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

INTRODUCTION: 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. METHODS: 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. RESULTS: [(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. CONCLUSION: 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.

Design, synthesis and in vitro evaluation of bridgehead fluoromethyl analogs of N-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}-N-(pyridin-2-yl)cyclohexanecarboxamide (WAY-100635) for the 5-HT(1A) receptor.

Fluorinated analogs that are related to the 5-hydroxytryptamine (5-HT(1A)) antagonist, N-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}-N-(pyridin-2-yl)cyclohexanecarboxamide (WAY-100635), have been synthesized and their binding affinity for the 5-HT(1A) receptor and other neurotransmitter receptors (adrenoceptors, sigma receptors, and dopamine receptors), and serotonin transporters was examined in vitro. These ligands were designed to provide a possible potential positron emission tomography (PET) ligand with high metabolic stability. To this end, the cyclohexyl moiety in WAY-100635 and in O-desmethyl WAY-100635 was replaced by a bridge-fused ring (BFR) such as adamantyl, cubyl, bicyclo[2.2.2]octyl and bicyclo[2.2.1]heptyl to reduce the metabolic rate of the amide bond hydrolysis, while a fluoromethyl group was introduced on the other bridgehead of the BFR to prevent defluorination by HF elimination. All synthesized analogs displayed high affinity in the (sub)nanomolar range for the 5-HT(1A) receptor, comparable to WAY-100635. In addition, 6b, 6c and 6d were reasonably selective to the 5-HT(1A) receptor over the above mentioned receptors. In human hepatocytes, 6b showed a suitable metabolic stability. In conclusion, the obtained data provides a promising starting point for the synthesis of the corresponding (18)F-labeled PET analogs.

Design, synthesis, radiolabeling, and in vitro and in vivo evaluation of bridgehead iodinated analogues of N-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}-N-(pyridin-2-yl)cyclohexanecarboxamide (WAY-100635) as potential SPECT ligands for the 5-HT1A receptor.

Here we describe the design, synthesis, and pharmacological profile of 5-HT(1A) receptor ligands related to 1 (WAY-100635). The cyclohexyl moiety in 1 and its O-desmethylated analogue 3 were replaced by the bridgehead iodinated bridge-fused rings: adamantyl, cubyl, bicyclo[2.2.2]octyl, or bicyclo[2.2.1]heptyl. All analogues displayed a (sub)nanomolar affinity for the 5-HT(1A) receptor in vitro. Compounds 6b and 7b appeared to be selective for this receptor over other relevant receptors and could easily be iodinated with radioactive iodine-123. In humane hepatocytes, [(123)I]6b showed a low propensity for amide hydrolysis and a stable carbon-iodine bond. The biodistribution of [(123)I]6b and [(123)I]7b in rats revealed that the carbon-iodine bond was also stable in vivo. Unfortunately, the brain uptake and the specificity for both radioligands were significantly lower than those of the parent molecule 1. In conclusion, the designed tracers are not suitable for SPECT imaging.