Current Topics in Medicinal Chemistry - Volume 7, Issue 18, 2007

Positron emission tomography (PET) in medicinal chemistry provides a new methodology for drug discovery and molecular imaging. PET has been used for drug research and development by directly assessing both pharmacokinetic and pharmacodynamic events in human and in animals. This issue of Current Topics in Medicinal Chemistry highlights recent developments in the synthesis and application of PET ligands which are of particular importance to pharmaceutical research and molecular imaging. Dr. Mishani from Hadassah Hebrew University (Jerusalem, Israel) describes the PET ligands of the epidermal growth factor receptor (EGFR) for the cancer molecular imaging. Overexpression of the EGFR tyrosine kinase (EGFR-TK) has been demonstrated in numerous human cancers of epithelial origin, and was found to correlate with resistance to treatment and poor prognosis. In this review, the role of EGFR playing in cancer development and therapy is briefly presented, followed by a short review of prominent milestones in the development of EGFR-TK inhibitors. The latter endeavors constitute the fundamental core structure for the development of PET ligands to image the EGFR in vivo. Dr. Furumoto from Tohoku University (Sendai, Japan) reviews the recent advances in the development of amyloid imaging ligands. Excessive amyloid-β (Aβ) deposition in the brain is one of the most crucial events in the early pathological stage of Alzheimer's disease (AD). This review provides an overview of amyloid imaging agents developed until now, and includes: a summary of the fundamental basis and clinical significance of amyloid imaging; lists of binding affinity data for 135 compounds classified into 12 molecular frameworks; a comprehensive discussion of the in vitro and in vivo features of representative Aβ ligands; and a discussion of the current state of clinical evaluation of these amyloid imaging ligands. Dr. Kikuchi from National Institute of Radiological Sciences (Chiba, Japan) describes the development of PET ligands for imaging acetylcholinesterase (AChE) in the cerebral cortex of brain. [11C]MP4A and [11C]MP4P have been developed for clinical studies of the demented disorders including Alzheimer's disease (AD), and these probes have demonstrated not only the reduction of AChE activity in the cerebral cortex of patients with AD but also the inhibitory effects of donepezil and rivastigmine on AChE activity in the brain of AD patients. Following this succession, widely available 18F-labeled analogues of MP4A and MP4P have been developed based on the structure-activity relationships between AChE and piperidinol esters. Dr. Yu from University of Tennessee (Knoxville, TN, USA) describes recent developments of the PET ligands for metabotropic glutamate receptor subtype 5 (mGluR5). MGluR5, a subtype in the group I mGluRs, presents in high density in many brain regions. Investigation of mGluR5 physiological functions under pathologic conditions in patients will be critically important in mGluR5 antagonist's therapy using PET imaging technique. There are eleven mGluR5 imaging PET tracers have been tested in animal studies. This review highlights efforts on the design and development of novel PET ligands for mGluR5 in vivo imaging. Dr. Schou from Karolinska Institute (Stockholm, Sweden) reviews development of radioligands for in vivo imaging of norepinephrine transporter (NET) using PET. The availability of PET ligands for NET may allow researchers to probe the contribution of the NET system to specific brain disorders, such as attention-deficit hyperactivity disorder, substance abuse, AD and Parkinson's disease, and to monitor NET occupancy during treatment with antidepressant drugs. This review summarizes the present status of the development of NET ligands labeled with 11C and 18F. A fluorinated derivative ((S,S)-[18F]FMeNER-D2) of reboxetine has been reported to show better properties over the parent ligand (S,S)-[11C]methylreboxetine for NET.....

Overexpression of the epidermal growth factor receptor tyrosine kinase (EGFR-TK) has been documented in numerous human cancers of epithelial origin, and was found to correlate with resistance to treatment and poor prognosis. Recognizing the central role that this receptor plays in cancer development and progression, various approaches have been developed to target it in order to more specifically eradicate cancer cells. These methods include, among others, low-molecular weight inhibitors of the TK domain that are commonly designed to treat those tumors that overexpress the EGFR. Nevertheless, no currently available assay provides non-invasive, longitudinal and sensitive quantitation of receptor levels in tumors so as to better identify candidate patients for EGFR-targeted therapies. Hence, attempts have been made to develop radiolabeled molecular imaging agents as potential bioprobes to quantitatively monitor treatment efficiency. Such EGFR-targeted bioprobes could not only improve patient selection and treatment monitoring, but also allow a direct delivery of radionuclides for radiotherapy. In this review, the role that EGFR plays in cancer development and therapy is briefly presented, followed by a short review of prominent milestones in the development of EGFR-TK inhibitors. These inhibitors constitute the fundamental core structure for the development of radiolabeled probes to visualize the EGFR in vivo. The considerations that need to be taken into account for the development of such probes will be presented, along with a critical examination on the progress that has been made thus far in the field.

Excessive amyloid-β (Aβ) deposition in the brain is one of the most crucial events in the early pathological stage of Alzheimer's disease (AD). Therefore, Aβ deposits have enough potential to become a useful biomarker for not only an early diagnosis of AD, but also for the assessment of the clinical efficacy of anti-Aβ therapies, if they can be measured non-invasively and reliably in living patients. As a potent candidate technique to measure this biomarker, PET amyloid imaging using a radioligand for Aβ deposits has received much attention. A large number of Aβ ligands have been synthesized and evaluated as candidates for amyloid imaging agents. These can be classified into six categories of derivatives: Congo-red, Thioflavine T, stilbene, vinylbenzoxazole, DDNP, and miscellaneous. Many of these derivatives exhibit high binding affinities to Aβ fibrils (below 20 nM) and some of them also show excellent brain pharmacokinetic profiles. The concept of amyloid imaging is currently being tested in human PET studies using optimized amyloid imaging agents. Despite the small number of subjects, these studies have demonstrated sufficiently promising results. This review article provides an overview of recent advances in the development of amyloid imaging agents, and includes: a summary of the fundamental basis and clinical significance of amyloid imaging; lists of binding affinity data for 135 compounds classified into 12 molecular frameworks; a comprehensive discussion of the in vitro and in vivo features of representative Aβ ligands; and a discussion of the current state of clinical evaluation of these amyloid imaging agents (PIB, SB-13, BF-227, and FDDNP).

Cerebral acetylcholinesterase (AChE) imaging is not only useful for diagnosis of dementia disorders but also for therapeutic monitoring of the effects of cholinesterase (ChE) inhibitors and for decision of the appropriate clinical dosage of newly developed ChE inhibitors. Several ChE inhibitors or the derivatives such as 1,2,3,4-tetrahydro-9-methylaminoacridine (MTHA), donepezil, physostigmine, CP126,998 and 2-fluoro-CP118,954 have been labeled with positron emitters for mapping cerebral AChE by positron emission tomography (PET). When [11C]MTHA or [11C]donepezil was injected in animals, the uptake poorly reflect the regional distribution of AChE in the brain because of high non-specific binding and/or less specific to AChE in vivo in the brain tissue. [11C]physostigmine, [11C]CP126,998 and 2-[18F]fluoro-CP118,954 were distributed corresponding well to the regional AChE activity in animals, and also former two probes were successfully applied to clinical PET trial. The other approach is measuring cerebral AChE activity with radiolabeled acetylcholine analogue substrates. We have developed the principle for measuring cerebral enzyme activity by PET and radiolabeled N-methylpiperidinyl esters for quantitative measurement of cerebral AChE activity. N-[11C]methylipiperidin-4-yl acetate (MP4A) and N-[11C]methylpiperidin-4-yl propionate (MP4P) have been used for clinical studies of other demented disorders including Alzheimer's disease (AD), and the probes have demonstrated not only the reduction of AChE activity in the cerebral cortex of patients with AD but also the inhibitory effects of donepezil and rivastigmine on AChE activity in the brain of AD patients. Following this succession, widely available [18F]-labeled derivatives of MP4A and MP4P have been developed based on the structure-activity relationships between AChE and piperidinol esters.

Glutamate is a major excitatory neurotransmitter in central nervous system (CNS) acting through ionotropic and G-protein coupled metabotropic glutamate receptors. Metabotropic glutamate receptor 5 (mGluR5), a subtype in the group I mGluRs, presents in high density in many brain regions (hippocampus, cortex and olfactory system). Stimulation of mGluR5 leads to the release of calcium from intracellular supplies and protein kinase C activation. Excessive activation of mGluR5 has been associated with psychiatric, neurological and neurodegenerative diseases, including Parkinson's disease, anxiety, depression, schizophrenia, pain, epilepsy, focal and global ischemia diseases. 2-methyl-6-(phenylethynyl)pyridine (MPEP) and 2-methyl-4-(pyridin-3-ylethynyl)thiazole (MTEP) are the first generation of non-competitive mGluR5 antagonists with potent, selective and systemically active properties. They have therapeutic functions in varied diseases. Investigation of mGluR5 physiological functions under pathologic conditions in patients will be critically important in mGluR5 antagonist's therapy using noninvasive positron emission tomography (PET) imaging technique. There are eleven mGluR5 imaging PET tracers have been tested in animal studies. This article highlights efforts on the design and development of novel PET tracers for mGluR5 in vivo imaging.

In the central nervous system (CNS) and in the periphery, specific proteins (transporters) are responsible for the regulation of the synaptic concentrations of the major monoamine neurotransmitters, noradrenaline (NE), serotonin (5-HT) and dopamine (DA). Several reports have shown that the expression of these transporters within the CNS may be altered in patients with certain neurodegenerative or neuropsychiatric disorders. Therefore, in the CNS the monoamine transporters are major targets for existing and developmental drugs. The best known drugs targeting these transporters are the selective 5-HT reuptake inhibitors (SSRIs) (e.g. citalopram, Celexa®) that are most frequently used in the treatment of clinical depression. Selective NE reuptake inhibitors (NRIs) have also found use for the treatment of depression and other conditions such as attention deficit hyperactivity (ADHD) disorder. Given that the NE transporter (NET) is also a binding site for cocaine and drugs of abuse, there is a great need for a probe to assess the densities of NET in vivo by brain imaging with either positron emission tomography (PET) or single photon emission tomography (SPET). PET in particular has the potential to measure NET densities quantitatively and with high resolution in the human brain in vivo. The quality of a PET image depends crucially on the radioligand used in the emission measurement. Commonly used radionuclides in PET radioligands are carbon-11 (t1/2 = 20.4 min) and fluorine-18 (t1/2 = 109.8 min). This review specifically summarizes the present status of the development of 11C- or 18F-labeled ligands as tools for imaging NET in brain with PET in support of neuropsychiatric clinical research and drug development.

Fluorine-18 (18F, β+; 96.7%, T1/2=109.8 min) is of considerable importance for developing positron emission tomography (PET) ligands for imaging receptor, enzyme, gene expression etc. in brain, tumor, myocardium and other regions or organs due to its optimal decay characteristics. To synthesize 18F-labeled PET ligands, reliable labeling techniques inserting 18F into a target molecule are necessary. [18F]Fluoroalkylation is a useful way of introducing 18F into target molecules containing amino, phenol, thiophenol, and amide functional groups. Here, we review the preparation, reactivity and application of [18F]fluoroalkyl agents for the development of 18Flabeled PET ligands in molecular imaging. [18F]Fluoroalkyl agents have been synthesized by reacting [18F]F- with the corresponding alkyl derivatives containing halogen and sulfonate as leaving groups. After the fluorination reaction, the radiolabeled products with relatively low boiling points were distilled from the reaction mixtures, sometimes added by Sep-Pak or gas chromatography separation. The [18F]fluoromethyl agents have high reactivity with nucleophilic substrates, but many [18F]fluoromethylated compounds are in vitro unstable. To increase the efficiency of [18F]fluoroethylation, [18F]FCH2CH2Br, the most frequently used [18F]fluoroethyl agent, was converted into [18F]FCH2CH2I or [18F]FCH2CH2OTf in situ. Most [18F]fluoromethylated ligands were found to be in vivo unstable due to defluorination. Deuterium substitution for the fluoromethyl group reduced defluorination to an extent. A number of [18F]fluoroethylated PET ligands have been developed for animal evaluation and clinical investigation.

An orally bioavailable MC4 antagonist with in vivo efficacy in animal models of cachexia. Cachexia is defined as a loss of weight, muscle atrophy and fatigue coupled with an extreme loss of appetite in an individual not actively attempting to lose weight [1]. Often seen in end-stage cancer, cachexia is often referred to as ‘cancer cachexia’ in this context and physically weakens cancer patients to a state of immobility [1]. Moreover, cancer cachexia significnatly impacts patient's quality of life, diminishes their response to standard chemotherapy and leads to increased rates of morbitiy and mortality [1-3]. Sadly, the currently available treatments for cancer cachexia are not very effective [1-3]. Recently, Chen and co-workers from Neuocrine Biosciences reported (J. Med. Chem. 2007, 50, 5249-5252) on a potential new treatment for cancer cachexia by antagonism of the melanocortin-4 receptor (MC4R) with an orally bioavailble small molecule [3]. The MC4 receptor is a member of the class A G protein-coupled receptor (GPCR) family and there are five subtypes of melanocortin receptors (MC1-5). MC4 is expressed in various regions of the brain, and plays a critical role in regulating feeding behavior and energy homeostatsis in both animals and humans [3]. MC4 agonists have been shown to suppress food intake and reduce body weight in animals, suggesting agonim of MC4 may be a theraputic approach for the treatment of obesity [3]. In contrast, MC4 antagonists have been demonstarted to promote food intake and increase weight gain [3]. After extensive lead optimization efforts, Chen and co-workers identified 1, of 1-{2-[(1S)-(3-dimethylaminopropionyl)amino-2- methylpropyl]-4-methylphenyl}-4-[(2R)-methyl-3-(4-chlorophenyl)- propionyl]piperazine, a potent (MC4 Ki = 2.8 nM, IC50 = 35 nM) and selective (>125-fold selective versus MC1, MC3, MC5) MC4 antagonist [3]. MC4 antagonist 1 possessed excellent aqueous solubility (>33 mg/mL at pH 7 and >71 mg/mL at pH 3), a good metabolic profile (no significant CYP inhibition, not a P-gp substrate (B/A-A/B = 1.9)) and good oral bioavailability (32%) in mice (as well as across species: rat, 43%, dog, 19%, rhesus, 19%). Despite a low to moderate brain/plasma ratio of 0.17 (based on AUCs), MC4 antagonist 1 significantly increased food intake on days 10-12 in Lewis lung carcinoma (LLC) tumor-bearing mice when dosed at either 5 or 20 mg/kg p.o. compared to tumor-bearing vehicle treated animals. Thus, selective antagonism of MC4 with small molecules holds promise as a potential new treatment for patients suffering from cancer cachexia, a truly unmet medical need. REFERENCES [1] www.wikipedia.com search string: cachexia [2] Bossola, M.; Pacceli, F.; Tortorelli, A.; Doglietto, G.B. ‘Cancer cachexia: It's time for more clinical trials’ Ann. Surg. Oncol. 2007, 14, 276-285. [3] Chen, C.; Jiang, W.; Tucci, F.; Tran, J.A.; Fleck, B.A.; Hoare, S.R.; Joppa, M.; Markison, S.; Wen, J.; Sai, Y.; Johns, M.; Madam, A.; Chen, T.; Chen, C.W.; Marinkovic, D.; Arellano, M.; Saunders, J. Foster, A.C. ‘Discovery of 1-{2-[(1S)-(3-dimethylaminopropionyl) amino-2-methylpropyl]-4-methylphenyl}-4-(2R)-methyl-3-(4-chlorophenyl)- propionyl]piperazine as an orally active antagonist of the melanocortin receptor for the potential treatment of cachexia’ J. Med. Chem. 2007, 50, 5249-5252, and references therein.