scholarly journals [11C]5-HTP and microPET are Not Suitable for Pharmacodynamic Studies in the Rodent Brain

2013 ◽  
Vol 34 (1) ◽  
pp. 118-125 ◽  
Author(s):  
Anniek KD Visser ◽  
Nisha K Ramakrishnan ◽  
Antoon TM Willemsen ◽  
Valentina Di Gialleonardo ◽  
Erik FJ de Vries ◽  
...  
Keyword(s):  
Tryptophan Hydroxylase ◽  
Compartment Model ◽  
Study Groups ◽  
Male Rats ◽  
Acid Decarboxylase ◽  
Model Parameters ◽  
Amino Acid Decarboxylase ◽  
Arterial Blood ◽  
Pet Tracer ◽  
Patlak Analysis

The PET tracer [11C]5-hydroxytryptophan ([11C]5-HTP), which is converted to [11C]5-hydroxytryptamine ([11C]5-HT) by aromatic amino acid decarboxylase (AADC), is thought to measure 5-HT synthesis rates. But can we measure these synthesis rates by kinetic modeling of [11C]5-HTP in rat? Male rats were scanned with [11C]5-HTP (60 minutes) after different treatments. Scans included arterial blood sampling and metabolite analysis. 5-HT synthesis rates were calculated by a two-tissue compartment model (2TCM) with irreversible tracer trapping or Patlak analysis. Carbidopa (inhibitor peripheral AADC) dose-dependently increased [11C]5-HTP brain uptake, but did not influence 2TCM parameters. Therefore, 10 mg/kg carbidopa was applied in all subsequent study groups. These groups included treatment with NSD 1015 (general AADC inhibitor) or p-chlorophenylalanine (PCPA, inhibitor of tryptophan hydroxylase, TPH). In addition, the effect of a low-tryptophan (Trp) diet was investigated. NSD 1015 or Trp depletion did not affect any model parameters, but PCPA reduced [11C]5-HTP uptake, and the k3. This was unexpected as NSD 1015 directly inhibits the enzyme converting [11C]5-HTP to [11C]5-HT, suggesting that trapping of radioactivity does not distinguish between parent tracer and its metabolites. As different results have been acquired in monkeys and humans, [11C]5-HTP-PET may be suitable for measuring 5-HT synthesis in primates, but not in rodents.

scholarly journals Kinetic Analysis of 2-[11C]Thymidine PET Imaging Studies of Malignant Brain Tumors: Compartmental Model Investigation and Mathematical Analysis

2002 ◽  
Vol 1 (3) ◽  
pp. 153535002002021
Author(s):  
Joanne M. Wells ◽  
David A. Mankoff ◽  
Mark Muzi ◽  
Finbarr O'Sullivan ◽  
Janet F. Eary ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Brain Tumors ◽  
Cellular Proliferation ◽  
Compartment Model ◽  
Response To Therapy ◽  
Model Parameters ◽  
Normal Brain ◽  
Identifiability Analysis ◽  
Pet Tracer ◽  
Thymidine Transport

2-[11C]Thymidine (TdR), a PET tracer for cellular proliferation, may be advantageous for monitoring brain tumor progression and response to therapy. We previously described and validated a five-compartment model for thymidine incorporation into DNA in somatic tissues, but the effect of the blood–brain barrier on the transport of TdR and its metabolites necessitated further validation before it could be applied to brain tumors. Methods: We investigated the behavior of the model under conditions experienced in the normal brain and brain tumors, performed sensitivity and identifiability analysis to determine the ability of the model to estimate the model parameters, and conducted simulations to determine whether it can distinguish between thymidine transport and retention. Results: Sensitivity and identifiability analysis suggested that the non-CO2 metabolite parameters could be fixed without significantly affecting thymidine parameter estimation. Simulations showed that K1t and KTdR could be estimated accurately ( r = .97 and .98 for estimated vs. true parameters) with standard errors < 15%. The model was able to separate increased transport from increased retention associated with tumor proliferation. Conclusion: Our model adequately describes normal brain and brain tumor kinetics for thymidine and its metabolites, and it can provide an estimate of the rate of cellular proliferation in brain tumors.

scholarly journals Impacts of a newly identified behaviour-altering trematode on its host amphipod: from the level of gene expression to population

Parasitology ◽  
2015 ◽  
Vol 142 (12) ◽  
pp. 1469-1480 ◽  
Author(s):  
YASMIN GULER ◽  
STEPHEN SHORT ◽  
AMAIA GREEN ETXABE ◽  
CHRISTOPHER M. SHERHOD ◽  
PETER KILLE ◽  
...  
Keyword(s):  
Serotonin Receptor ◽  
Tryptophan Hydroxylase ◽  
Parasite Prevalence ◽  
Body Cavity ◽  
The Body ◽  
Trematode Species ◽  
Acid Decarboxylase ◽  
Altered Expression ◽  
Amino Acid Decarboxylase ◽  
Transcriptomic Level

SUMMARYChanges to host behaviour induced by some trematode species, as a means of increased trophic transmission, represents one of the seminal examples of host manipulation by a parasite. The amphipodEchinogammarus marinus (Leach, 1815) is infected with a previously undescribed parasite, with infected individuals displaying positive phototaxic and negative geotaxic behaviour. This study reveals that the unknown parasite encysts in the brain, nerve cord and the body cavity ofE. marinus, and belongs to the Microphallidae family. An 18 month population study revealed that host abundance significantly and negatively correlated with parasite prevalence. Investigation of the trematode's influence at the transcriptomic level revealed genes with putative neurological functions, such as serotonin receptor 1A, an inebriated-like neurotransmitter, tryptophan hydroxylase and amino acid decarboxylase, present consistent altered expression in infected animals. Therefore, this study provides one of the first transcriptomic insights into the neuronal gene pathways altered in amphipods infected with a trematode parasite associated with changes to its host's behaviour and population structure.

Gastrointestinal immunity against tryptophan hydroxylase-1, aromatic L-amino-acid decarboxylase, AIE-75, villin and Paneth cells in APECED

2015 ◽  
Vol 158 (2) ◽  
pp. 212-220 ◽  
Author(s):  
Nicolas Kluger ◽  
Martta Jokinen ◽  
Anu Lintulahti ◽  
Kai Krohn ◽  
Annamari Ranki
Keyword(s):  
Amino Acid ◽  
Tryptophan Hydroxylase ◽  
Paneth Cells ◽  
Acid Decarboxylase ◽  
Amino Acid Decarboxylase

scholarly journals The effects of molar activity on [18F]FDOPA uptake in patients with neuroendocrine tumors

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Gilles N. Stormezand ◽  
Romano S. B. H. Schreuder ◽  
Adrienne H. Brouwers ◽  
Riemer H. J. A. Slart ◽  
Philip H. Elsinga ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Acid Decarboxylase ◽  
New Production ◽  
Physiological Uptake ◽  
Amino Acid Decarboxylase ◽  
Molar Activity ◽  
Pet Tracer ◽  
Tumor Load ◽  
Activity Yield ◽  
The Difference

Abstract Background 6-[18F]fluoro-l-3,4-dihydroxyphenyl alanine ([18F]FDOPA) is a commonly used PET tracer for the detection and staging of neuroendocrine tumors. In neuroendocrine tumors, [18F]FDOPA is decarboxylated to [18F]dopamine via the enzyme amino acid decarboxylase (AADC), leading to increased uptake when there is increased AADC activity. Recently, in our hospital, a new GMP compliant multi-dose production of [18F]FDOPA has been developed, [18F]FDOPA-H, resulting in a higher activity yield, improved molar activity and a lower administered mass than the conventional method ([18F]FDOPA-L). Aims This study aimed to investigate whether the difference in molar activity affects the [18F]FDOPA uptake at physiological sites and in tumor lesions, in patients with NET. It was anticipated that the specific uptake of [18F]FDOPA-H would be equal to or higher than [18F]FDOPA-L. Methods We retrospectively analyzed 49 patients with pathologically confirmed NETs and stable disease who underwent PET scanning using both [18F]FDOPA-H and [18F]FDOPA-L within a time span of 5 years. A total of 98 [18F]FDOPA scans (49 [18F]FDOPA-L and 49 [18F]FDOPA-H with average molar activities of 8 and 107 GBq/mmol) were analyzed. The SUVmean was calculated for physiological organ uptake and SUVmax for tumor lesions in both groups for comparison, and separately in subjects with low tumor load (1–2 lesions) and higher tumor load (3–10 lesions). Results Comparable or slightly higher uptake was demonstrated in various physiological uptake sites in subjects scanned with [18F]FDOPA-H compared to [18F]FDOPA-L, with large overlap being present in the interquartile ranges. Tumor uptake was slightly higher in the [18F]FDOPA-H group with 3–10 lesion (SUVmax 6.83 vs. 5.19, p < 0.001). In the other groups, no significant differences were seen between H and L. Conclusion [18F]FDOPA-H provides a higher activity yield, offering the possibility to scan more patients with one single production. Minor differences were observed in SUV’s, with slight increases in uptake of [18F]FDOPA-H in comparison to [18F]FDOPA-L. This finding is not a concern for clinical practice, but could be of importance when quantifying follow-up scans while introducing new production methods with a higher molar activity of [18F]FDOPA.

scholarly journals Quantification of Cerebral Nicotinic Acetylcholine Receptors by PET Using 2-[18F]Fluoro-A-85380 and the Multiinjection Approach

2007 ◽  
Vol 28 (1) ◽  
pp. 172-189 ◽  
Author(s):  
Jean-Dominique Gallezot ◽  
Michel A Bottlaender ◽  
Jacques Delforge ◽  
Héric Valette ◽  
Wadad Saba ◽  
...  
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Compartment Model ◽  
Input Function ◽  
Graphical Analysis ◽  
Dissociation Rate ◽  
Model Parameters ◽  
Nicotinic Acetylcholine ◽  
Arterial Blood

The multiinjection approach was used to study in vivo interactions between α4β2* nicotinic acetylcholine receptors and 2-[18F]fluoro-A-85380 in baboons. The ligand kinetics was modeled by the usual nonlinear compartment model composed of three compartments (arterial plasma, free and specifically bound ligand in tissue). Arterial blood samples were collected to generate a metabolite-corrected plasma input function. The experimental protocol, which consisted of three injections of labeled or unlabeled ligand, was aiming at identifying all parameters in one experiment. Various parameters, including B'max (the binding sites density) and Kd VR (the apparent in vivo affinity of 2-[18F]fluoro-A-85380) could then be estimated in thalamus and in several receptor-poor regions. B'max estimate was 3.0±0.3 pmol/mL in thalamus, and ranged from 0.25 to 1.58 pmol/ml_ in extrathalamic regions. Although Kd VR could be precisely estimated, the association and dissociation rate constants kon/ VR and koff could not be identified separately. A second protocol was then used to estimate koff more precisely in the thalamus. Having estimated all model parameters, we performed simulations of 2-[18F]fluoro-A-85380 kinetics to test equilibrium hypotheses underlying simplified approaches. These showed that a pseudo-equilibrium is quickly reached between the free and bound compartments, a favorable situation to apply Logan graphical analysis. In contrast, the pseudo-equilibrium between the plasma and free compartments is only reached after several hours. The ratio of radioligand concentration in these two compartments then overestimates the true equilibrium value, an unfavorable situation to estimate distribution volumes from late images after a bolus injection.

scholarly journals Synthesis, transport, and metabolism of serotonin formed from exogenously applied 5-HTP after spinal cord injury in rats

2014 ◽  
Vol 111 (1) ◽  
pp. 145-163 ◽  
Author(s):  
Yaqing Li ◽  
Lisa Li ◽  
Marilee J. Stephens ◽  
Dwight Zenner ◽  
Katherine C. Murray ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Brain Stem ◽  
Tryptophan Hydroxylase ◽  
Acid Decarboxylase ◽  
Amino Acid Decarboxylase ◽  
Cord Injury ◽  
Motoneuron Activity

Spinal cord transection leads to elimination of brain stem-derived monoamine fibers that normally synthesize most of the monoamines in the spinal cord, including serotonin (5-hydroxytryptamine, 5-HT) synthesized from tryptophan by enzymes tryptophan hydroxylase (TPH, synthesizing 5-hydroxytryptophan, 5-HTP) and aromatic l-amino acid decarboxylase (AADC, synthesizing 5-HT from 5-HTP). Here we examine whether spinal cord caudal to transection remains able to manufacture and metabolize 5-HT. Immunolabeling for AADC reveals that, while most AADC is confined to brain stem-derived monoamine fibers in spinal cords from normal rats, caudal to transection AADC is primarily found in blood vessel endothelial cells and pericytes as well as a novel group of neurons (NeuN positive and GFAP negative), all of which strongly upregulate AADC with injury. However, immunolabeling for 5-HT reveals that there is no detectable endogenous 5-HT synthesis in any structure in the spinal cord caudal to a chronic transection, including in AADC-containing vessels and neurons, consistent with a lack of TPH. In contrast, when we applied exogenous 5-HTP (in vitro or in vivo), AADC-containing vessels and neurons synthesized 5-HT, which contributed to increased motoneuron activity and muscle spasms (long-lasting reflexes, LLRs), by acting on 5-HT2receptors (SB206553 sensitive) located on motoneurons (TTX resistant). Blocking monoamine oxidase (MAO) markedly increased the sensitivity of the motoneurons (LLR) to 5-HTP, more than it increased the sensitivity of motoneurons to 5-HT, suggesting that 5-HT synthesized from AADC is largely metabolized in AADC-containing neurons and vessels. In summary, after spinal cord injury AADC is upregulated in vessels, pericytes, and neurons but does not endogenously produce 5-HT, whereas when exogenous 5-HTP is provided AADC does produce functional amounts of 5-HT, some of which is able to escape metabolism by MAO, diffuse out of these AADC-containing cells, and ultimately act on 5-HT receptors on motoneurons.

scholarly journals Autoantibodies to human tryptophan hydroxylase and aromatic L-amino acid decarboxylase

2004 ◽  
pp. 313-321 ◽  
Author(s):  
C Dal Pra ◽  
S Chen ◽  
C Betterle ◽  
R Zanchetta ◽  
V McGrath ◽  
...  
Keyword(s):  
Amino Acid ◽  
Autoimmune Diseases ◽  
Coeliac Disease ◽  
Tryptophan Hydroxylase ◽  
Acid Decarboxylase ◽  
Type I ◽  
Type Ii ◽  
Autoimmune Thyroid ◽  
Amino Acid Decarboxylase

OBJECTIVE: To assess the prevalence of autoantibodies (Abs) to tryptophan hydroxylase (TPH) and aromatic l-amino acid decarboxylase (AADC) in patients with different autoimmune diseases and to analyse their respective epitopes. DESIGN: TPH and AADC Abs were measured in an immunoprecipitation assay using (35)S-labelled full-length and fragments of TPH and AADC. METHODS: Patients with different autoimmune adrenal diseases (n=84), non-adrenal autoimmune diseases (n=37), idiopathic vitiligo (n=8) and 56 healthy blood donors were studied. RESULTS: Fourteen of twenty-three (61%) of patients with autoimmune polyglandular syndrome (APS) type I and 1/34 (3%) of patients with isolated Addison's disease (AD) were positive for TPH Abs. None of the patients with APS type II (n=27), coeliac disease (n=10), autoimmune thyroid disease (AITD) (n=11), type 1 diabetes mellitus (DM) (n=16) or idiopathic vitiligo (n=8) was positive for TPH Abs. AADC Abs were detected in 12/23 (52%) patients with APS type I, in 1/29 (3%) patients with APS type II and 1/34 (3%) patients with isolated AD. None of the patients with coeliac disease, type 1 DM, AITD or idiopathic vitiligo was positive for AADC Abs. TPH Abs were found to interact with the C-terminal amino acids (aa) 308-423, central aa 164-205 and N-terminal aa 1-105 of the TPH molecule. AADC Ab binding epitopes were within the C-terminal aa 382-483, the central aa 243-381 and the N-terminal aa 1-167. CONCLUSIONS: Our study suggests that TPH Abs and AADC Abs react with several different epitopes and that different epitopes are recognized by different sera. The prevalence of TPH Abs and AADC Abs in patients with APS type I in our study is in agreement with previous reports. TPH Abs and AADC Abs were found very rarely in patients with other forms of autoimmune adrenal disease and were not detected in patients with non-adrenal autoimmune diseases.

Sign in / Sign up

Export Citation Format

Share Document