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Development of Radioligands for In Vivo Imaging of NMDA Receptors

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PET and SPECT of Neurobiological Systems

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Abstract

N-methyl-d-aspartate receptors (NMDARs) play an important role in the neurotransmission of the central nervous system (CNS). On the other hand, aberrant functioning of the NMDARs has been implicated in various CNS disorders. Positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging of NMDARs may provide novel insights on CNS functions and various CNS disorders that could lead to the discovery of potential drug therapies. Despite numerous efforts to develop a number of radioligands for NMDARs since the late 1980s, none have been deemed satisfactory as in vivo imaging probes. In this chapter, we summarize the progress in the development of PET and SPECT imaging agents for NMDARs and discuss the prospects in this field.

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Abbreviations

% ID/g:

Percent injected dose per gram of tissue

% ID/mL:

Percent injected dose per milliliter of tissue

3MPICA:

3-[2-[(3-methoxyphenylamino)carbonyl]ethenyl]-4,6-dichloroindole-2-carboxylic acid

AD:

Alzheimer’s disease

BBB:

Blood-brain barrier

BP:

Binding potential

CBZ:

Benzyloxycarbonyl

cis-HPTC:

cis-2-hydroxymethyl-r-1-(N-piperidyl)-1-(2-thienyl)cyclohexane

CNS:

Central nervous system

CNS 1261:

N-(1-naphthyl)-N′-(3-iodophenyl)-N′-methylguanidine

CNS 5161:

N-(2-chloro-5-(methylmercapto)phenyl)-N′-methylguanidine monohydrochloride

CP-101,606:

(1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol

DAO:

d-amino acid oxidase

DCKA:

5,7-dichlorokynurenic acid

DTG:

1,3-di-o-tolylguanidine

EMD-95885:

6-3-4-(4-fluorobenzyl)piperidinopropionyl-3H-benzoxazol-2-one

GMOM:

N-(2-chloro-5-thiomethylphenyl)-N′-(3-methoxy-phenyl)-N′-methylguanidine

GV150526A:

3-(2-((phenylamino)carbonyl)ethyenyl)-4,6-dichloroindol-2-carboxylic acid

HON0001:

7-hydroxy-6-methoxy-2-methyl-1-(2-(4-(trifluoromethyl)phenyl)ethyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride

HPLC:

High-performance liquid chromatography

Ifenprodil:

4-[2-(4-benzylpiperidin-1-yl)-1-hydroxypropyl]phenol

Ketamine:

(R,S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone

Kryptofix 2.2.2:

4 7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]-hexacosane

L-689,560:

trans-2-carboxy-5,7-dichloro-4-phenylaminocarbonylamino-1,2,3,4-tetrahydroquinoline

L-703,717:

3-[3-(4-methoxybenzyl)phenyl]-4-hydroxy-7-chloroquinolin-2(1H)-one

MDL-104,653:

3-phenyl-4-hydroxy-7-chloro-quinolin-2(1H)-one

MDL-105519:

(Z)-2-carboxy-4,6-dichloroindole-3-(2′-phenyl-2′-carboxy)-ene

MEM:

1-amino-3-fluoromethyl-5-methyl-adamantane

Memantine:

3,5-dimethyladamantan-1-amine

MK-0657:

(3S,4R)-4-methylbenzyl 3-fluoro-4-((pyrimidin-2-ylamino)methyl) piperidine-1-carboxylate

MK-801:

dizocilpine maleate {(+)-10,11-dihydro-5-methyl-5H-dibenzo[a,d] cyclohepten-5,10-diyldiammonium maleate}

NCAM:

N-[2-(N-(2-mercaptoethyl)) amino ethyl]-N-(2-mercaptoethyl)-3,5-dimethyl acetamide amantadine

NHAM:

1-[N-[N-(2-mercaptoethyl)]-N-[2-(2-mercaptoethyl)amino] amino ethyl] amino-3,5-dimethyladamantane

NMDAR:

N-methyl-d-aspartate receptors

NPS 1506:

[3-fluoro-γ-(3-fluorophenyl)-N-methylbenzenepropamine]

PAMQX:

(d)-7-iodo-N-(1-phosphonoethyl)-5-aminomethylquinoxaline-2,3-dione

PCP:

Phencyclidine {1-(1-phenylcyclohexyl) piperidine}

PD:

Parkinson’s disease

PET:

Positron emission tomography

rCBF:

Regional cerebral blood flow

RGH-896:

2-[4-[(4-fluorophenyl)methyl]piperidin-1-yl]-2-oxo-N-(2-oxo-N-3H-1,3-benzoxazol-6-yl)acetamide

Ro 25–6981:

[(±)-(αR,βS)]-α-(4-Hydroxyphenyl)-β-methyl-4-(phenylmethyl)-1-piperidine propanol

Ro-647312:

[2-(3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-4-yl]-dimethylamine

SAR:

Structure activity relationship

SPECT:

Single photon emission computed tomography

TCP:

N-[1-(2-Thienyl)cyclohexyl]-3,4-piperidine

TLC:

Thin-layer chromatography

V T :

Total volume of distribution

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Authors and Affiliations

  1. Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, 852-8521, Japan

    Takeshi Fuchigami & Morio Nakayama

  2. Medical Photonics Research Center, Hamamatsu University School of Medicine, Hamamatsu, 431-3192, Japan

    Yasuhiro Magata

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  1. Takeshi Fuchigami
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  2. Morio Nakayama
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  3. Yasuhiro Magata
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Correspondence to Yasuhiro Magata .

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  1. Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, Groningen, The Netherlands

    Rudi A.J.O. Dierckx

  2. Faculty of Electrical Engineering and Information Technology, University of Applied Sciences Offenburg, Offenburg, Germany

    Andreas Otte

  3. Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, Groningen, The Netherlands

    Erik F.J. de Vries

  4. Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, Groningen, The Netherlands

    Aren van Waarde

  5. Molecular Neurobiology, Universtiy of Groningen, Groningen, The Netherlands

    Paul G.M. Luiten

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Fuchigami, T., Nakayama, M., Magata, Y. (2014). Development of Radioligands for In Vivo Imaging of NMDA Receptors. In: Dierckx, R., Otte, A., de Vries, E., van Waarde, A., Luiten, P. (eds) PET and SPECT of Neurobiological Systems. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-42014-6_18

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