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Nucl Med Biol. 2012 Oct;39(7):1068-76. doi: 10.1016/j.nucmedbio.2012.04.002. Epub 2012 May 17.

Synthesis, biodistribution and PET studies in rats of (18)F-Labeled bridgehead fluoromethyl analogues of WAY-100635.

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Department of Nuclear Medicine and PET Research, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands.



In vitro screening of fluoromethyl bridge-fused ring (BFR) analogues of WAY-100635 (5a, 5b and 5c) has shown a high binding affinity and a good selectivity for the 5-HT(1A) receptor. As these compounds were designed to provide PET ligands with high metabolic stability, they are now radiolabeled with fluorine-18 and investigated in vivo.


BFR precursors were synthesized and reacted with fluorine-18 in dry MeCN in the presence of 2,2,2-kryptofix and K(2)CO(3). In rats, biodistribution and PET studies were performed using [(18)F]5a, [(18)F]5b and [(18)F]5c. The binding specificity was determined by administration of non-labeled WAY-100635 prior to the radiolabeled ligands.


[(18)F]5 ligands were synthesized in overall radiochemical yields of 24%-45%, respectively with a radiochemical purity of >98%. Relatively good hippocampus to cerebellum ratios of 5.55, 4.79 and 5.45, respectively were reached at 45 min pi. However, PET studies indicated defluorination of the radioligands by showing high accumulation of radioactivity in the bones in the order of [(18)F]5a≈[(18)F]5b>[(18)F]5c.


Also in vivo, the radioligands bind preferentially to the 5-HT(1A) receptor. Unfortunately, no metabolic stability with regard to defluorination was observed in rats.

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