Concise and Scalable Radiosynthesis of (+)-[F]MDL100907 as a Serotonin 5-HT Receptor Antagonist for PET.

5-Hydroxytryptamine (5-HT) receptors play an important role in several psychiatric disorders. In order to investigate the serotonin (5-HT) receptor , reliable syntheses are required for positron emission tomography (PET) 5-HT radioligands. Owing to the excellent properties of [F]MDL100907 for PET, there has been great interest to develop a novel synthetic route for [F]MDL100907.

PET imaging of dopamine transporters and D2/D3 receptors in female monkeys: effects of chronic cocaine self-administration.

Brain imaging studies using positron emission tomography (PET) have shown that long-term cocaine use is associated with lower levels of dopamine (DA) D2/D3 receptors (D2/D3R); less consistent are the effects on DA transporter (DAT) availability. However, most studies have been conducted in male subjects (humans, monkeys, rodents). In this study, we used PET imaging in nine drug-naïve female cynomolgus monkeys to determine if baseline measures of DAT, with [F]FECNT, and D2/D3R availability, with [C]raclopride, in the caudate nucleus, putamen and ventral striatum were associated with rates of cocaine self-administration and if these measures changed during long-term (~13 months) cocaine self-administration and following time-off (3-9 months) from cocaine.

Synthesis and Evaluation of [C]7-Halogen-2-Phenyl Isoindolone Derivatives: Potential PET Radioligands for Imaging of 5-HT Receptors.

The serotonin 5-HT receptor (5-HT R) is abundantly expressed throughout the central nervous system, and involved in a variety of neuroendocrine and neurobehavioral processes. The development of a selective radioligand that will enable imaging and quantification of 5-HT R densities represents a significant technological advancement in understanding both the normal function and pathophysiology of the 5-HT R. Four 7-halogen-2-phenyl isoindolones (7-F, Cl, Br, I) were synthesized and displayed high affinities for 5-HT R and high selectivity over 5-HT and 5-HT .

Synthesis, Radiolabeling, and Biological Evaluation of the -Stereoisomers of 1-Amino-3-(fluoro-F)-4-fluorocyclopentane-1-carboxylic Acid as PET Imaging Agents.

The enantiomeric non-natural cyclic amino acids (3,4)-1-amino-3-fluoro-4-(fluoro-F)cyclopentane-1-carboxylic acid and (3,4)-1-amino-3-fluoro-4-(fluoro-F)cyclopentane-1-carboxylic acid ( ) have been prepared as a racemic mixture in 1.3% decay corrected radiochemical yield and in greater than 99% radiochemical purity. is transported primarily via system L with some transport occurring via system ASC, as assessed in rat 9L gliosarcoma, human U87 ΔEGFR glioblastoma, and human DU145 androgen-independent prostate carcinoma tumor cells.

A Swine Hind Limb Ischemia Model Useful for Testing Peripheral Artery Disease Therapeutics.

Currently, there is no large animal model of sustained limb ischemia suitable for testing novel angiogenic therapeutics for peripheral artery disease (PAD) such as drugs, genes, materials, or cells. We created a large animal model suitable for efficacy assessment of these therapies by testing 3 swine hind limb ischemia (HLI) variations and quantifying vascular perfusion, muscle histology, and limb function. Ligation of the ipsilateral external and bilateral internal iliac arteries produced sustained gait dysfunction compared to isolated external iliac or unilateral external and internal iliac artery ligations.

Synthesis, Radiolabeling, and Biological Evaluation of the Stereoisomers of 1-Amino-3-Fluoro-4-(fluoro-)Cyclopentane-1-Carboxylic Acid as PET Imaging Agents.

The non-natural cyclic amino acids (1,3,4)-1-amino-3-fluoro-4-(fluoro-)cyclopentane-1-carboxylic acid () and (1,3,4)-1-amino-3-fluoro-4-(fluoro-)cyclopentane-1-carboxylic acid () have been prepared in 10 and 1.7% decay corrected radiochemical yield, respectively, and in greater than 99% radiochemical purity. Cell assays in rat 9L gliosarcoma, human U87 ΔEGFR glioblastoma, and human DU145 androgen-independent prostate carcinoma tumor cells indicated that both compounds are substrates for amino acid transport primarily by system L, with some transport taking place via system ASC.

Microglia, inflammation and gut microbiota responses in a progressive monkey model of Parkinson's disease: A case series.

Inflammation has been linked to the development of nonmotor symptoms in Parkinson's disease (PD), which greatly impact patients' quality of life and can often precede motor symptoms. Suitable animal models are critical for our understanding of the mechanisms underlying disease and the associated prodromal disturbances. The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkey model is commonly seen as a "gold standard" model that closely mimics the clinical motor symptoms and the nigrostriatal dopaminergic loss of PD, however MPTP toxicity extends to other nondopaminergic regions.

A benzenesulfonamide derivative as a novel PET radioligand for CXCR4.

CXCR4 is involved in various diseases such as inflammation, tumor growth, and cancer metastasis through the interaction with its natural endogenous ligand, chemokine CXCL12. In an effort to develop imaging probes for CXCR4, we developed a novel small molecule CXCR4-targeted PET agent (compound 5) by combining our established benzenesulfonamide scaffold with a labeling component by virtue of click chemistry. 5 shows nanomolar affinity (IC = 6.

Synthesis and Evaluation of Pyridyloxypyridyl Indole Carboxamides as Potential PET Imaging Agents for 5-HT Receptors.

Nine pyridyloxypyridyl indole carboxamides were synthesized and displayed high affinities for 5-HT receptors and high selectivity over 5-HT and 5-HT. Among them, 6-methyl--[6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinyl]1-indole-3-carboxamide () exhibits the highest 5-HT binding affinity ( = 1.3 nM) and high selectivity over 5-HT (∼1000 times) and 5-HT (∼140 times).

Re(CO)([F]FEDA), a novel F PET renal tracer: Radiosynthesis and preclinical evaluation.

Introduction: Our previous work demonstrated that the Tc renal tracer, Tc(CO)(FEDA) (Tc-1), has a rapid clearance comparable in rats to that of I-OIH, the radioactive gold standard for the measurement of effective renal plasma flow. The uncharged fluoroethyl pendant group of Tc-1 provides a route to the synthesis of a structurally analogous rhenium-tricarbonyl F renal imaging agent, Re(CO)([F]FEDA) (F-1). Our goal was to develop an efficient one-step method for the preparation of F-1 and to compare its pharmacokinetic properties with those of I-OIH in rats.

Radiochemical Synthesis and Evaluation of N-Labeled 5-Aminolevulinic Acid for PET Imaging of Gliomas.

The endogenous amino acid, 5-aminolevulinic acid (5-ALA), has received significant attention as an imaging agent, including ongoing clinical trials for image-guided tumor resection due to its selective uptake and subsequent accumulation of the fluorescent protoporphyrin IX in tumor cells. Based on the widely reported selectivity of 5-ALA, a new positron emission tomography imaging probe was developed by reacting methyl 5-bromolevulinate with [N] ammonia. The radiotracer, [N] 5-ALA, was produced in high radiochemical yield (65%) in 10 min and could be purified using only solid phase cartridges.

In Vitro Metabolic Stability and in Vivo Biodistribution of 3-Methyl-4-furoxancarbaldehyde Using PET Imaging in Rats.

Painful diabetic neuropathy (PDN) is a type of peripheral neuropathic pain that is currently difficult to treat using clinically available analgesics. Recent work suggests a progressive depletion of nitric oxide (NO) in nerve cells may be responsible for the pathobiology of PDN. The nitric oxide donor, 3-methyl-4-furoxancarbaldehyde (PRG150), has been shown to produce dose-dependent analgesia in a rat model of PDN.

Synthesis, binding affinity, radiolabeling, and microPET evaluation of 4-(2-substituted-4-substituted)-8-(dialkylamino)-6-methyl-1-substituted-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-ones as ligands for brain corticotropin-releasing factor type-1 (CRF1) receptors.

Compounds 1-14 were synthesized in a search for high-affinity CRF1 receptor ligands that could be radiolabeled with (11)C or (18)F for use as positron emission tomography (PET) radiotracers. Derivatives of 2 were developed which contained amide N-fluoroalkyl substituents. Compounds [(18)F]24 and [(18)F]25 were found to have appropriate lipophilicities of logP7.

Synthesis, F-18 radiolabeling, and microPET evaluation of 3-(2,4-dichlorophenyl)-N-alkyl-N-fluoroalkyl-2,5-dimethylpyrazolo[1,5-a]pyrimidin-7-amines as ligands of the corticotropin-releasing factor type-1 (CRF1) receptor.

A series of 3-(2,4-dichlorophenyl)-N-alkyl-N-fluoroalkyl-2,5-dimethylpyrazolo[1,5-a]pyrimidin-7-amines were synthesized and evaluated as potential positron emission tomography (PET) tracers for the corticotropin-releasing factor type-1 (CRF1) receptor. Compounds 27, 28, 29, and 30 all displayed high binding affinity (⩽1.2 nM) to the CRF1 receptor when assessed by in vitro competition binding assays at 23 °C, whereas a decrease in affinity (⩾10-fold) was observed with compound 26.

Quantification of dopamine transporter density with [18F]FECNT PET in healthy humans.

Introduction: Fluorine-18 labeled 2β-carbomethoxy-3β-(4-chlorophenyl)-8-(2-fluoroethyl)nortropane ([(18)F]FECNT) binds reversibly to the dopamine transporter (DAT) with high selectivity. [(18)F]FECNT has been used extensively in the quantification of DAT occupancy in non-human primate brain and can distinguish between Parkinson's and healthy controls in humans. The purpose of this work was to develop a compartment model to characterize the kinetics of [(18)F]FECNT for quantification of DAT density in healthy human brain.

An improved synthesis of [11C]MENET via Suzuki coupling with [11C]methyl iodide.

[(11) C]MENET, a promising norepinephrine transporter imaging agent, was prepared by Suzuki cross coupling of 1 mg N-t-Boc pinacolborate precursor with [(11) C]CH3 I in DMF using palladium complex generated in situ from Pd2 (dba)3 and (o-CH3 C6 H4 )3 P together with K2 CO3 as the co-catalyst, followed by deprotection with trifluoroacetic acid. This improved radiolabeling method provided [(11) C]MENET in high radiochemical yield at end of synthesis (EOS, 51 ± 3%, decay-corrected from end of (11) CH3 I synthesis, n = 6), moderate specific activity (1.5-1.

Synthesis of a phenolic precursor and its efficient O-[18F]fluoroethylation with purified no-carrier-added [18F]2-fluoroethyl brosylate as the labeling agent.

[(18)F]2-Fluoroethyl-p-toluenesulfonate also called [(18)F]2-fluoroethyl tosylate has been widely used for labeling radioligands for positron emission tomography (PET). [(18)F]2-Fluoroethyl-4-bromobenzenesulfonate, also called [(18)F]2-fluoroethyl brosylate ([(18)F]F(CH2)2OBs), was used as an alternative radiolabeling agent to prepare [(18)F]FEOHOMADAM, a fluoroethoxy derivative of HOMADAM, by O-fluoroethylating the phenolic precursor. Purified by reverse-phase HPLC, the no-carrier-added [(18)F]F(CH2)2OBs was obtained in an average radiochemical yield (RCY) of 35%.

Investigation of an F-18 oxytocin receptor selective ligand via PET imaging.

The compound 1-(1-(2-(2-(2-fluoroethoxy)-4-(piperidin-4-yloxy)phenyl)acetyl)piperidin-4-yl)-3,4-dihydroquinolin-2(1H)-one (1) was synthesized and positively evaluated in vitro for high potency and selectivity with human oxytocin receptors. The positron emitting analogue, [F-18]1, was synthesized and investigated in vivo via PET imaging using rat and cynomolgus monkey models. PET imaging studies in female Sprague-Dawley rats suggested [F-18]1 reached the brain and accumulated in various regions of the brain, but washed out too rapidly for adequate quantification and localization.

Carbon-11 N-methyl alkylation of L-368,899 and in vivo PET imaging investigations for neural oxytocin receptors.

Compound L-368,899 was successfully alkylated with [(11)C]iodomethane to generate the oxytocin receptor selective (2R)-2-amino-N-((2S)-7,7-dimethyl-1-(((4-(o-tolyl)piperazin-1-yl)sulfonyl)methyl)bicyclo[2.2.1]heptan-2-yl)-N-[(11)C]methyl-3-(methylsulfonyl)propanamide ([(11)C]1) with very high radiochemical purity and high specific activity.

Development of a unique small molecule modulator of CXCR4.

Background: Metastasis, the spread and growth of tumor cells to distant organ sites, represents the most devastating attribute and plays a major role in the morbidity and mortality of cancer. Inflammation is crucial for malignant tumor transformation and survival. Thus, blocking inflammation is expected to serve as an effective cancer treatment.

Neurobiological changes mediating the effects of chronic fluoxetine on cocaine use.

Acute SSRI (selective serotonin reuptake inhibitor) treatment has been shown to attenuate the abuse-related effects of cocaine; however, SSRIs have had limited success in clinical trials for cocaine abuse, possibly due to neurobiological changes that occur during chronic administration. In order to better understand the role of serotonin (5HT) in cocaine abuse and treatment, we examined the effects of chronic treatment with the SSRI fluoxetine at clinically relevant serum concentrations on cocaine-related neurobiology and behavior. Rhesus macaques self-administering cocaine underwent a 6-week dosing regimen with fluoxetine designed to approximate serum concentrations observed in humans.

Synthesis and evaluation of C-11, F-18 and I-125 small molecule radioligands for detecting oxytocin receptors.

Compounds 1-4 were synthesized and investigated for selectivity and potency for the oxytocin receptor (OTR) to determine their viability as radioactive ligands. Binding assays determined 1-4 to have high binding affinity for both the human and rodent OTR and also have high selectivity for the human OTR over human vasopressin V1a receptors (V1aR). Inadequate selectivity for OTR over V1aR was found for rodent receptors in all four compounds.

Simultaneous measurement of extracellular dopamine and dopamine transporter occupancy by cocaine analogs in squirrel monkeys.

Several classes of drugs bind to the dopamine transporter (DAT) with high affinity, but some are weaker positive reinforcers than cocaine, suggesting that affinity for and occupancy of the DAT is not the only determinant of a drug's reinforcing effectiveness. Other factors such as the rate of onset have been positively and strongly correlated with the reinforcing effects of DAT inhibitors in nonhuman primates. In the current studies, we examined the effects of acute systemic administration of cocaine and three cocaine analogs (RTI-150, RTI-177, and RTI-366) on binding to DAT in squirrel monkey brain using positron emission tomography (PET) neuroimaging.