Background:
Major depressive disorder (MDD) may have many underlying causes. One theory is that brain cells with low levels of a molecule called cyclic AMP (cAMP) may cause depression. A drug called ketamine may increase the levels of cAMP in a person's brain cells.
Objective:
To find out if administering ketamine to people with depression affects cAMP levels in their brains.
Eligibility:
People aged 18 to 70 with MDD who are enrolled in another NIH study that uses ketamine.
Design:
Participants will visit the NIH clinic 5 times in up to 6 weeks. Some of the visits may be spread out over more than 1 day.
Participants will be screened. They will have a physical exam with blood and urine tests. They will have a test of their heart function. They will have a psychiatric evaluation. They will answer questions about their family history and mental health.
Participants will have a positron emission tomography (PET) scan. A small amount of a radioactive drug will be injected into a vein in their arm. Participants will lie on a bed that slides in and out of a doughnut-shaped machine that records images of their brains. They will have their heads in a holder to prevent movement. Each scan will last up to 2 hours.
After their first PET scan, participants will receive ketamine in a different study they are enrolled in. Then they will come back for another PET scan with the radioactive drug.
Participants will also have another scan called an MRI. They will lie on a table that slides into a metal tube. They will lie still for up to an hour....

Start Date08 Feb 2023

Sponsor / Collaborator

National Institute of Mental Health

NCT02743377 / CompletedPhase 1/2IIT

PET Imaging of Phosphodiesterase-4 (PDE4) in Brain and Peripheral Organs of Mccune-Albright Syndrome

Background:
McCune-Albright Syndrome (MAS) is a disorder that affects the bones, skin, and some hormone-producing tissues. It is associated with a mutation in a gene. This gene affects enzymes in the brain and body. Researchers want to learn more about one of these enzymes, Phosphodiesterase 4 (PDE4), in people with MAS.
Objective:
To see if people with MAS have higher levels of PDE4 than people without MAS.
Eligibility:
People ages 18 and older who have MAS and participated in protocol 98-D-0145, Screening and Natural History of Patients with Polyostotic Fibrous Dysplasia and the McCune-Albright Syndrome. Healthy adult volunteers are also needed.
Design:
This study requires 1 to 4 outpatient visits to the NIH Clinical Center. Some visits may take place on the same day.
Participants with MAS will be screened with medical history and physical exam. They will have blood and urine tests.
Participants will have a magnetic resonance imaging scan.
Participants will have a full body positron emission tomography (PET) scan. A small amount of a radioactive chemical, [11C](R)-rolipram, will be given through an intravenous tube.
Participants will have a brain PET scan with [11C](R)-rolipram. For this, a thin plastic tube will also be put into an artery at their wrist or elbow crease area.
For the scans, participants will lie on a bed that slides in and out of a scanner. They may wear a plastic mask to hold their head in place. They will have blood drawn.
Participants with MAS will be interviewed about their thinking and mood. They may complete questionnaires about how they feel or think.

Start Date04 Apr 2018

Sponsor / Collaborator

National Institute of Mental Health

NCT00250172 / CompletedPhase 1IIT

PET Whole Body Biodistribution and Test Retest Brain Imaging Studies Using a Phosphodiesterase 4 Inhibitor (R)-[11C]Rolipram

The purpose of this study is to measure a particular protein in the brain called the phosphodiesterase by using the imaging techniques of positron emission tomography (PET) and magnetic resonance imaging (MRI).
...

Start Date31 Oct 2005

Sponsor / Collaborator

National Institute of Mental Health

100 Clinical Results associated with [C-11](R)-rolipram

100 Translational Medicine associated with [C-11](R)-rolipram

100 Patents (Medical) associated with [C-11](R)-rolipram

Literatures (Medical) associated with [C-11](R)-rolipram

05 Feb 2024·Molecular Pharmaceutics

Performance and Sensitivity of [^99mTc]Tc-sestamibi Compared with Positron Emission Tomography Radiotracers to Measure P-glycoprotein Function in the Kidneys and Liver

Article

Author: Pahnke, Jens ; Wanek, Thomas ; Zacher, Anna S. ; Langer, Oliver ; Mairinger, Severin ; Hacker, Marcus ; Hernández-Lozano, Irene ; Zeitlinger, Markus ; Leterrier, Sarah ; Stanek, Johann ; Breyer, Lara ; Tournier, Nicolas

P-glycoprotein (P-gp, encoded in humans by the ABCB1 gene and in rodents by the Abcb1a/b genes) is a membrane transporter that can restrict the intestinal absorption and tissue distribution of many drugs and may also contribute to renal and hepatobiliary drug excretion. The aim of this study was to compare the performance and sensitivity of currently available radiolabeled P-gp substrates for positron emission tomography (PET) with the single-photon emission computed tomography (SPECT) radiotracer [^99mTc]Tc-sestamibi for measuring the P-gp function in the kidneys and liver. Wild-type, heterozygous (Abcb1a/b^(+/-)), and homozygous (Abcb1a/b^(-/-)) Abcb1a/b knockout mice were used as models of different P-gp abundance in excretory organs. Animals underwent either dynamic PET scans after intravenous injection of [¹¹C]N-desmethyl-loperamide, (R)-[¹¹C]verapamil, or [¹¹C]metoclopramide or consecutive static SPECT scans after intravenous injection of [^99mTc]Tc-sestamibi. P-gp in the kidneys and liver of the mouse models was analyzed with immunofluorescence labeling and Western blotting. In the kidneys, Abcb1a/b⁽⁾ mice had intermediate P-gp abundance compared with wild-type and Abcb1a/b^(-/-) mice. Among the four tested radiotracers, renal clearance of radioactivity (CL_urine,kidney) was significantly reduced (-83%) in Abcb1a/b^(-/-) mice only for [^99mTc]Tc-sestamibi. Biliary clearance of radioactivity (CL_bile,liver) was significantly reduced in Abcb1a/b^(-/-) mice for [¹¹C]N-desmethyl-loperamide (-47%), [¹¹C]metoclopramide (-25%), and [^99mTc]Tc-sestamibi (-79%). However, in Abcb1a/b^(+/-) mice, CL_bile,liver was significantly reduced (-47%) only for [^99mTc]Tc-sestamibi. Among the tested radiotracers, [^99mTc]Tc-sestamibi performed best in measuring the P-gp function in the kidneys and liver. Owing to its widespread clinical availability, [^99mTc]Tc-sestamibi represents a promising probe substrate to assess systemic P-gp-mediated drug-drug interactions and to measure renal and hepatic P-gp function under different (patho-)physiological conditions.

01 Jan 2024·Journal of Cerebral Blood Flow & Metabolism

[¹¹C]metoclopramide is a sensitive radiotracer to measure moderate decreases in P-glycoprotein function at the blood-brain barrier

Article

Author: Pahnke, Jens ; Hacker, Marcus ; Zeitlinger, Markus ; Stanek, Johann ; Mairinger, Severin ; Löbsch, Mathilde ; Wanek, Thomas ; Tournier, Nicolas ; Filip, Thomas ; Leterrier, Sarah ; Hernández-Lozano, Irene ; Langer, Oliver

The efflux transporter P-glycoprotein (P-gp) at the blood-brain barrier limits the cerebral uptake of various xenobiotics. To assess the sensitivity of [11C]metoclopramide to measure decreased cerebral P-gp function, we performed [11C]metoclopramide PET scans without (baseline) and with partial P-gp inhibition by tariquidar in wild-type, heterozygous Abcb1a/b(+/−) and homozygous Abcb1a/b(−/−) mice as models with controlled levels of cerebral P-gp expression. Brains were collected to quantify P-gp expression with immunohistochemistry. Brain uptake of [11C]metoclopramide was expressed as the area under the brain time-activity curve (AUCbrain) and compared with data previously obtained with ( R)-[11C]verapamil and [11C] N-desmethyl-loperamide. Abcb1a/b(+/−) mice had intermediate P-gp expression compared to wild-type and Abcb1a/b(−/−) mice. In baseline scans, all three radiotracers were able to discriminate Abcb1a/b(−/−) from wild-type mice (2.5- to 4.6-fold increased AUCbrain, p ≤ 0.0001). However, only [11C]metoclopramide could discriminate Abcb1a/b(+/−) from wild-type mice (1.46-fold increased AUCbrain, p ≤ 0.001). After partial P-gp inhibition, differences in [11C]metoclopramide AUCbrain between Abcb1a/b(+/−) and wild-type mice (1.39-fold, p ≤ 0.001) remained comparable to baseline. There was a negative correlation between baseline [11C]metoclopramide AUCbrain and ex-vivo-measured P-gp immunofluorescence (r = −0.9875, p ≤ 0.0001). Our data suggest that [11C]metoclopramide is a sensitive radiotracer to measure moderate, but (patho-)physiologically relevant decreases in cerebral P-gp function without the need to co-administer a P-gp inhibitor.

01 Apr 2023·European Journal of Pharmaceutical Sciences

Influence of P-glycoprotein on pulmonary disposition of the model substrate [11C]metoclopramide assessed by PET imaging in rats

Article

Author: Tournier, Nicolas ; Stanek, Johann ; Löbsch, Mathilde ; Ehrhardt, Carsten ; Hacker, Marcus ; Mairinger, Severin ; Hernández-Lozano, Irene ; Wanek, Thomas ; Langer, Oliver ; Filip, Thomas ; Zeitlinger, Markus

In the lungs, the membrane transporter P-glycoprotein (P-gp) is expressed in the apical (i.e. lumen-facing) membrane of airway epithelial cells and in the luminal (blood-facing) membrane of pulmonary capillary endothelial cells. To better understand the influence of P-gp on the pulmonary disposition of inhaled P-gp substrate drugs, we measured the intrapulmonary pharmacokinetics of the intratracheally (i.t.) aerosolized model P-gp substrate [¹¹C]metoclopramide in presence and absence of P-gp activity by means of positron emission tomography (PET) imaging in rats. Data were compared to data previously acquired with the model P-gp substrates (R)-[¹¹C]verapamil and [¹¹C]N-desmethyl-loperamide, using the same experimental set-up. Groups of wild-type rats, either untreated or treated with the P-gp inhibitor tariquidar, and Abcb1a/b^(-/-) rats underwent 90-min dynamic PET scans after i.t. aerosolization of [¹¹C]metoclopramide. Lung exposure to [¹¹C]metoclopramide was expressed as the area under the right lung concentration-time curve (AUC_lung). AUC_lung values were significantly higher in Abcb1a/b^(-/-) rats (1.8-fold, p ≤ 0.0001) and in tariquidar-treated wild-type rats (1.6-fold, p ≤ 0.01) than in untreated wild-type rats. This differed from previously obtained results with (R)-[¹¹C]verapamil and [¹¹C]N-desmethyl-loperamide, which showed decreased exposure in the rat lung in absence of P-gp activity. Our results suggest that transepithelial transfer of [¹¹C]metoclopramide was not or only to a small extent affected by P-gp activity, presumably due to the compound's high passive permeability. The increased lung retention of [¹¹C]metoclopramide may be due to decreased P-gp-mediated clearance into the blood in absence of P-gp activity in capillary endothelial cells. The overall effect of P-gp on the lung exposure to inhaled P-gp substrate drugs may, thus, be determined by a balance of opposing effects at the pulmonary epithelium and endothelium.

100 Deals associated with [C-11](R)-rolipram

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Depressive Disorder	Phase 2	US	National Institute of Mental Health	08 Feb 2023
Fibrous Dysplasia, Polyostotic	Phase 2	US	National Institute of Mental Health	04 Apr 2018
Nervous System Diseases	Phase 2	US	National Institute of Mental Health	04 Apr 2018
Brain Diseases	Phase 2	US	National Institute of Mental Health	31 Oct 2005
Mood Disorders	Phase 2	US	National Institute of Mental Health	31 Oct 2005
Unspecified drug dependence	Phase 2	US	National Institute of Mental Health	31 Oct 2005

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02743377 (CTgov)	Phase 1/2	Fibrous Dysplasia, Polyostotic \| Nervous System Diseases	16	11C Rolipram (Healthy Control)	vmzpgrrbem(qlxirgtgny) = xfpyjjzonk ovixpyfqmt (vqvsziahhc, zgfowhxuva - bteiwcroit) View more	-	19 Oct 2020
				11C Rolipram+Roflumilast (Subjects With McCune-Albright Syndrome (MAS))	vmzpgrrbem(qlxirgtgny) = igyfjxkvul ovixpyfqmt (vqvsziahhc, ktprhopidd - gauulemeig) View more
SNMMI2014	Not Applicable	-	-	11 C-( R )-rolipram (Disc1 KO mice)	nvasceiorg(asripzkcaz) = gxgcsueppt pkhvfueggo (uxmutktoab, 31)	-	05 Nov 2014
				11 C-( R )-rolipram (WT mice)	nvasceiorg(asripzkcaz) = wqqwbmovcx pkhvfueggo (uxmutktoab, 15)

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