Synthesis and in vivo biodistribution of F-18 labeled 3-cis-, 3-trans-, 4-cis-, and 4-trans-fluorocyclohexane derivatives of WAY 100635

Lang, Lixin; Jagoda, Elaine M.; Ma, Ying; Sassaman, Mark B.; Eckelman, William C.

doi:10.1016/j.bmc.2006.01.064

Cited by 25 publications

(24 citation statements)

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“…The ratio of cis- and trans-[ 18 F]mefway BP ND values was approximately 15 when averaged across the cortical regions reported in Table 1. These differences in specific binding of cis- and trans-compounds follow those reported for cis- and trans- 4-[ 18 F]FCWAY and cis- and trans- 3-[ 18 F]FCWAY, with ratios in hippocampal specific binding between isomers of 5 (trans-/cis-), and 3 (trans-/cis-), respectively, based upon biodistribution studies at 30 minutes in rats[12]. By assuming that both cis- and trans-[ 18 F]mefway compounds target the identical receptor pool and have equal nonspecific binding in the brain, we can attribute this difference to the apparent (in vivo) equilibrium dissociation constant, K D .…”

Section: Discussionsupporting

confidence: 79%

“…The conformation of trans- and cis- [ 18 F]FCWAY displayed a dramatic difference in 5-HT 1A binding with reported IC 50 values of 1.7nM and 21nM, respectively. In vivo PET measures revealed similar blood metabolic profiles, but hippocampus to cerebellum ratios were 19.3 and 3.6 for trans- and cis- [ 18 F]FCWAY respectively [6]. Preliminary in vitro measures have also been made for [ 18 F]mefway, which have indicated that the cis- isomer has lower affinity for the 5-HT 1A receptor than the trans- isomer [7].…”

Section: Introductionmentioning

confidence: 99%

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An in vivo comparison of cis- and trans-[18F]mefway in the nonhuman primate

Hillmer

Murali

Barnhart

et al. 2011

Nuclear Medicine and Biology

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Introduction [18F]Mefway is a serotonin 5-HT1A PET radiotracer with high specificity and favorable in vivo imaging properties. The chemical structure of 18F]mefway permits 18F labeling in either the cis- or trans- positions at the 4-cyclohexyl site. We have previously reported on the in vivo kinetics of trans-[18F]mefway in the nonhuman primate. In this work we compare in vivo binding of cis-[18F]mefway and trans-[18F]mefway to evaluate the properties of cis-[18F]mefway for 5-HT1A PET imaging. Methods The cis- and trans- [18F]mefway tracers were synthesized via nucleophilic substitution with their respective tosylate precursors. Two monkeys (1m, 1f) were given bolus injections of both cis- and trans- labeled [18F]mefway in separate experiments. Dynamic scans were acquired for 90 minutes with a microPET P4 scanner. Time activity curves were extracted in the areas of the mesial temporal cortex (MTC), anterior cingulate gyrus (aCG), insular cortex (IC), raphe nuclei (RN), and cerebellum (CB). The in vivo behavior of the radiotracers were compared based upon the nondisplaceable binding potential (BPND) using the CB as a reference region. Results Averaged over the 2 subjects, BPND values were MTC: 7.7, 0.58; aCG: 4.95, 0.32; IC: 3.27, 0.2; and RN: 3.05, 0.13 for trans-[18F]mefway and cis-[18F]mefway, respectively. Conclusion The cis- labeled [18F]mefway tracer has low specific binding throughout the 5-HT1A regions of brain compared to trans-[18F]mefway suggesting that the target to background binding of cis-[18F]mefway may limit its use for in vivo assessment of 5-HT1A binding.

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Section: Discussionsupporting

confidence: 79%

Section: Introductionmentioning

confidence: 99%

An in vivo comparison of cis- and trans-[18F]mefway in the nonhuman primate

Hillmer

Murali

Barnhart

et al. 2011

Nuclear Medicine and Biology

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“…The unlabeled mefway used in these experiments was a commercially purchased reference standard consisting of an isomeric mixture of cis-and transmefway (15:85 (Wooten et al, 2011b). This profound difference in the binding affinity of isomeric pairs has been reported for other 5-HT 1A PET radiotracers (Lang et al, 1999;Wilson et al, 1999). In this work, the reported injected masses are based only on the measured trans-mefway mass and exclude the cis-mefway mass fraction.…”

Section: Considerations In Experimental Designmentioning

confidence: 71%

Measurement of 5-HT_1A Receptor Density and in-vivo Binding Parameters of [¹⁸F]mefway in the Nonhuman Primate

Hillmer

Moirano

Ahlers

et al. 2012

J Cereb Blood Flow Metab

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The goal of this work was to characterize the in-vivo behavior of [ 18 F]mefway as a suitable positron emission tomography (PET) radiotracer for the assay of 5-hydroxytryptamine 1A (5-HT 1A ) receptor density (B max ). Six rhesus monkeys were studied using a multiple-injection (M-I) protocol consisting of three sequential bolus injections of [ 18 F]mefway. Injection times and amounts of unlabeled mefway were optimized for the precise measurement of B max and specific binding parameters k off and k on for estimation of apparent K D . The PET time series were acquired for 180 minutes with arterial sampling performed throughout. Compartmental analysis using the arterial input function was performed to obtain estimates for K 1 , k 2 , k off , B max , and K Dapp in the cerebral cortex and raphe nuclei (RN) using a model that accounted for nontracer doses of mefway. Averaged over subjects, highest binding was seen in the mesial temporal and dorsal anterior cingulate cortices with B max values of 42 ± 8 and 36 ± 8 pmol/mL, respectively, and lower values in the superior temporal cortex, RN, and parietal cortex of 24 ± 4, 19 ± 4, and 13 ± 2 pmol/mL, respectively. The K Dapp of mefway for the 5-HT 1A receptor sites was 4.3 ± 1.3 nmol/L. In conclusion, these results show that M-I [ 18 F]mefway PET experiments can be used for the in-vivo measurement of 5-HT 1A receptor density.

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“…Previous studies on a related analog, 18 F-FCWAY ([N-{2-[4-(2-methoxyphenyl)piperazino]ethyl}-N-(2-pyridinyl)-4-[ 18 F]fluoro-cyclohexanecarboxamide) found changes in the position of the 18 F-radiolabel resulted in achange in the affinity of the compound (Ma et al 2006). Shifting the 18 F-radiolabel from the 4 position ( 18 F-FCWAY) to the 3 position ( 18 F-3-FCWAY) had the effect of lowered affinity,faster pharmacokinetics and lower defluorination, giving 18 F-3-FCWAY better characteristics for measuring dynamic change in 5-HT 1A receptors (Lang et al 2006). …”

Section: Introductionmentioning

confidence: 99%

Synthesis and evaluation of mefway analogs as ligands for serotonin 5HT1A receptors

et al. 2014

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18F-Mefway (N-{2-[4-(2′-methoxyphenyl)piperazinyl]ethyl}-N-(2-pyridyl)-N-(4′-18F-fluoro-methylcyclohexane)carboxamide) was developed and evaluated for use as a PET ligand for imaging 5-HT1A receptors. Ongoing studies of 18F-Mefway have shown it to be an effective PET radiotracer. We have synthesized isomers of Mefway by changing the position of the methyl-group in attempts to evaluate stability for imaging purposes. 2-Methyl-, 3-methyl-, and 4-methyl-cyclohexane-1-carboxylic acids and 3-carbomethoxy-, 4-carbomethoxycyclohexane-1-carboxylic acids were coupled with WAY-100634 to provide the methylcyclohexyl derivatives (2-, 3- and 4-methyl). Mefway and 3-Mefway analogs were prepared by reduction of carbomethoxy-derivatives followed by fluorination. In vitro binding affinities for the methylated derivatives in rat brain homogenates was found to be 10.4 nM (2-methyl), 77 nM (3-methyl) and 21.5 nM (4-methyl). Binding affinity of 3-Mefway and 4-Mefway was found to be 17.4 nM and 6.26 nM, respectively. Our results suggest that 3-methyl/3-fluoromethyl substituent has approx. 3-fold lower affinities compared to the 4-methyl/4-fluoromethyl substituent.

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Synthesis and in vivo biodistribution of F-18 labeled 3-cis-, 3-trans-, 4-cis-, and 4-trans-fluorocyclohexane derivatives of WAY 100635

Cited by 25 publications

References 25 publications

An in vivo comparison of cis- and trans-[18F]mefway in the nonhuman primate

An in vivo comparison of cis- and trans-[18F]mefway in the nonhuman primate

Measurement of 5-HT_1A Receptor Density and in-vivo Binding Parameters of [¹⁸F]mefway in the Nonhuman Primate

Synthesis and evaluation of mefway analogs as ligands for serotonin 5HT1A receptors

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Synthesis and in vivo biodistribution of F-18 labeled 3-cis-, 3-trans-, 4-cis-, and 4-trans-fluorocyclohexane derivatives of WAY 100635

Cited by 25 publications

References 25 publications

An in vivo comparison of cis- and trans-[18F]mefway in the nonhuman primate

An in vivo comparison of cis- and trans-[18F]mefway in the nonhuman primate

Measurement of 5-HT1A Receptor Density and in-vivo Binding Parameters of [18F]mefway in the Nonhuman Primate

Synthesis and evaluation of mefway analogs as ligands for serotonin 5HT1A receptors

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Measurement of 5-HT_1A Receptor Density and in-vivo Binding Parameters of [¹⁸F]mefway in the Nonhuman Primate