Multimodality imaging probe for positron emission tomography and fluorescence imaging studies.

Our goal is to develop multimodality imaging agents for use in cell tracking studies by positron emission tomography (PET) and optical imaging (OI). For this purpose, bovine serum albumin (BSA) was complexed with biotin (histologic studies), 5(6)-carboxyfluorescein, succinimidyl ester (FAM SE) (OI studies), and diethylenetriamine pentaacetic acid (DTPA) for chelating gallium 68 (PET studies). For synthesis of BSA-biotin-FAM-DTPA, BSA was coupled to (+)-biotin N-hydroxysuccinimide ester (biotin-NHSI).

Initial characterization of a PDE10A selective positron emission tomography tracer [11C]AMG 7980 in non-human primates.

Introduction: Phosphodiesterase 10A (PDE10A) is an intracellular enzyme responsible for the breakdown of cyclic nucleotides which are important secondary messengers in the central nervous system. Inhibition of PDE10A has been identified as a potential therapeutic target for treatment of various neuropsychiatric disorders. To assist the drug development program, we have identified a selective PDE10A PET tracer, [(11)C]AMG 7980, for imaging PDE10A distribution using positron emission tomography.

Imaging P-glycoprotein function in rats using [(11)C]-N-desmethyl-loperamide.

Objective: One mechanism that may be responsible for drug resistance in epilepsy is the upregulation of P-glycoprotein (P-gp), a drug efflux pump, at the epileptogenic focus. In this study, we sought to evaluate the potential of a recently developed P-gp PET radiotracer, [(11)C]N-desmethyl-loperamide ([(11)C]dLop), for measuring P-gp function in the rat brain.

Methods: The precursor to [(11)C]dLop was synthesized in two steps from commercially available starting materials and subsequently radiolabeled in one step using [(11)C]methyl iodide.

Nicotinic α4β2 receptor imaging agents. Part IV. Synthesis and biological evaluation of 3-(2-(S)-3,4-dehydropyrrolinyl methoxy)-5-(3'-¹⁸F-fluoropropyl)pyridine (¹⁸F-Nifrolene) using PET.

Imaging agents for nicotinic α4β2 receptors in the brain have been under way for studying various CNS disorders. Previous studies from our laboratories have reported the successful development of agonist, ¹⁸F-nifene. In attempts to develop potential antagonists, ¹⁸F-nifrolidine and ¹⁸F-nifzetidine were previously reported.

Evaluation of F-nifene binding to α4β2 nicotinic receptors in the rat brain using microPET imaging.

MicroPET imaging studies using (18)F-nifene, a new positron emission tomography (PET) radiotracer for nicotinic acetylcholinergic receptors (nAChR) α4β2 receptors in rats, have been carried out. Rats were imaged for 90 min after intravenous injection of (18)F-nifene (0.8 to 1 mCi), and binding potential (BP(ND)) was measured.

Nicotinic α4β2 receptor imaging agents. Part III. Synthesis and biological evaluation of 3-(2-(S)-azetidinylmethoxy)-5-(3'-18F-fluoropropyl)pyridine (18F-nifzetidine).

Thalamic and extrathalamic nicotinic α4β2 receptors found in the brain have been implicated in Alzheimer's disease, Parkinson's disease, substance abuse and other disorders. We report here the development of 3-(2-(S)-azetidinylmethoxy)-5-(3'-fluoropropyl)pyridine (nifzetidine) as a new putative high-affinity antagonist for nicotinic α4β2 receptors. Nifzetidine in rat brain homogenate assays containing α4β2 sites labeled with (3)H-cytisine exhibited a binding affinity: Ki=0.

Characterization of in vivo pharmacological properties and sensitivity to endogenous serotonin of [11C] P943: a positron emission tomography study in Papio anubis.

[11 C] P943 is a recently developed PET radiotracer for serotonin 5-HT1B receptors. We characterized a number of its in vivo pharmacokinetic properties, including the evaluation of its two stereo-isomers, saturability of specific binding, selectivity for 5-HT1B and 5-HT1D receptors, and vulnerability to pharmacologically induced increases in endogenous 5-HT levels. Six isoflurane-anesthetized baboons were scanned with [11 C] P943 at baseline, and following various pharmacological manipulations.

Imaging changes in glutamate transmission in vivo with the metabotropic glutamate receptor 5 tracer [11C] ABP688 and N-acetylcysteine challenge.

Background: An imaging method to probe glutamate levels in vivo would allow the study of glutamate transmission in disease states and in response to therapeutic interventions. Here we demonstrate the feasibility of this approach for the first time using positron emission tomography and [(11)C] ABP688, a radiotracer for an allosteric site on the metabotropic glutamate receptor 5.

Methods: We conducted two sets of experiments in anesthetized baboons: test and retest without pharmacologic challenge and in combination with N-acetylcysteine (NAC), a promoter of the cystine-glutamate antiporter that increases extrasynaptic glutamate release.

In vivo binding of antipsychotics to D3 and D2 receptors: a PET study in baboons with [11C]-(+)-PHNO.

Measuring the in vivo occupancy of antipsychotic drugs at dopamine D(2) and D(3) receptors separately has been difficult because of the lack of selective radiotracers. The recently developed [(11)C]-(+)-PHNO is D(3)-preferring, allowing estimates of the relative D(2) and D(3) binding of antipsychotic drugs. We used positron emission tomography (PET) imaging in baboons with [(11)C]-(+)-PHNO to examine the binding of clozapine and haloperidol to D(2) and D(3) receptors.