[18F]D


Status
Molecule Category	UNKNOWN
UNII	Y1H4D2VKZD


Active Pharmaceutical Ingredients Bioactive chemicals	Exact Similarity SubStructure	Threshold (%) >= 70

Structure


InChI Key	FLZZFWBNYJNHMY-UHFFFAOYSA-N
Smiles	CCN(CC)C(=O)Cc1c(-c2ccc(OCCF)cc2)nn2c(C)cc(C)nc12
InChI	InChI=1S/C22H27FN4O2/c1-5-26(6-2)20(28)14-19-21(17-7-9-18(10-8-17)29-12-11-23)25-27-16(4)13-15(3)24-22(19)27/h7-10,13H,5-6,11-12,14H2,1-4H3

Physicochemical Descriptors

Property Name	Value
Molecular Formula	C22H27FN4O2
Molecular Weight	398.48
AlogP	3.77
Hydrogen Bond Acceptor	5.0
Hydrogen Bond Donor	0.0
Number of Rotational Bond	8.0
Polar Surface Area	59.73
Molecular species	NEUTRAL
Aromatic Rings	3.0
Heavy Atoms	29.0

Reference

Journal : J. Med. Chem.

Title : Synthesis and biological evaluation of substituted [18F]imidazo[1,2-a]pyridines and [18F]pyrazolo[1,5-a]pyrimidines for the study of the peripheral benzodiazepine receptor using positron emission tomography.

PubMed ID : 18557607

DOI : 10.1021/jm7014556

Year : 2008

Volume : 51

Issue : 13

First Page : 3700

Last Page : 3712

Authors : Fookes CJ, Pham TQ, Mattner F, Greguric I, Loc'h C, Liu X, Berghofer P, Shepherd R, Gregoire MC, Katsifis A.

Abstract : The fluoroethoxy and fluoropropoxy substituted 2-(6-chloro-2-phenyl)imidazo[1,2- a]pyridin-3-yl)- N, N-diethylacetamides 8 (PBR102) and 12 (PBR111) and 2-phenyl-5,7-dimethylpyrazolo[1,5- a]pyrimidin-3-yl)- N, N-diethylacetamides 15 (PBR099) and 18 (PBR146) were synthesized and found to have high in vitro affinity and selectivity for the peripheral benzodiazepine receptors (PBRs) when compared with the central benzodiazepine receptors (CBRs). The corresponding radiolabeled compounds [ (18)F] 8 [ (18)F] 12, [ (18)F] 15, and [ (18)F] 18 were prepared from their p-toluenesulfonyl precursors in 50-85% radiochemical yield. In biodistribution studies in rats, the distribution of radioactivity of the [ (18)F]PBR compounds paralleled the known localization of PBRs. In the olfactory bulbs, where the uptake of radioactivity was higher than in the rest of the brain, PK11195 and Ro 5-4864 were able to significantly inhibit [ (18)F] 12, while little or no pharmacological action of these established PBR drugs were observed on the uptake of [ (18)F] 8, [ (18)F] 15, and [ (18)F] 18 compared to control animals. Hence, [ (18)F] 12 appeared to be the best candidate for evaluation as an imaging agent for PBR expression in neurodegenerative disorders.

Reference

Journal : J. Med. Chem.

PubMed ID : 18557607

DOI : 10.1021/jm7014556

Year : 2008

Volume : 51

Issue : 13

First Page : 3700

Last Page : 3712

Authors : Fookes CJ, Pham TQ, Mattner F, Greguric I, Loc'h C, Liu X, Berghofer P, Shepherd R, Gregoire MC, Katsifis A.

Reference

Journal : J. Med. Chem.

Title : The translocator protein (18 kDa): central nervous system disease and drug design.

PubMed ID : 19133775

DOI : 10.1021/jm8011678

Year : 2009

Volume : 52

Issue : 3

First Page : 581

Last Page : 592

Authors : Scarf AM, Ittner LM, Kassiou M.

Reference

Journal : Bioorg. Med. Chem. Lett.

Title : Pyrazolo[1,5-a]pyrimidine acetamides: 4-Phenyl alkyl ether derivatives as potent ligands for the 18 kDa translocator protein (TSPO).

PubMed ID : 20727749

DOI : 10.1016/j.bmcl.2010.07.135

Year : 2010

Volume : 20

Issue : 19

First Page : 5799

Last Page : 5802

Authors : Reynolds A, Hanani R, Hibbs D, Damont A, Da Pozzo E, Selleri S, Dollé F, Martini C, Kassiou M.

Abstract : Herein, we report the synthesis of four new phenyl alkyl ether derivatives (7, 9-11) of the pyrazolo[1,5-a]pyrimidine acetamide class, all of which showed high binding affinity and selectivity for the TSPO and, in the case of the propyl, propargyl, and butyl ether derivatives, the ability to increase pregnenolone biosynthesis by 80-175% over baseline in rat C6 glioma cells. While these compounds fit our in silico generated pharmacophore for TSPO binding the current model does not account for the observed functional activity.

Reference

Journal : J. Med. Chem.

Title : Synthesis and structure-activity relationships of 5,6,7-substituted pyrazolopyrimidines: discovery of a novel TSPO PET ligand for cancer imaging.

PubMed ID : 23521048

DOI : 10.1021/jm4001874

Year : 2013

Volume : 56

Issue : 8

First Page : 3429

Last Page : 3433

Authors : Tang D, McKinley ET, Hight MR, Uddin MI, Harp JM, Fu A, Nickels ML, Buck JR, Manning HC.

Abstract : Focused library synthesis and structure-activity relationship development of 5,6,7-substituted pyrazolopyrimidines led to the discovery of 2-(5,7-diethyl-2-(4-(2-fluoroethoxy)phenyl)pyrazolo[1,5-a]pyrimidin-3-yl)-N,N-diethylacetamide (6b), a novel translocator protein (TSPO) ligand exhibiting a 36-fold enhancement in affinity compared to another pyrazolopyrimidine-based TSPO ligand, 6a (DPA-714). Radiolabeling with fluorine-18 ((18)F) facilitated production of 2-(5,7-diethyl-2-(4-(2-[(18)F]fluoroethoxy)phenyl)pyrazolo[1,5-a]pyrimidin-3-yl)-N,N-diethylacetamide ((18)F-6b) in high radiochemical yield and specific activity. In vivo studies of (18)F-6b were performed which illuminated this agent as an improved probe for molecular imaging of TSPO-expressing cancers.

Reference

Journal : Bioorg. Med. Chem. Lett.

Title : Preparation and evaluation of novel pyrazolo[1,5-a]pyrimidine acetamides, closely related to DPA-714, as potent ligands for imaging the TSPO 18kDa with PET.

PubMed ID : 24560538

DOI : 10.1016/j.bmcl.2014.01.080

Year : 2014

Volume : 24

Issue : 6

First Page : 1550

Last Page : 1556

Authors : Médran-Navarrete V, Damont A, Peyronneau MA, Kuhnast B, Bernards N, Pottier G, Marguet F, Puech F, Boisgard R, Dollé F.

Abstract : A series of four novel analogues of DPA-714, bearing a fluoroalkynyl side chain (with a length ranging from three to six carbon atoms) in replacement of the fluoroethoxy motif, have been synthetized in six steps from commercially available methyl 4-iodobenzoate. The synthetic strategy for the preparation of these N,N-diethyl-2-(2-(4-(ω-fluoroalk-1-ynyl)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamides (7a-d) consisted in derivatizing a key iodinated building block featuring the pyrazolopyrimidine acetamide backbone of DPA-714, by Sonogashira couplings with various alkynyl reagents. The resulting alkynols were subsequently fluorinated, yielding the expected target derivatives. All four analogues exhibited slightly higher affinity and selectivity towards the TSPO 18kDa (Ki vs [(3)H]PK11195: 0.35-0.79nM; Ki vs [(3)H]flunitrazepam: >1000nM) when compared to DPA-714 (Ki vs [(3)H]PK11195: 0.91nM; Ki vs [(3)H]flunitrazepam: >1000nM). Lipophilicities (HPLC, logD7.4) increased with the chain length (from 3.6 to 4.3) and were significantly higher than the one determined for DPA-714 (2.9). Preliminary in vitro metabolism evaluation using rat microsomal incubations and LC-MS analyses showed, for all four novel analogues, the absence of defluorinated metabolites. Among them, the fluoropentynyl compound, DPA-C5yne (7c), was selected, labelled in one single step with fluorine-18 from the corresponding tosylate and in vivo evaluated with PET on our in-house-developed rat model of acute local neuroinflammation.

Reference

Journal : Eur J Med Chem

Title : Synthesis and in vitro characterization of novel fluorinated derivatives of the translocator protein 18 kDa ligand CfO-DPA-714.

PubMed ID : 27688189

DOI : 10.1016/j.ejmech.2016.09.025

Year : 2017

Volume : 125

First Page : 346

Last Page : 359

Authors : Cacheux F, Médran-Navarrete V, Dollé F, Marguet F, Puech F, Damont A.

Abstract : The translocator protein 18 kDa (TSPO) is today a validated target for a number of therapeutic applications, but also a well-recognized diagnostic/imaging biomarker for the evaluation of inflammatory related-disease state and progression, prompting the development of specific and dedicated TSPO ligands worldwide. For this purpose, pyrazolo[1,5-a]pyrimidine acetamides constitute a unique class of high affinity and selectivity TSPO ligands; it includes DPA-714, a fluorine-containing derivative that has also been labelled with the positron-emitter fluorine-18, and is nowadays widely used as a Positron Emission Tomography imaging probe. Recently, to prevent defluorination issues encountered in vivo with this tracer, a first series of analogues was reported where the oxygen atom bridging the phenyl ring of the core structure and the fluorinated moiety was replaced with a more robust linkage. Among this new series, CfO-DPA-714 was discovered as a highly promising TSPO ligand. Herein, a novel series of fluorinated analogues of the latter molecule were synthesized and in vitro characterized, where the pharmacomodulation at the amide position of the molecule was explored. Thirteen compounds were thus prepared from a common key-ester intermediate (synthesized in 7 steps from 4-iodobenzoate - 11% overall yield) and a set of commercially available amines and obtained with moderate to good yields (23-81%) and high purities (>95%). With one exception, all derivatives displayed nanomolar to subnanomolar affinity for the TSPO and also high selectivity versus the CBR (Ki (CBR)/Ki (TSPO) > 103). Within this series, three compounds showed better Ki values (0.25, 0.26 and 0.30 nM) than that of DPA-714 (0.91 nM) and CfO-DPA-714 (0.37 nM), and favorable lipophilicity for brain penetration (3.6 < logD7.4 < 4.4). Among these three compounds, the N-methyl-N-propyl amide analogue (9) exhibited similar metabolic stability when compared to CfO-DPA-714 in mouse, rat and human microsomes. Therefore, the latter compound stands out as a promising candidate for drug development or for use as a PET probe, once fluorine-18-labelled, for in vivo neuroinflammation imaging.

Reference

Journal : Eur J Med Chem

Title : Synthesis and in vitro characterization of novel fluorinated derivatives of the translocator protein 18 kDa ligand CfO-DPA-714.

PubMed ID : 27688189

DOI : 10.1016/j.ejmech.2016.09.025

Year : 2017

Volume : 125

First Page : 346

Last Page : 359

Authors : Cacheux F, Médran-Navarrete V, Dollé F, Marguet F, Puech F, Damont A.

Assay Description	Organism	Bioactivity
Displacement of [3H]PK11195 from peripheral benzodiazepine receptor in rat kidney membrane	Rattus norvegicus	5.6 nM
Displacement of [3H]Ro 5-4864 from peripheral benzodiazepine receptor in rat kidney membrane	Rattus norvegicus	5.7 nM
Displacement of [3H]PK11195 from TSPO in rat cortex	Rattus norvegicus	7.0 nM
Displacement of [3H]PK11195 from TSPO in rat kidney	Rattus norvegicus	7.0 nM
Displacement of [3H]-PK 11195 from TSPO in rat C6 cell lysates after 2 hrs by scintillation counting analysis	Rattus norvegicus	9.73 nM
Displacement of [3H]PK11195 from TSPO in rat heart membrane homogenates	Rattus norvegicus	0.91 nM
Displacement of [3H]PK11195 from TSPO in rat heart membranes after 15 mins by scintillation counting method	Rattus norvegicus	0.91 nM
Displacement of [3H]flunitrazepam from CBR in rat cerebral cortex membranes at 1 uM relative to control	Rattus norvegicus	0.0 %

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Cross References

Resources	Reference
ChEMBL	CHEMBL512306
FDA SRS	Y1H4D2VKZD
SureChEMBL	SCHEMBL2513934
ZINC	ZINC000040395766

CONTENTS

Structure
Chemical and Physical Properties
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