Synthesis and PET studies of [11C-cyano]letrozole (Femara®), an aromatase inhibitor drug

2009

Abstract Introduction Aromatase, a member of the cytochrome P 450 family, converts androgens such as androstenedione and testosterone into estrone and estradiol, respectively. Letrozole (1-[bis-(4-cyanophenyl)methyl]-1 H -1,2,4-triazole; Femara) is a high-affinity aromatase inhibitor ( K i =11.5 nM) that has Food and Drug Administration approval for breast cancer treatment. Here we report the synthesis of carbon-11-labeled letrozole and its assessment as a radiotracer for brain aromatase in the baboon. Methods Letrozole and its precursor (4-[(4-bromophenyl)-1 H -1,2,4-triazol-1-ylmethyl]benzonitrile) were prepared in a two-step synthesis from 4-cyanobenzyl bromide and 4-bromobenzyl bromide,…

[(11)C]PR04.MZ, a promising DAT ligand for low concentration imaging: Synthesis, efficient (11)C-O-methylation and initial small animal PET studies.

2009

PR04.MZ was designed as a highly selective dopamine transporter inhibitor, derived from natural cocaine. Its binding profile indicates that [{sup 11}C]PR04.MZ may be suited as a PET radioligand for the non-invasive exploration of striatal and extrastriatal DAT populations. As a key feature, its structural design facilitates both, labelling with fluorine-18 at its terminally fluorinated butynyl moiety and carbon-11 at its methyl ester function. The present report concerns the efficient [{sup 11}C]MeI mediated synthesis of [{sup 11}C]PR04.MZ from an O-desmethyl precursor trifluoroacetic acid salt with Rb{sub 2}CO{sub 3} in DMF in up to 95 {+-} 5% labelling yield. A preliminary {mu}PET-experim…

An efficient and practical synthesis of [2-11C]indole via superfast nucleophilic [11C]cyanation and RANEY® Nickel catalyzed reductive cyclization

2015

A rapid method for the synthesis of carbon-11 radiolabeled indole was developed using a sub-nanomolar quantity of no-carrier-added [(11)C]cyanide as radio-precursor. Based upon a reported synthesis of 2-(2-nitrophenyl)acetonitrile (), a highly reactive substrate 2-nitrobenzyl bromide () was evaluated for nucleophilic [(11)C]cyanation. Additionally, related reaction conditions were explored with the goal of obtaining of highly reactive 2-(2-nitrophenyl)-[1-(11)C]acetonitrile () while inhibiting its rapid conversion to 2,3-bis(2-nitrophenyl)-[1-(11)C]propanenitrile (). Next, a RANEY® Nickel catalyzed reductive cyclization method was utilized for synthesizing the desired [2-(11)C]indole with h…

Characterisation of [11C]PR04.MZ in Papio anubis baboon: A selective high-affinity radioligand for quantitative imaging of the dopamine transporter

2012

N-(4-fluorobut-2-yn-1-yl)-2β-carbomethoxy-3β-(4′-tolyl)nortropane (PR04.MZ, 1) is a PET radioligand for the non-invasive exploration of the function of the cerebral dopamine transporter (DAT). A reliable automated process for routine production of the carbon-11 labelled analogue [11C]PR04.MZ ([11C]-1) has been developed using GMP compliant equipment. An adult female Papio anubis baboon was studied using a test–retest protocol with [11C]-1 in order to assess test–retest reliability, metabolism and CNS distribution profile of the tracer in non-human primates. Blood sampling was performed throughout the studies for determination of the free fraction in plasma (fP), plasma input functions and m…

Invagination of the Sphenoid Sinus Mucosa after Endoscopic Endonasal Transsphenoidal Approach and Its Significance

2016

Objective To describe the clinical features of invagination of the sphenoid sinus mucosa (ISM) and compare them with other similar cases using a visual analog scale (VAS) to assess the various nasal symptoms and to discuss its clinical significance and means of prevention. Study design Retrospective chart review at a tertiary referral center. Methods Between 2010 and 2015, 8 patients who had undergone EETSA surgery displayed postoperative ISM. The comparison group consisted of 147 patients who underwent the same surgical procedures and were diagnosed with the same diseases. Pre- or postoperative paranasal sinus computed tomography (PNS CT) and VAS were performed and subsequently analyzed. R…

Image-Guided Synthesis Reveals Potent Blood-Brain Barrier Permeable Histone Deacetylase Inhibitors

2014

Recent studies have revealed that several histone deacetylase (HDAC) inhibitors, which are used to study/treat brain diseases, show low blood-brain barrier (BBB) penetration. In addition to low HDAC potency and selectivity observed, poor brain penetrance may account for the high doses needed to achieve therapeutic efficacy. Here we report the development and evaluation of highly potent and blood-brain barrier permeable HDAC inhibitors for CNS applications based on an image-guided approach involving the parallel synthesis and radiolabeling of a series of compounds based on the benzamide HDAC inhibitor, MS-275 as a template. BBB penetration was optimized by rapid carbon-11 labeling and PET im…

Evaluation of [11C]Metergoline as a PET Radiotracer for 5HTR in Nonhuman Primates

2010

Metergoline, a serotonin receptor antagonist, was labeled with carbon-11 in order to evaluate its pharmacokinetics and distribution in non-human primates using positron emission tomography. [{sup 11}C]Metergoline had moderate brain uptake and exhibited heterogeneous specific binding, which was blocked by pretreatment with metergoline and altanserin throughout the cortex. Non-specific binding and insensitivity to changes in synaptic serotonin limit its potential as a PET radiotracer. However, the characterization of [{sup 11}C]metergoline pharmacokinetics and binding in the brain and peripheral organs using PET improves our understanding of metergoline drug pharmacology.

Reinvestigation of the synthesis and evaluation of [N-methyl-11C]vorozole, a radiotracer targeting cytochrome P450 aromatase

2009

Abstract Introduction We reinvestigated the synthesis of [ N -methyl- 11 C]vorozole, a radiotracer for aromatase, and discovered the presence of an N -methyl isomer which was not removed in the original purification method. Herein we report the preparation and positron emission tomography (PET) studies of pure [ N -methyl- 11 C]vorozole. Methods Norvorozole was alkylated with [ 11 C]methyl iodide as previously described and also with unlabeled methyl iodide. A high-performance liquid chromatography (HPLC) method was developed to separate the regioisomers. Nuclear magnetic resonance (NMR) spectroscopy ( 13 C and 2D-nuclear Overhauser effect spectroscopy NMR) was used to identify and assign s…

Automated GMP production of [11C]PR04.MZ via the captive solvent method and PET studies in non-human primates: A promising tracer for extrastriatal D…

2010

Synthesis of [11C]SSR149415 and preliminary imaging studies using positron emission tomography.

2010

Abstract SSR149415 was the first non-peptide vasopressin-(V1b) receptor antagonist reported. It has been used to probe the role of V1b receptors in animal models of depression, aggression, and stress-anxiety, and was progressed to clinical trials for the treatment of depression. Due to the interest in V1b receptors as a therapeutic target and the growing use of SSR149415 in preclinical research, we developed a method to label SSR145419 with carbon-11 and have studied its pharmacokinetics in non-human primates using positron emission tomography.

Whole-body pharmacokinetics of HDAC inhibitor drugs, butyric acid, valproic acid and 4-phenylbutyric acid measured with carbon-11 labeled analogs by …

2013

The fatty acids, n-butyric acid (BA), 4-phenylbutyric acid (PBA) and valproic acid (VPA, 2-propylpentanoic acid) have been used for many years in the treatment of a variety of CNS and peripheral organ diseases including cancer. New information that these drugs alter epigenetic processes through their inhibition of histone deacetylases (HDACs) has renewed interest in their biodistribution and pharmacokinetics and the relationship of these properties to their therapeutic and side effect profiles. In order to determine the pharmacokinetics and biodistribution of these drugs in primates, we synthesized their carbon-11 labeled analogues and performed dynamic positron emission tomography (PET) in…