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Pharmaceuticals 2018, 11(1), 30; https://doi.org/10.3390/ph11010030

Comparison Study of Two Differently Clicked 18F-Folates—Lipophilicity Plays a Key Role

1
Johannes Gutenberg-University Mainz, Institute of Nuclear Chemistry, Fritz-Straßmann-Weg 2, 55128 Mainz, Germany
2
Hannover Medical School, Department of Nuclear Medicine, Radiopharmaceutical Chemistry, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
3
University Medical Center of Johannes Gutenberg-University Mainz, Polyclinic of Nuclear Medicine, Langenbeckstr. 1, 55131 Mainz, Germany
The authors contributed equally.
*
Author to whom correspondence should be addressed.
Received: 26 January 2018 / Revised: 12 March 2018 / Accepted: 14 March 2018 / Published: 17 March 2018
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Abstract

Within the last decade, several folate-based radiopharmaceuticals for Single Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET) have been evaluated; however, there is still a lack of suitable 18F-folates for clinical PET imaging. Herein, we report the synthesis and evaluation of two novel 18F-folates employing strain-promoted and copper-catalyzed click chemistry. Furthermore, the influence of both click-methods on lipophilicity and pharmacokinetics of the 18F-folates was investigated. 18F-Ala-folate and 18F-DBCO-folate were both stable in human serum albumin. In vitro studies proved their high affinity to the folate receptor (FR). The lipophilic character of the strain-promoted clicked 18F-DBCO-folate (logD = 0.6) contributed to a higher non-specific binding in cell internalization studies. In the following in vivo PET imaging studies, FR-positive tumors could not be visualized in a maximum intensity projection images. Compared with 18F-DBCO-folate, 18F-Ala-folate (logD = −1.4), synthesized by the copper-catalyzed click reaction, exhibited reduced lipophilicity, and as a result an improved in vivo performance and a clear-cut visualization of FR-positive tumors. In view of high radiochemical yield, radiochemical purity and favorable pharmacokinetics, 18F-Ala-folate is expected to be a promising candidate for FR-PET imaging. View Full-Text
Keywords: 18F-folates; PET; folic acid; folate receptor; click chemistry; copper-catalyzed click; strain promoted click 18F-folates; PET; folic acid; folate receptor; click chemistry; copper-catalyzed click; strain promoted click
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Kettenbach, K.; Reffert, L.M.; Schieferstein, H.; Pektor, S.; Eckert, R.; Miederer, M.; Rösch, F.; Ross, T.L. Comparison Study of Two Differently Clicked 18F-Folates—Lipophilicity Plays a Key Role. Pharmaceuticals 2018, 11, 30.

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