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¹¹C-Labeling of Aryl Ketones as Candidate Histamine Subtype-3 Receptor PET Radioligands through Pd(0)-Mediated ¹¹C-Carbonylative Coupling.

ABSTRACT: Pd(0)-mediated coupling between iodoarenes, [¹¹C]carbon monoxide and aryltributylstannanes has been used to prepare simple model [¹¹C]aryl ketones. Here, we aimed to label four 2-aminoethylbenzofuran chemotype based molecules ([¹¹C]1-4) in the carbonyl position, as prospective positron emission tomography (PET) radioligands for the histamine subtype 3 receptor (H3R) by adapting this methodology with use of aryltrimethylstannanes. Radiosynthesis was successfully performed on a platform equipped with a mini-autoclave and a liquid handling robotic arm, within a lead-shielded hot-cell. Candidate radioligands were readily formulated in saline containing ethanol (10%, v/v) and ascorbic acid (0.5 mg/10 mL). Yields for preclinical use were in the range of 5-9%, decay-corrected from cyclotron-produced [¹¹C]CO₂ and molar activities were >115 GBq/µmol at end of synthesis. Radiochemical purities exceeded >97%.

SUBMITTER: Simeon FG

PROVIDER: S-EPMC5530730 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Type 1 diabetes mellitus (T1DM) is characterized by a loss of ?-cells in the islets of Langerhans of the pancreas and subsequent deficient insulin secretion in response to hyperglycemia. Development of an in vivo test to measure ?-cell mass (BCM) would greatly enhance the ability to track diabetes therapies. ?-cells and neurologic tissues have common cellular receptors and transporters, therefore, we screened brain radioligands for their ability to identify ?-cells. Methods: We examined a ?-cell gene atlas for endocrine pancreas receptor targets and cross-referenced these targets with brain radioligands that were available at our institution. Twelve healthy control subjects and 2 T1DM subjects underwent dynamic PET/CT scans with 6 tracers. Results: The D2/D3 receptor agonist radioligand 11C-(+)-4-propyl-9-hydroxynaphthoxazine (PHNO) was the only radioligand to demonstrate sustained uptake in the pancreas with high contrast versus abdominal organs such as the kidneys, liver, and spleen, based on the first 30 min of data. Mean SUV from 20 to 30 min demonstrated high uptake of 11C-(+)-PHNO in healthy controls (SUV, 13.8) with a 71% reduction in a T1DM subject with undetectable levels of C-peptide (SUV, 4.0) and a 20% reduction in a T1DM subject with fasting C-peptide level of 0.38 ng/mL (SUV, 11.0). SUV in abdominal organs outside the pancreas did not show measurable differences between the control and T1DM subjects, suggesting that the changes in SUV of 11C-(+)-PHNO may be specific to changes in the pancreas between healthy controls and T1DM subjects. When D3 and D2 antagonists were used in nonhuman primates, specific pancreatic binding (SUVR-1) of 11C-PHNO was reduced by 57% and 38%, respectively. Conclusion:11C-(+)-PHNO is a potential marker of BCM, with 2:1 binding of D3 receptors over D2 receptors. Further in vitro and in vivo studies to establish D2/D3 receptor specificity to ?-cells is warranted to characterize 11C-(+)-PHNO as a candidate for clinical measurement of BCM in healthy control and diabetic subjects.

Project description:BackgroundThe level of expression of cannabinoid receptor type 2 (CB2R) in healthy and diseased brain has not been fully elucidated. Therefore, there is a growing interest to assess the regional expression of CB2R in the brain. Positron emission tomography (PET) is an imaging technique, which allows quantitative monitoring of very low amounts of radiolabelled compounds in living organisms at high temporal and spatial resolution and, thus, has been widely used as a diagnostic tool in nuclear medicine. Here, we report on the radiofluorination of N-aryl-oxadiazolyl-propionamides at two different positions in the lead structure and on the biological evaluation of the potential of the two tracers [18F]1 and [18F]2 as CB2 receptor PET imaging agents.ResultsHigh binding affinity and specificity towards CB2 receptors of the lead structure remained unaffected by the structural changes such as the insertion of the aliphatic and aromatic fluorine in the selected labelling sites of 1 and 2. Aliphatic and aromatic radiofluorinations were optimized, and [18F]1 and [18F]2 were achieved in radiochemical yields of ?30% with radiochemical purities of ?98% and specific activities of 250 to 450 GBq/?mol. Organ distribution studies in female CD1 mice revealed that both radiotracers cross the blood-brain barrier (BBB) but undergo strong peripheral metabolism. At 30 min after injection, unmetabolized [18F]1 and [18F]2 accounted for 60% and 2% as well as 68% and 88% of the total activity in the plasma and brain, respectively. The main radiometabolite of [18F]2 could be identified as the free acid [18F]10, which has no affinity towards the CB1 and CB2 receptors but can cross the BBB.ConclusionsN-aryl-oxadiazolyl-propionamides can successfully be radiolabelled with 18F at different positions. Fluorine substitution at these positions did not affect affinity and specificity towards CB2R. Despite a promising in vitro behavior, a rather rapid peripheral metabolism of [18F]1 and [18F]2 in mice and the generation of brain permeable radiometabolites hamper the application of these radiotracers in vivo. However, it is expected that future synthetic modification aiming at a replacement of metabolically susceptible structural elements of [18F]1 and [18F]2 will help to elucidate the potential of this class of compounds for CB2R PET studies.

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¹¹C-Labeling of Aryl Ketones as Candidate Histamine Subtype-3 Receptor PET Radioligands through Pd(0)-Mediated ¹¹C-Carbonylative Coupling.

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11C-Labeling of Aryl Ketones as Candidate Histamine Subtype-3 Receptor PET Radioligands through Pd(0)-Mediated 11C-Carbonylative Coupling.

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¹¹C-Labeling of Aryl Ketones as Candidate Histamine Subtype-3 Receptor PET Radioligands through Pd(0)-Mediated ¹¹C-Carbonylative Coupling.