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[18F]1-(3-Fluoropropyl)-4-[(4-cyanophenoxy)methyl]piperidine
[18F]FPS

, PhD
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD

Created: ; Last Update: December 20, 2007.

Chemical name:[18F]1-(3-Fluoropropyl)-4-[(4-cyanophenoxy)methyl]piperidineimage 17422994 in the ncbi pubchem database
Abbreviated name:[18F]FPS
Synonym:
Backbone:Compound
Target:Sigma (σ) receptor
Mechanism:Receptor binding
Method of detection:Positron Emission Tomography (PET)
Source of signal:18F
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
  • Checkbox Non-primate non-rodent mammals

Click on the above structure for additional information in PubChem.

Background

[PubMed]

[18F]1-(3-Fluoropropyl)-4-[4-cyanophenoxy)methyl]piperidine ([18F]FPS) is a radioligand developed for positron emission tomography (PET) imaging of the sigma (σ) receptors (1-3). It is a potent σ1 receptor agonist labeled with 18F, a positron emitter with a physical half-life (t½) of 109.8 min.

σ receptors are functional, membrane-bound, G-protein−coupled receptors distributed in the central nervous system (CNS) and peripheral organs (4). The CNS σ receptors are unique binding sites related to higher brain functions (5). They are distinct from opiate and phencyclidine binding sites. There are at least two subtypes of σ receptors σ1 and σ2 receptors. The precise mechanism of the functional response of these receptors is not entirely known. These receptors appear to be involved in numerous pharmacological and physiological functions, and they also modulate a number of central neurotransmitter systems, including noradrenergic, glutamatergic, and dopaminergic systems. Phencyclidine and derivatives, cocaine and derivatives, some neuroleptics, atypical antipsychotic agents, and other chemically unrelated compounds can bind to the σ receptor sites. Studies have shown that these receptors may play a role in pathogenesis of psychiatric disorders (6, 7). These receptors are also expressed on a number of human and murine tumors (8).

The σ1 receptor subtypes have a molecular weight of ≈25 kDa, and through the process of cloning they have shown a 30% sequence homology with the yeast C89-C7 sterol isomerase (4, 9, 10). The σ2 receptor subtypes have a molecular weight of ≈21.5 kDa and have not been cloned. The σ1 receptors are thought to be involved in certain neuropsychiatric disorders, and both σ1 and σ2 receptors are also implicated in malignant neoplastic diseases. Because of these effects, σ receptor ligands may be useful for detection and treatment in neurology and oncology (11). A number of ligands for these receptors have been labeled with 11C and 18F for PET imaging to map their in vivo brain distribution and expression on tumors (12). Waterhouse et al. (13, 14) synthesized a number of selective σ1 receptor ligands for both PET and single-photon emission tomography. [18F]FPS was found to be a high-affinity σ1 receptor ligand with a dissociation constant (Kd) of 0.5 nM.

Synthesis

[PubMed]

Collier et al. (15) reported the synthesis of FPS and [18F]FPS. 4-(4-Cyanophenoxymethyl)piperidine was first prepared in five steps from ethyl isonepecotate. This compound was dissolved in ethanol-free dichloromethane and then alkylated with 3-bromo-1-fluoropropane in the presence of potassium carbonate at room temperature for 24 h to give FPS (84% yield). The mesylate precursor for radiosynthesis of [18F]FPS was similarly prepared from 4-(4-cyanophenoxymethyl)piperidine by alkylation with 3-bromo-1-propanol to produce1(3-hydroxypropyl)-4-(4-cyanophenoxymethyl)piperidine. This intermediate compound was then treated with methanesulfonyl chloride in the presence of triethylamine at room temperature for 30 min to produce the mesylate precursor (88% final yield). In the radiosynthesis of [18F]FPS, the precursor was heated in a solution of [18F]fluoride and Kryptofix−potassium carbonate mixture in acetonitrile. The mixture was heated at 85 ºC for 15 min. Aqueous 0.1 N sodium hydroxide was added and heated for an additional 10 min to destroy excess unreacted mesylate precursor before purification by high-performance liquid chromatography (HPLC). The average yield after purification was 62.3 ± 5.2% (n = 5) at the end of bombardment, and the radiochemical purities were >99%. The average time for the synthesis and HPLC purification was 80 min. The specific activity was >74,000 mBq/μmol (2 Ci/μmol).

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Collier et al. (15) reported that the lipophilicity of [18F]FPS was determined by the HPLC method (mobile phase of methanol and phosphate buffer in 85:15 v/v, pH = 7.5 and compared with standards of known log P values) as log P7.5 = 2.8. Competitive binding assays of FPS determined that the inhibition constants (Ki) were 4.3 nM and 144 nM for the σ1 and σ2 receptors, respectively. The σ12 ratio was calculated to be 0.03.

HPLC analysis of unlabeled FPS used for toxicity studies showed no significant degradation during storage at room temperature for 72 h (16).

Animal Studies

Rodents

[PubMed]

Waterhouse et al. (16) performed biodistribution and dosimetry studies of [18F]FPS and acute toxicity studies of FPS in rats. The biodistribution data (n = 3)showed that the radioactivity levels (percentage dose per injected dose per g, % ID/g) in the brain were 1.04 ± 0.36 (5 min), 0.93 ± 0.27 (15 min), 1.14 ± 0.23 (60 min), 1.01 ± 0.25 (240 min), and 0.71 ± 0.11 (840 min). At 60 min, the kidney and the adrenal gland had the highest radioactivity levels of 1.50 ± 0.51% ID/g and 1.03 ± 0.26% ID/g, respectively. The radioactivity levels in other major organs at 60 min were 0.52 ± 0.08 (heart), 0.36 ± 0.04 (liver), 0.90 ± 0.15 (spleen), 0.29 ± 0.09 (bone), and 0.02 ± 0.00 (blood). Human dosimetry estimation based on the rat distribution data indicated that the adrenal was the critical organ with 0.035 mGy/MBq (0.131 rad/mCi). The brain and the whole body had doses of 0.027 mGy/MBq (0.100 rad rad/mCi) and 0.013 mGy/MBq (0.047 rad/mCi), respectively. In the acute toxicity studies of FPS in rats, the no observable effect level (NOEL) was determined to be 6 mg/kg. With the exception of the transient convulsion immediately after administration of 8.8 mg/kg of FPS, no evidence of CNS or cardiovascular toxicity (0.088−8.8 mg/kg) was observed in rats.

Other Non-Primate Mammals

[PubMed]

Waterhouse et al. (2) conducted acute toxicity studies of FPS in rabbits and dogs. In the rabbit studies, the FPS doses ranged from 0.088-8.8 mg/kg and were given as a single i.v. injection. The NOEL was 0.044 mg/kg and the maximum tolerated dose was <4.4 mg/kg. No drug-related changes were observed in the rabbits’ eyes and no drug-related lesions were found during gross or microscopic examination. In the dog studies, single i.v. administrations of FPS (13.2 μg/kg–2640 μg/kg) were used. The NOEL dose was 0.013 mg/kg, and the maximum tolerated dose was <0.13 mg/kg. Clinical signs of toxicity were overt aggressiveness and EKG changes.

Non-Human Primates

[PubMed]

No publication is currently available.

Human Studies

[PubMed]

No publication is currently available.

NIH Support

NIH 1RO1 NS40402, NIMH 2003.

References

1.
Waterhouse R.N., Chang R.C., Zhao J., Carambot P.E. In vivo evaluation in rats of [(18)F]1-(2-fluoroethyl)-4-[(4-cyanophenoxy)methyl]piperidine as a potential radiotracer for PET assessment of CNS sigma-1 receptors. Nucl Med Biol. 2006;33(2):211–5. [PubMed: 16546675]
2.
Waterhouse R.N., Zhao J., Stabin M.G., Ng H., Schindler-Horvat J., Chang R.C., Mirsalis J.C. Preclinical acute toxicity studies and dosimetry estimates of the novel sigma-1 receptor radiotracer, [18F]SFE. Mol Imaging Biol. 2006;8(5):284–91. [PubMed: 16924428]
3.
Zhao J., Chang R., Carambot P., Waterhouse R.N. Radiosynthesis and in vivo study of [18F]1-(2-fluoroethyl)-4-[(cyanophenoxy)methyl]piperidine: a promising new sigma-1 receptor ligand. Journal of Labelled Compounds and Radiopharmaceuticals. 2005;48:547–555.
4.
Lever J.R., Gustafson J.L., Xu R., Allmon R.L., Lever S.Z. Sigma1 and sigma2 receptor binding affinity and selectivity of SA4503 and fluoroethyl SA4503. Synapse. 2006;59(6):350–8. [PubMed: 16463398]
5.
Skuza G., Wedzony K. Behavioral pharmacology of sigma-ligands. Pharmacopsychiatry. 2004;37 Suppl 3:S183–8. [PubMed: 15547784]
6.
Skuza G. Potential antidepressant activity of sigma ligands. Pol J Pharmacol. 2003;55(6):923–34. [PubMed: 14730086]
7.
Ishiguro H., Ohtsuki T., Toru M., Itokawa M., Aoki J., Shibuya H., Kurumaji A., Okubo Y., Iwawaki A., Ota K., Shimizu H., Hamaguchi H., Arinami T. Association between polymorphisms in the type 1 sigma receptor gene and schizophrenia. Neurosci Lett. 1998;257(1):45–8. [PubMed: 9857962]
8.
Vilner B.J., John C.S., Bowen W.D. Sigma-1 and sigma-2 receptors are expressed in a wide variety of human and rodent tumor cell lines. Cancer Res. 1995;55(2):408–13. [PubMed: 7812973]
9.
Mach R.H., Gage H.D., Buchheimer N., Huang Y., Kuhner R., Wu L., Morton T.E., Ehrenkaufer R.L. N-[18F]4'-fluorobenzylpiperidin-4yl-(2-fluorophenyl) acetamide ([18F]FBFPA): a potential fluorine-18 labeled PET radiotracer for imaging sigma-1 receptors in the CNS. Synapse. 2005;58(4):267–74. [PubMed: 16206186]
10.
Hanner M., Moebius F.F., Flandorfer A., Knaus H.G., Striessnig J., Kempner E., Glossmann H. Purification, molecular cloning, and expression of the mammalian sigma1-binding site. Proc Natl Acad Sci U S A. 1996;93(15):8072–7. [PMC free article: PMC38877] [PubMed: 8755605]
11.
Hashimoto K., Ishiwata K. Sigma receptor ligands: possible application as therapeutic drugs and as radiopharmaceuticals. Curr Pharm Des. 2006;12(30):3857–76. [PubMed: 17073684]
12.
Mahmood, A. and A.G. Jones, Technetium Radiopharmaceuticals, in Handbooks of Radiopharmaceuticals, M.J. Welch and C.S. Redvanley, Editors. 2003, John Wiley & Sons, Ltd.: West Sussex. p. 323-349.
13.
Waterhouse R.N., Collier T.L. In vivo evaluation of [18F]1-(3-fluoropropyl)-4-(4-cyanophenoxymethyl)piperidine: a selective sigma-1 receptor radioligand for PET. Nucl Med Biol. 1997;24(2):127–34. [PubMed: 9089705]
14.
Waterhouse R.N., Mardon K., Giles K.M., Collier T.L., O'Brien J.C. Halogenated 4-(phenoxymethyl)piperidines as potential radiolabeled probes for sigma-1 receptors: in vivo evaluation of [123I]-1-(iodopropen-2-yl)-4-[(4-cyanophenoxy)methyl]piperidine. J Med Chem. 1997;40(11):1657–67. [PubMed: 9171875]
15.
Collier T.L., O'Brien J.C., Waterhouse R.N. Synthesis of [18F]-1-(3-Fluoropropyl)-4-(4-cyanophenoxymethyl)-piperidine. Journal of Labelled Compounds and Radiopharmaceuticals. 1996;38(9):785–794.
16.
Waterhouse R.N., Stabin M.G., Page J.G. Preclinical acute toxicity studies and rodent-based dosimetry estimates of the novel sigma-1 receptor radiotracer [(18)F]FPS. Nucl Med Biol. 2003;30(5):555–63. [PubMed: 12831995]
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