Publications (18) View all
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Article: Ex vivo imaging of pancreatic beta cells using a radiolabeled GLP-1 receptor agonist.
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ABSTRACT: The purpose of this study was to evaluate the binding specificity of the radiolabeled glucagon-like peptide 1 receptor (GLP-1R) agonist (Lys⁴⁰(DOTA)NH₂)Exendin-4 in the pancreas using a combination of ex vivo autoradiography and immunohistochemistry. Sprague-Dawley rats were administered [⁶⁴Cu](Lys⁴⁰(DOTA)NH₂)Exendin-4 i.v. with or without unlabeled Exendin (9-39) to determine binding specificity. Similar experiments were performed using Zucker diabetic fatty (ZDF) and Zucker lean (ZLC) rats. Animals were euthanized and the pancreas was extracted, immediately frozen, and sectioned. The sections were apposed to phosphor imaging plates, scanned, and immunostained for insulin. Co-registration of the autoradiographic and immunohistochemical images revealed that [⁶⁴Cu] (Lys⁴⁰(DOTA)NH₂)Exendin-4 specific binding was restricted to islet cells. This binding was blocked by the co-administration of Exendin(9-39) indicating that the radiotracer uptake is mediated by GLP-1R. Uptake of [⁶⁴Cu](Lys⁴⁰(DOTA)NH₂)Exendin-4 was greatly decreased in the pancreas of ZDF rats. Ex vivo autoradiography results using [⁶⁴Cu](Lys⁴⁰(DOTA)NH₂)Exendin-4 suggest that GLP-1R agonists based on Exendin-4 are attractive PET ligands for the in vivo determination of β-cell mass.Molecular imaging and biology: MIB: the official publication of the Academy of Molecular Imaging 03/2011; 14(1):79-87. · 2.47 Impact Factor -
Article: Comparison of the in vivo distribution of four different annexin a5 adducts in rhesus monkeys.
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ABSTRACT: Annexin A5 has been used for the detection of apoptotic cells, due to its ability to bind to phosphatidylserine (PS). Four different labeled Annexin A5 adducts were evaluated in rhesus monkey, with radiolabeling achieved via 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). Of these adducts differing conjugation methods were employed which resulted in nonspecific radiolabeling (AxA5-I), or site-specific radiolabeling (AxA5-II). A nonbinding variant of Annexin A5 was also evaluated (AxA5-II(NBV)), conjugation here was site specific. The fourth adduct examined had both specific and nonspecific conjugation techniques employed (AxA5-II(mDOTA)). Blood clearance for each adduct was comparable, while appreciable uptake was observed in kidney, liver, and spleen. Significant differences in uptake of AxA5-I and AxA5-II were observed, as well as between AxA5-II and AxA5-II(NBV). No difference between AxA5-II and AxA5-II(mDOTA) was observed, suggesting that conjugating DOTA nonspecifically did not affect the in vivo biodistribution of Annexin A5.International journal of molecular imaging. 01/2011; 2011:405840. -
Article: [18F]Fluoroazabenzoxazoles as potential amyloid plaque PET tracers: synthesis and in vivo evaluation in rhesus monkey.
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ABSTRACT: An (18)F-labeled positron emission tomography (PET) tracer for amyloid plaque is desirable for early diagnosis of Alzheimer's disease, particularly to enable preventative treatment once effective therapeutics are available. Similarly, such a tracer would be useful as a biomarker for enrollment of patients in clinical trials for evaluation of antiamyloid therapeutics. Furthermore, changes in the level of plaque burden as quantified by an amyloid plaque PET tracer may provide valuable insights into the effectiveness of amyloid-targeted therapeutics. This work describes our approach to evaluate and select a candidate PET tracer for in vivo quantification of human amyloid plaque. Ligands were evaluated for their in vitro binding to human amyloid plaques, lipophilicity and predicted blood-brain barrier permeability. Candidates with favorable in vitro properties were radiolabeled with (18)F and evaluated in vivo. Baseline PET scans in rhesus monkey were conducted to evaluate the regional distribution and kinetics of each tracer using tracer kinetic modeling methods. High binding potential in cerebral white matter and cortical grey matter was considered an unfavorable feature of the candidate tracers. [(18)F]MK-3328 showed the most favorable combination of low in vivo binding potential in white matter and cortical grey matter in rhesus monkeys, low lipophilicity (Log D=2.91) and high affinity for human amyloid plaques (IC(50)=10.5±1.3 nM). [(18)F]MK-3328 was identified as a promising PET tracer for in vivo quantification of amyloid plaques, and further evaluation in humans is warranted.Nuclear Medicine and Biology 07/2011; 38(8):1193-203. · 3.02 Impact Factor -
Article: Synthesis, characterization, and monkey PET studies of [¹⁸F]MK-1312, a PET tracer for quantification of mGluR1 receptor occupancy by MK-5435.
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ABSTRACT: Two moderately lipophilic, high affinity ligands for metabotropic glutamate receptor subtype 1 (mGluR1) were radiolabeled with a positron-emitting radioisotope and evaluated in rhesus monkey as potential PET tracers. Both ligands were radiolabeled with fluorine-18 via nucleophilic displacement of the corresponding 2-chloropyridine precursor with [¹⁸F]potassium fluoride. [¹⁸F]MK-1312 was found to have a suitable signal for quantification of mGluR1 receptors in nonhuman primates and was more thoroughly characterized. In vitro autoradiographic studies with [¹⁸F]MK-1312 in rhesus monkey and human brain tissue slices revealed an uptake distribution consistent with the known distribution of mGluR1, with the highest uptake in the cerebellum, moderate uptake in the hippocampus, thalamus, and cortical regions, and lowest uptake in the caudate and putamen. In vitro saturation binding studies in rhesus monkey and human cerebellum homogenates confirmed that [¹⁸F]MK-1312 binds to a single site with a B(max) /K(d) ratio of 132 and 98, respectively. PET studies in rhesus monkey with [¹⁸F]MK-1312 showed high brain uptake and a regional distribution consistent with in vitro autoradiography results. Blockade of [¹⁸F]MK-1312 uptake with mGluR1 allosteric antagonist MK-5435 dose-dependently reduced tracer uptake in all regions of gray matter to a similarly low level of tracer uptake. This revealed a large specific signal useful for determination of mGluR1 receptor occupancy in rhesus monkey. Taken together, these results are promising for clinical PET studies with [¹⁸F]MK-1312 to determine mGluR1 occupancy of MK-5435.Synapse 02/2011; 65(2):125-35. · 2.94 Impact Factor -
Article: Biodistribution and radiation dosimetry of the hypoxia marker 18F-HX4 in monkeys and humans determined by using whole-body PET/CT.
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ABSTRACT: F-HX4 is a novel positron emission tomography (PET) tracer for imaging hypoxia. The purpose of this study was to determine the biodistribution and estimate the radiation dose of F-HX4 using whole-body PET/computed tomography (CT) scans in monkeys and humans. Successive whole-body PET/CT scans were done after the injection of F-HX4 in four healthy humans (422±142 MBq) and in three rhesus monkeys (189±3 MBq). Biodistribution was determined from PET images and organ doses were estimated using OLINDA/EXM software. The bladder, liver, and kidneys showed the highest percentage of the injected radioactivity for humans and monkeys. For humans, approximately 45% of the activity is eliminated by bladder voiding in 3.6 h, and for monkeys 60% is in the bladder content after 3 h. The critical organ is the urinary bladder wall with the highest absorbed radiation dose of 415±18 (monkeys) and 299±38 μGy/MBq (humans), in the 4.8-h bladder voiding interval model. The average value of effective dose for the adult male was estimated at 42±4.2 μSv/MBq from monkey data and 27±2 μSv/MBq from human data. Bladder, kidneys, and liver have the highest uptake of injected F-HX4 activity for both monkeys and humans. The urinary bladder wall receives the highest dose of F-HX4 and is the critical organ. Thus, patients should be encouraged to maintain adequate hydration and void frequently. The effective dose of F-HX4 is comparable with that of other F-based imaging agents.Nuclear Medicine Communications 12/2010; 31(12):1016-24. · 1.40 Impact Factor
