NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.

Cover of Molecular Imaging and Contrast Agent Database (MICAD)

Molecular Imaging and Contrast Agent Database (MICAD) [Internet].

Show details

3-(4-[18F]Fluorobenzyl)-8-methoxy-1,2,3,4 tetrahydrochromeno[3,4-c]pyridin-5-one

, PhD
Corresponding author.

Created: ; Last Update: February 7, 2012.

Chemical name:3-(4-[18F]Fluorobenzyl)-8-methoxy-1,2,3,4-tetrahydrochromeno[3,4-c]pyridin-5-oneimage 7854918 in the ncbi pubchem database
Abbreviated name:[18F]FMTP
Agent category:Compound
Target:Dopamine D4 receptor
Target category:Receptor
Method of detection:Positron emission tomography (PET)
Source of signal:18F
  • Checkbox In vitro
  • Checkbox Rodents
Click on the above structure for additional information in PubChem.



Dopamine, a neurotransmitter, plays an important role in the mediation of movement, cognition, and emotion (1, 2). Dopamine receptors are involved in the pathophysiology of neuropsychiatric diseases, such as Parkinson’s disease, Alzheimer's disease, Huntington’s disease, and schizophrenia (3). Five subtypes of dopamine receptors, D1-5, were well-characterized pharmacologically and biochemically (4). These five subtypes were classified into two subfamilies of D1-like (D1, D5) and D2-like (D2, D3, D4) dopamine receptors. D1-like and D2-like receptors exert synergistic as well as opposite effects at the biochemical and overall system levels. A great majority of striatal D1 and D2/3 receptors are localized postsynaptically on the caudate-putamen neurons and to a lesser extent presynaptically on nigrostiatal axons. On the other hand, D4 receptors are mostly found in the extrastriatal regions of the brain, such as the cortex, hippocampus, thalamus and medulla. These areas are believed to control emotion and cognition.

Beside D2 receptors, D4 receptors may play an important role in the pathophysiology of schizophrenia from clinical studies of the atypical neuroleptic clozapine in patients (5, 6). Clozapine is not only effective against positive symptoms of schizophrenia but also is efficacious against the negative symptoms. Clozapine has a 10-fold greater affinity for D4 than for D2 receptors (7). However, it also has high affinities for 5-HT1A,1B,2A,2C,6,7, α1A,2A,2C, muscarinic M1 and histamine H1 receptors. The neurophysiologic role of D4 receptors remains to be defined. Thus, there is a need to for selective ligands to investigate the pharmacological role of D4 receptors.

There have been several attempts to develop specific D4 antagonists for PET radioligands for D4 receptors (8-10). However, none has proved suitable because of lack of selectivity and other pharmacological issues. Unangst et al. (11) reported that 3-(4-fluorobenzyl)-8-methoxy-1,2,3,4-tetrahydrochromeno[3,4-c]pyridin-5-one is a potent inhibitor of D4 receptors with >100-fold selectivity over D2 and D3 receptors. This led to the development of 3-(4-[18F]fluorobenzyl)-8-methoxy-1,2,3,4-tetrahydrochromeno[3,4-c]pyridin-5-one ([18F]FMTP) as a potential D4 receptor radioligand (12). [18F]FMTP was shown to identify extrastriatal D4 receptors in the regions of cortex and medulla in rat brain.



4-[18F]Fluorobenzaldehyde was obtained by nucleophilic aromatic substitution of 4-trimethylammonium-benzaldehyde triflate with K[18F]F/Kryptofix2.2.2 in DMSO. [18F]FMTP radiosynthesis was accomplished by the reductive amination of 4-[18F]fluorobenzaldehyde with 8-methoxy-1,2,3,4-tetrahydrochromeno[3,4-c]pyridin-5-one, followed by high-performance liquid chromatography (HPLC) purification (12). The overall radiochemical yield of the radiosynthesis was 19.5% (decay corrected), the specific radioactivity was about 110 GBq/µmol (2.5 Ci/µmol) and the radiochemical purity was greater than 99%, the time of synthesis and purification was approximately 110 min.

In Vitro Studies: Testing in Cells and Tissues


FMTP was reported to have high-affinity binding affinities to D4 receptor sites and not to D2/3 receptors in recombinant cell lines (11). The Ki values for D2, D3, and D4 receptors using [3H]spiperone were 5800, 548 and 4.3 nM, respectively. The D2/D4 Ki ratio was calculated to be 1,350.

Animal Studies



Biodistribution studies in rat showed a moderate accumulation of radioactivity in the whole brain, showing 0.6%, 0.5%, 0.4%, and 0.2% ID/g. at 2, 15, 30, and 120 min after injection of [18F]FMTP, respectively (12). There was a marked accumulation of the tracer in the frontal cortex within the first 10 min (0.69% ID/g), followed by a slow decrease of radioactivity to 0.35% ID/g at 60 min. The medulla exhibited a slightly higher radioactivity compared to other brain regions at 15, 30, 60 and 120 min. The maximum medulla-to-striatum and cortex-to-striatum ratios were 2.03 and 1.15, respectively. The accumulation of [18F]FMTP in frontal cortex and medulla were blocked by 1 mg/kg of unlabeled FMTP injected 15 min before the tracer with 84-86% decrease in radioactivity. The fraction of unchanged [18F]FMTP in blood samples determined by HPLC was 40% after 60 min after injection. The radioactivity remained intact in the brain. Further studies are needed to define the selectivity of [18F]FMTP as a D4 PET radioligand in vivo.

Other Non-Primate Mammals


No publication is currently available.

Non-Human Primates


No publication is currently available.

Human Studies


No publication is currently available.


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. [PubMed: 12811735]
Chesselet M.F., Delfs J.M. Basal ganglia and movement disorders: an update. Trends Neurosci. 1996;19(10):417–22. [PubMed: 8888518]
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]
Stoof J.C., Kebabian J.W. Two dopamine receptors: biochemistry, physiology and pharmacology. Life Sci. 1984;35(23):2281–96. [PubMed: 6390056]
Seeman P. Dopamine receptor sequences. Therapeutic levels of neuroleptics occupy D2 receptors, clozapine occupies D4. Neuropsychopharmacology. 1992;7(4):261–84. [PubMed: 1362057]
Seeman P., Guan H.C., Van Tol H.H. Dopamine D4 receptors elevated in schizophrenia. Nature. 1993;365(6445):441–5. [PubMed: 8413587]
Van Tol H.H., Bunzow J.R., Guan H.C., Sunahara R.K., Seeman P., Niznik H.B., Civelli O. Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine. Nature. 1991;350(6319):610–4. [PubMed: 1840645]
Bender D., Holschbach M., Stocklin G. Synthesis of n.c.a. carbon-11 labelled clozapine and its major metabolite clozapine-N-oxide and comparison of their biodistribution in mice. Nucl Med Biol. 1994;21(7):921–5. [PubMed: 9234345]
Boy C., Klimke A., Holschbach M., Herzog H., Muhlensiepen H., Rota Kops E., Sonnenberg F., Gaebel W., Stocklin G., Markstein R., Muller-Gartner H.W. Imaging dopamine D4 receptors in the living primate brain: a positron emission tomography study using the novel D1/D4 antagonist [11C]SDZ GLC 756. Synapse. 1998;30(4):341–50. [PubMed: 9826226]
Zhang M.R., Haradahira T., Maeda J., Okauchi T., Kawabe K., Noguchi J., Kida T., Suzuki K., Suhara T. Syntheses and pharmacological evaluation of two potent antagonists for dopamine D4 receptors: [11C]YM-50001 and N-[2-[4-(4-Chlorophenyl)-piperizin-1-yl]ethyl]-3-[11C]methoxybenzamide. Nucl Med Biol. 2002;29(2):233–41. [PubMed: 11823129]
Unangst P.C., Capiris T., Connor D.T., Heffner T.G., MacKenzie R.G., Miller S.R., Pugsley T.A., Wise L.D. Chromeno[3,4-c]pyridin-5-ones: selective human dopamine D4 receptor antagonists as potential antipsychotic agents. J Med Chem. 1997;40(17):2688–93. [PubMed: 9276014]
Hai-Bin T., Duan-Zhi Y., Lan Z., Li-Hua W., Chun-Fu Z., Ming-Wei W., Chun-Ying W., Gu-Cai L., Yong-Xian W. Dopamine D(4) receptor antagonist 3-(4-[(18)F]fluorobenzyl)-8-methoxy-1,2,3,4-tetrahydrochromeno[3,4-c]pyrid in-5-one([(18)F]FMTP): radiosynthesis and in vivo characterization in rats. Appl Radiat Isot. 2005;63(3):333–42. [PubMed: 15972259]


  • PubReader
  • Print View
  • Cite this Page
  • PDF version of this page (85K)
  • MICAD Summary (CSV file)

Search MICAD

Limit my Search:

Related information

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...