroxytryptamine-1A recep- tabolite and selective radioligand [carbonyl-11C]desmethyl- tors; WAY-100635; desmethyl-WAY-100635; kinetic modeling WAY-100635 (11C-DWAY). Methods: A PET examination was J Nucl Med 2002; 43:292–303 performed on each of 5 healthy male volunteers after intra- venous injection of 11C-WAY and 11C-DWAY on separate occasions. Radioactive metabolites in plasma were deter- mined with high-performance liquid chromatography. The plasma metabolite–corrected input function was used in a A technique currently applied to examine the pathophys- kinetic compartment analysis. The simplified reference tissue iology of neuropsychiatric disorders and to establish the model and peak equilibrium method, using the cerebellum as reference region, was applied for comparison of data. Re- pharmacology of central nervous system drugs is PET (1). sults: For both radioligands, the highest radioactivity was The progress of PET for brain imaging is related to the observed in the neocortex and the raphe nuclei, whereas development of suitable radioligands for the multitude of radioactivity was low in the cerebellum. The regional binding neuroreceptor subtypes that are expressed in the human potentials were similar for the 2 radioligands. The brain up- brain. take was more than 2-fold higher for 11C-DWAY than for Imaging of serotonin 5-hydroxytryptamine-1A receptors 11C-WAY, in part because of higher delivery (first-order rate (5-HT ) is of high interest in research on the pathophysi- constant K1, 0.38 vs. 0.16). The time–activity curves were well 1A described by a 3-compartment model for all regions, whereas ology and treatment of anxiety, depression, and schizophre- uptake in the cerebellum could not be described by a 2-com- nia (2–5). Presynaptic 5-HT1A receptors mediate inhibition partment model, supporting the existence of kinetically dis- of 5-hydroxytryptamine release (6) and are highly concen- tinguishable nonspecific binding in the cerebellum or radio- trated on cell bodies in the raphe nuclei, whereas postsyn- active metabolites in the brain for both radioligands. Both aptic receptors are abundant in the neocortex, as shown by radioligands were rapidly metabolized, and Ͻ10% of the radioactivity in plasma represented unchanged 11C-WAY or in vitro studies (7). 11C-DWAY at 10 min after injection. The metabolic pattern The 5-HT1A receptor has recently been characterized in was similar for both radioligands, with the formation of radio- the postmortem human brain using the receptor antagonist labeled cyclohexanecarboxylic acid and more polar compo- 3H-(N-(2-(1-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N- (2-pyridyl) cyclohexane-carboxamide (WAY-100635), which binds selectively and with high affinity (dissociation Received Feb. 5, 2001; revision accepted Dec. 3, 2001. For correspondence or reprints contact: Bengt Andre´ e, MD, PhD, Psychi- constant [Kd], approximately 0.4 nmol/L) to this receptor atry Section, Department of Clinical Neuroscience, Karolinska Hospital, Karo- subtype (8,9). Labeling of WAY-100635 in its carbonyl linska Institutet, S-17176 Stockholm, Sweden. E-mail: [email protected] group with 11C (half-life, 20.4 min) yields a radioligand 292 THE JOURNAL OF NUCLEAR MEDICINE • Vol. 43 • No. 3 • March 2002 (Fig. 1) that accurately delineates the distribution of 5-HT1A MATERIALS AND METHODS receptors in the human brain (10). Subjects [carbonyl-11C]WAY-100635 (11C-WAY) has been char- The study was approved by the ethics and the radiation safety acterized and used for quantitative studies of 5-HT1A recep- committees of the Karolinska Hospital. Six men (age range, 20–32 tors in the brains of humans and other primates (11–15). A y) participated in 2 PET measurements after giving informed common quantitative approach has been to use the cerebel- consent. One of the 6 men was excluded because of arterial lum as reference tissue for the free radioactivity concentra- blood-sampling failure. All men were healthy according to history, tion in brain because this region is almost devoid of 5-HT physical examination, psychiatric interview, blood and urine anal- 1A ysis, and MRI of the brain. All were nonsmokers and used no receptors. A consistent finding has been a significantly medication. better description of the cerebellar time–radioactivity curves by a 3-compartment model (3-CM) than by a 2-compart- MRI and Head Fixation System ment model (2-CM) (13–15). One hypothesis to explain the The MRI system was a 1.5-T Signa (General Electric Medical better fit of data using a 3-CM for the cerebellum is the Systems, Milwaukee, WI). T2-weighted and proton density MR existence of kinetically distinguishable nonspecific binding. images of the brain were obtained for all participants. A head fixation system with an individual plaster helmet was used for the An alternative explanation is that the observation may rep- PET and MRI examinations to allow mastery of positioning be- resent uptake of a radioactive metabolite (13,14). Interest- tween the 2 modalities and to ensure accuracy on repositioning ingly, WAY-100635 labeling in the carbonyl position (10) (5,20). The helmet was made so that the plane defined by the gives radioactive metabolites, such as 11C-cyclohexanecar- external anatomic landmarks of the meatus acusticus externus and boxylic acid and, to a low extent, [carbonyl-11C]desmethyl- the lateral angle of the orbita was oriented along the expected WAY-100635 (11C-DWAY) (Fig. 1), that may contribute to image plane. radioactivity in the cerebellum (11,16,17). Radiochemistry 11 The metabolite C-DWAY has high affinity to 5-HT1A 11C-WAY (Fig. 1) was synthesized as described previously (9). receptors (inhibitory concentration of 50% [IC50], 1.4 The specific radioactivity of 11C-WAY at the time of intravenous nmol/L) and has recently been suggested as a putative injection was between 47,138 and 75,332 GBq/mmol. The radio- radioligand for PET (11,18,19). One reason is that 11C- activity injected ranged from 257 to 300 MBq, and the injected DWAY has the possible advantage of not forming any mass ranged from 1.7 to 2.6 ␮g. further labeled metabolite that passes the blood–brain bar- 11C-DWAY (Fig. 1) was prepared by 11C-acylation of the ap- rier other than 11C-cyclohexanecarboxylic acid. The binding propriate secondary amine precursor, as described previously (18). 11C-DWAY was isolated by HPLC on a ␮Bondapak C-18 column of 11C-DWAY to central 5-HT receptors has been char- 1A (Waters, Milford, MA) eluted with methanol and 0.1 mol/L am- acterized by autoradiography and in preliminary PET stud- monium formate. All chemicals were of analytic grade. The ra- ies in monkeys and humans (11,18,19). diochemical purity, chemical purity, and specific radioactivity of The current PET study evaluated the prospects for using each batch were determined by HPLC. The radiochemical purity of 11C-DWAY as an alternative to 11C-WAY for quantification the final products was Ͼ99%. The specific radioactivity of 11C- of central 5-HT1A receptors in the human brain. Two- and DWAY at the time of intravenous injection ranged from 25,942 to 3-compartment analyses and 2 reference tissue approaches 41,736 GBq/mmol, and the radioactivity injected was between 157 were applied in 5 healthy male volunteers to calculate rate and 306 MBq, corresponding to an injected mass of 3.1–4.6 ␮g. constants and estimate regional radioligand binding in the Arterial Blood Sampling brain. Radioactive metabolites in plasma were examined To obtain the arterial input function, an automated blood sam- with high-performance liquid chromatography (HPLC). pling system was used during the first 5 min of each PET mea- FIGURE 1. Chemical structure of [car- bonyl-11C]WAY-100635 (11C-WAY) and 2 metabolites, [carbonyl-11C]desmethyl-WAY- 100635 (11C-DWAY) and [carbonyl-11C]cy- clohexanecarboxylic acid. 11C-WAY AND 11C-DWAY PET IN HUMAN BRAIN • Andre´eetal. 293 surement (21). Subsequent arterial blood samples were taken man- cingulate cortex, the frontal and lateral temporal cortices, the ually at the midpoint of each frame until the end of the PET insular cortex and the medial temporal cortices, the hippocampus, measurement (22). The experimentally defined difference between the raphe, and the cerebellar cortex. ROIs were delineated on MR the appearance of radioactivity in the automated blood sampling images according to anatomic boundaries and were transferred to system and brain was approximately 10 s.
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