Background

[PubMed]

Dopamine, a neurotransmitter, plays an important role in the mediation of movement, cognition, and emotion (1, 2). Dopamine shortage plays a role in various neuropsychiatric disorders, such as Parkinson’s disease (PD), schizophrenia, autism, attention deficit hyperactivity disorder, and drug abuse. Two subtypes of dopamine receptors, D₁ and D₂, were well-characterized pharmacologically and biochemically (3). D₂ dopamine receptors have been implicated in the pathophysiology of PD, Alzheimer's disease, and schizophrenia (4).

Serotonin (5-hydroxytryptamine, 5-HT) has diverse physiological roles as a neurotransmitter in the central nervous system (5). It also is a regulator of smooth muscle function and platelet aggregation. The brain cortical 5-HT system has been implicated in several neuropsychiatric disorders, including major depression, anxiety, obsessive-compulsive disorder, and schizophrenia (6, 7).

Spiperone and its analog, 3-N-(2-fluoroethyl)spiperone (FESP) are high-affinity D₂ dopamine and 5-HT₂ serotonin receptor antagonists, showing a low affinity for α1-adrenergic receptors and marginal binding to other receptors (8). 3-N-(2-[¹⁸F]Fluoroethyl)spiperone ([¹⁸F]FESP) has been studied as a positron emission tomography (PET) tracer for imaging D₂ and 5HT₂ receptor densities. It has also used as a reporter probe for dopamine D₂ receptor in imaging transgene expression in rodents (9-11).

Synthesis

[PubMed]

[¹⁸F]FESP can be synthesized by either N-alkylation or nucleophilic substitution (12-15). Alkylation of the amide nitrogen in spiperone by [¹⁸F]fluorobromoethane in the presence of NaOH provided [¹⁸F]FESP in 35-40% radiochemical yield (5-8% overall radiochemical yield). [¹⁸F]Fluorobromoethane was easily prepared by the reaction of 1,2-bromoethane with potassium [¹⁸F]fluoride Kryptofix complex in 15-20% radiochemical yield. The radiochemical purity of [¹⁸F]FESP was found to be >99% by high-performance liquid chromatography (HPLC). The specific activity was 185-370 GBq/μmol (5-10 Ci/μmol) at the end of synthesis with a total synthesis time of 70 min.

A one-step, one-pot synthesis of [¹⁸F]FESP using nucleophilic fluorination of 3-(2'-bromoethyl)spiperone or 3-(2'-methylsulfonyloxyethyl)spiperone with K[¹⁸F]F/Kryptofix2.2.2 in acetonitrite in <60 min was performed (12). This method provided a 99% chemical purity and a specific activity of 74-370 GBq/μmol (2-10 Ci/μmol) at the end of synthesis (EOS). The radiochemical yield was 30-40% (EOS).

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

FESP was reported to have selective binding affinity to D₂ (striatum) and 5-HT₂ (frontal cortex) receptor sites in homogenates of rat brain membranes (8). The K_i values for D₂ and 5-HT₂ were 0.44 nm and 0.57 nm, respectively. It has a K_i value of 23 nm for the α1-adrenergic receptor in rat forebrain membrane and negligible binding to other sites.

Animal Studies

Human Studies

[[PubMed]

Human dosimetry was estimated based on human dynamic PET scans after injection of 37 MBq (1 mCi) [¹⁸F]FESP (23). The gallbladder received the highest dose (0.207 mGy/MBq or 797 mrad/mCi). Other organs that received high doses were the urinary bladder (0.083 mGy/MBq or 308 mrad/mCi) and liver (0.065 mGy/MBq or 110 mrad/mCi). The total body dose was 0.0119 mGy/MBq (44 mrad/mCi).

[¹⁸F]FESP PET studies of D₂ receptor distribution in human brain were reported, showing a localization of radioactivity in the striatum (16, 24, 25). Only about 1% of [¹⁸F]PESP entered the brain. [¹⁸F]FESP was metabolized peripherally with 54% intact [¹⁸F]FESP in arterial plasma at 2 h after injection (16). Striatal-to-cerebellum ratio and kinetic constants are commonly used as analytical parameters in [¹⁸F]FESP PET studies. Wienhard et al. (25) reported on [¹⁸F]FESP PET studies in 30 patients with various disorders related to the dopaminergic system and in 6 normal subjects. PET brain scans of normal subjects showed that the highest uptake was in the caudate and pituitary, followed by the cortex and cerebellum at 3 h after injection of 185 MBq (5 mCi) [¹⁸F]FESP. PET scans of patients showed decreases in the number of available D₂ receptors in the striatum and striatum-to-cerebellum ratio. Patients with brain damage also showed both low [¹⁸F]FDG and [¹⁸F]FESP uptake in the striatum.

5-HT₂ receptor distribution in human brain were studied by [¹⁸F]FESP PET in 20 healthy volunteers and 34 patients with unipolar depression (26) There was a significant reduction of binding capacity in 19 non-drug-treated patients as compared with healthy controls in the cortical regions but not in the striatum. In paroxetine-treated patients (n = 15), there was no significant difference between the drug-treated patients and healthy volunteers. Paroxetine is a specific serotonin reuptake inhibitor. Paroxetine treatment led to remission in these patients. Chronic treatment with fluvoxamine (27), another specific serotonin reuptake inhibitor, significantly increased the in vivo binding of [¹⁸F]FESP in the frontal and occipital cortex but not in the striatum of drug-naïve, unipolar, depressed patients (n = 9).

[¹⁸F]FESP PET is useful for objective monitoring of D₂ and 5-HT₂ receptor sites in patients with serotonergic and dopaminergic disorders. It revealed stage-related changes in depression and dopaminergic disorders. [¹⁸F]FESP has also demonstrated its usefulness as a PET tracer in the imaging of non-functioning pituitary adenomas from meningiomas and craniopharyngiomas (28).

References

1.

Carbon M., Ghilardi M.F., Feigin A., Fukuda M., Silvestri G., Mentis M.J., Ghez C., Moeller J.R., Eidelberg D. Learning networks in health and Parkinson's disease: reproducibility and treatment effects. Hum Brain Mapp. 2003;19(3):197–211. [PMC free article: PMC6871830] [PubMed: 12811735]

2.

Chesselet M.F., Delfs J.M. Basal ganglia and movement disorders: an update. Trends Neurosci. 1996;19(10):417–22. [PubMed: 8888518]

3.

Stoof J.C., Kebabian J.W. Two dopamine receptors: biochemistry, physiology and pharmacology. Life Sci. 1984;35(23):2281–96. [PubMed: 6390056]

4.

Seeman P., Bzowej N.H., Guan H.C., Bergeron C., Reynolds G.P., Bird E.D., Riederer P., Jellinger K., Tourtellotte W.W. Human brain D1 and D2 dopamine receptors in schizophrenia, Alzheimer's, Parkinson's, and Huntington's diseases. Neuropsychopharmacology. 1987;1(1):5–15. [PubMed: 2908095]

5.

Lucki I. The spectrum of behaviors influenced by serotonin. Biol Psychiatry. 1998;44(3):151–62. [PubMed: 9693387]

6.

Abi-Dargham A., Laruelle M., Aghajanian G.K., Charney D., Krystal J. The role of serotonin in the pathophysiology and treatment of schizophrenia. J Neuropsychiatry Clin Neurosci. 1997;9(1):1–17. [PubMed: 9017523]

7.

Charney D.S. Monoamine dysfunction and the pathophysiology and treatment of depression. J Clin Psychiatry. 1998;59 Suppl 14:11–4. [PubMed: 9818625]

8.

Goffinet A.M., Leysen J., Labar D. In vitro pharmacological profile of 3-N-(2-fluoroethyl)spiperone. J Cereb Blood Flow Metab. 1990;10(1):140–2. [PubMed: 2137131]

9.

MacLaren D.C., Gambhir S.S., Satyamurthy N., Barrio J.R., Sharfstein S., Toyokuni T., Wu L., Berk A.J., Cherry S.R., Phelps M.E., Herschman H.R. Repetitive, non-invasive imaging of the dopamine D2 receptor as a reporter gene in living animals. Gene Ther. 1999;6(5):785–91. [PubMed: 10505102]

10.

Yaghoubi S.S., Wu L., Liang Q., Toyokuni T., Barrio J.R., Namavari M., Satyamurthy N., Phelps M.E., Herschman H.R., Gambhir S.S. Direct correlation between positron emission tomographic images of two reporter genes delivered by two distinct adenoviral vectors. Gene Ther. 2001;8(14):1072–80. [PubMed: 11526454]

11.

Chen I.Y., Wu J.C., Min J.J., Sundaresan G., Lewis X., Liang Q., Herschman H.R., Gambhir S.S. Micro-positron emission tomography imaging of cardiac gene expression in rats using bicistronic adenoviral vector-mediated gene delivery. Circulation. 2004;109(11):1415–20. [PMC free article: PMC4154818] [PubMed: 15007006]

12.

Satyamurthy N., Bida G.T., Barrio J.R., Luxen A., Mazziotta J.C., Huang S.C., Phelps M.E. No-carrier-added 3-(2'-[18F]fluoroethyl)spiperone, a new dopamine receptor-binding tracer for positron emission tomography. Int J Rad Appl Instrum B. 1986;13(6):617–24. [PubMed: 3494003]

13.

Satyamurthy N., Barrio J.R., Bida G.T., Huang S.C., Mazziotta J.C., Phelps M.E. 3-(2'-[18F]fluoroethyl)spiperone, a potent dopamine antagonist: synthesis, structural analysis and in-vivo utilization in humans. Int J Rad Appl Instrum [A] 1990;41(2):113–29. [PubMed: 2158942]

14.

Chi D.Y., Kilbourn M.R., Katzenellenbogen J.A., Brodack J.W., Welch M.J. Synthesis of no-carrier-added N-([18F]fluoroalkyl)spiperone derivatives. Int J Rad Appl Instrum [A] 1986;37(12):1173–80. [PubMed: 3028983]

15.

Kiesewetter D.O., Eckelman W.C., Cohen R.M., Finn R.D., Larson S.M. Syntheses and D2 receptor affinities of derivatives of spiperone containing aliphatic halogens. Int J Rad Appl Instrum [A] 1986;37(12):1181–8. [PubMed: 3028984]

16.

Barrio J.R., Satyamurthy N., Huang S.C., Keen R.E., Nissenson C.H., Hoffman J.M., Ackermann R.F., Bahn M.M., Mazziotta J.C., Phelps M.E. 3-(2'-[18F]fluoroethyl)spiperone: in vivo biochemical and kinetic characterization in rodents, nonhuman primates, and humans. J Cereb Blood Flow Metab. 1989;9(6):830–9. [PubMed: 2531146]

17.

Coenen H.H., Laufer P., Stocklin G., Wienhard K., Pawlik G., Bocher-Schwarz H.G., Heiss W.D. 3-N-(2-[18F]-fluoroethyl)-spiperone: a novel ligand for cerebral dopamine receptor studies with pet. Life Sci. 1987;40(1):81–8. [PubMed: 2948091]

18.

Coenen H.H., Wienhard K., Stocklin G., Laufer P., Hebold I., Pawlik G., Heiss W.D. PET measurement of D2 and S2 receptor binding of 3-N-[(2'-18F]fluoroethyl)spiperone in baboon brain. Eur J Nucl Med. 1988;14(2):80–7. [PubMed: 2968911]

19.

Huang S.C., Bahn M.M., Barrio J.R., Hoffman J.M., Satyamurthy N., Hawkins R.A., Mazziotta J.C., Phelps M.E. A double-injection technique for in vivo measurement of dopamine D2-receptor density in monkeys with 3-(2'-[18F]fluoroethyl)spiperone and dynamic positron emission tomography. J Cereb Blood Flow Metab. 1989;9(6):850–8. [PubMed: 2531148]

20.

Jovkar S., Wienhard K., Coenen H.H., Pawlik G., Heiss W.D. Quantification of baboon cortical S2 serotonin receptors in vivo with 3-N-(2'-F18)fluoroethylspiperone and positron emission tomography. Eur J Nucl Med. 1991;18(3):158–63. [PubMed: 2040338]

21.

Jovkar S., Wienhard K., Pawlik G., Coenen H.H. The quantitative analysis of D2-dopamine receptors in baboon striatum in vivo with 3-N-[2'-18F]fluoroethylspiperone using positron emission tomography. J Cereb Blood Flow Metab. 1990;10(5):720–6. [PubMed: 2384543]

22.

Schetz J.A., Kim O.J., Sibley D.R. Pharmacological characterization of mammalian D1 and D2 dopamine receptors expressed in Drosophila Schneider-2 cells. J Recept Signal Transduct Res. 2003;23(1):99–109. [PMC free article: PMC3108030] [PubMed: 12680592]

23.

Herzog H., Coenen H.H., Kuwert T., Langen K.J., Feinendegen L.E. Quantification of the whole-body distribution of PET radiopharmaceuticals, applied to 3-N-([18F]fluoroethyl)spiperone. Eur J Nucl Med. 1990;16(2):77–83. [PubMed: 2311622]

24.

Bahn M.M., Huang S.C., Hawkins R.A., Satyamurthy N., Hoffman J.M., Barrio J.R., Mazziotta J.C., Phelps M.E. Models for in vivo kinetic interactions of dopamine D2-neuroreceptors and 3-(2'-[18F]fluoroethyl)spiperone examined with positron emission tomography. J Cereb Blood Flow Metab. 1989;9(6):840–9. [PubMed: 2531147]

25.

Wienhard K., Coenen H.H., Pawlik G., Rudolf J., Laufer P., Jovkar S., Stocklin G., Heiss W.D. PET studies of dopamine receptor distribution using [18F]fluoroethylspiperone: findings in disorders related to the dopaminergic system. J Neural Transm Gen Sect. 1990;81(3):195–213. [PubMed: 2144427]

26.

Messa C., Colombo C., Moresco R.M., Gobbo C., Galli L., Lucignani G., Gilardi M.C., Rizzo G., Smeraldi E., Zanardi R., Artigas F., Fazio F. 5-HT(2A) receptor binding is reduced in drug-naive and unchanged in SSRI-responder depressed patients compared to healthy controls: a PET study. Psychopharmacology (Berl). 2003;167(1):72–8. [PubMed: 12632246]

27.

Moresco R.M., Colombo C., Fazio F., Bonfanti A., Lucignani G., Messa C., Gobbo C., Galli L., Del Sole A., Lucca A., Smeraldi E. Effects of fluvoxamine treatment on the in vivo binding of [F-18]FESP in drug naive depressed patients: a PET study. Neuroimage. 2000;12(4):452–65. [PubMed: 10988039]

28.

Lucignani G., Losa M., Moresco R.M., Del Sole A., Matarrese M., Bettinardi V., Mortini P., Giovanelli M., Fazio F. Differentiation of clinically non-functioning pituitary adenomas from meningiomas and craniopharyngiomas by positron emission tomography with [18F]fluoro-ethyl-spiperone. Eur J Nucl Med. 1997;24(9):1149–55. [PubMed: 9283109]