Synthesis and Characterization of N-alkyl-3-(2,4-dichlorophenyl)-N-fluoroalkyl-2,5- dimethylpyrazolo[1,5-a]pyrimidin-7-amines as Potential CRF1 Receptor PET Radiotracers Pubblico

Abstract

N-alkyl-3-(2,4-dichlorophenyl)-N-fluoroalkyl-2,5-dimethylpyrazolo[1,5-a]pyrimidin-7- amines were synthesized from commercial starting materials. As hypothesized, binding assays indicate that this class of molecules is a strong inhibitor of the CRF1 receptor (Ki= 0.72-33 nM). As lipophilicity of the 7-amine alkyl chains increases, binding strength increases. One molecule has been successfully radiolabeled indicating that these molecules are potential CRF1 receptor PET radiotracers.

Table of Contents

Table of Contents

1. INTRODUCTION...............................................................................................................................1

1.1 POSITRON EMISSION TOMOGRAPHY ..................................................................................................1

1.2 CROSSING THE BLOOD BRAIN BARRIER..............................................................................................3

1.3 CORTICOTROPIN-RELEASING FACTOR ................................................................................................3

1.4 NON-PEPTIDIC CRF1 RECEPTOR ANTAGONISTS.....................................................................................4

1.5 CRF1 PET TRACER DEVELOPMENTS.....................................................................................................5

1.6 PET TRACER DESIGN........................................................................................................................7

2. SYNTHESIS .....................................................................................................................................9

3. EXPERIMENTAL ................................................................................................................................12

3.1 GENERAL EXPERIMENTAL PROCEDURES...............................................................................................12

3.2 CHEMISTRY ...................................................................................................................................12

3.3 BINDING STUDIES ..........................................................................................................................28

4. RESUL TS AND DISCUSSION ..............................................................................................................29

5. CONCLUSIONS.................................................................................................................................33

6. REFERENCES ...................................................................................................................................34

APPENDIX I. NMR SPECTRA ...................................................................................................................A

APPENDIX II. HPLC DATA FOR RADIOLABELING ..........................................................................................S

About this Honors Thesis

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School	Emory College
Department	Chemistry
Degree	BS
Submission	Honors Thesis
Language	English
Research Field	Chemistry, Organic Chemistry, Pharmaceutical Chemistry, Radiation
Parola chiave	Radiotracer CRF
Committee Chair / Thesis Advisor	Stehouwer, Jeffrey Scott, Emory University
Committee Members	Lutz, Stefan, Emory University Weaver, Jeremy, Emory University

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