Assessment of a white matter reference region for 11C-UCB-J PET quantification

11C-UCB-J is a positron emission tomography (PET) radioligand that has been used in humans for synaptic vesicle glycoprotein 2A (SV2A) imaging and as a potential synaptic density marker. The centrum semiovale (CS) is a proposed reference region for noninvasive quantification of 11C-UCB-J, due to negligible concentrations of SV2A in this region in baboon brain assessed by in vitro methods. However, in displacement scans with SV2A-specific drug levetiracetam in humans, a decrease in 11C-UCB-J concentration was observed in the CS, consistent with some degree of specific binding. The current study aims to validate the CS as a reference region by (1) optimizing CS region of interest (ROI) to minimize spill-in from gray matter with high radioactivity concentrations; (2) investigating convergence of CS ROI values using ordered subset expectation maximization (OS-EM) reconstruction, and (3) comparing baseline CS volume of distribution ( VT) to nondisplaceable uptake in gray matter, VND. Improving ROI definition and increasing OS-EM iterations during reconstruction decreased the difference between CS VT and VND. However, even with these corrections, CS VT overestimated VND by ∼35–40%. These measures showed significant correlation, suggesting that, though biased, the CS may be a useful estimate of nondisplaceable uptake, allowing for noninvasive quantification for SV2A PET.

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Quantification of Ligand PET Studies using a Reference Region with a Displaceable Fraction: Application to Occupancy Studies with [11C]-DASB as an Example

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2011.108 ◽

2011 ◽

Vol 32 (1) ◽

pp. 70-80 ◽

Cited By ~ 21

Author(s):

Federico E Turkheimer ◽

Sudhakar Selvaraj ◽

Rainer Hinz ◽

Venkatesha Murthy ◽

Zubin Bhagwagar ◽

...

Keyword(s):

Specific Binding ◽

Normal Subjects ◽

Volume Of Distribution ◽

Binding Potential ◽

Accurate Estimation ◽

Data Sets ◽

Reference Region ◽

Reference Tissue ◽

Positron Emission ◽

Definition Of

This paper aims to build novel methodology for the use of a reference region with specific binding for the quantification of brain studies with radioligands and positron emission tomography (PET). In particular: (1) we introduce a definition of binding potential BPD = DVR–1 where DVR is the volume of distribution relative to a reference tissue that contains ligand in specifically bound form, (2) we validate a numerical methodology, rank-shaping regularization of exponential spectral analysis (RS-ESA), for the calculation of BPD that can cope with a reference region with specific bound ligand, (3) we demonstrate the use of RS-ESA for the accurate estimation of drug occupancies with the use of correction factors to account for the specific binding in the reference. [11C]-DASB with cerebellum as a reference was chosen as an example to validate the methodology. Two data sets were used; four normal subjects scanned after infusion of citalopram or placebo and further six test—retest data sets. In the drug occupancy study, the use of RS-ESA with cerebellar input plus corrections produced estimates of occupancy very close the ones obtained with plasma input. Test-retest results demonstrated a tight linear relationship between BPD calculated either with plasma or with a reference input and high reproducibility.

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Measuring Drug Occupancy in the Absence of a Reference Region: The Lassen Plot Re-Visited

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2009.190 ◽

2009 ◽

Vol 30 (1) ◽

pp. 46-50 ◽

Cited By ~ 138

Author(s):

Vincent J Cunningham ◽

Eugenii A Rabiner ◽

Mark Slifstein ◽

Marc Laruelle ◽

Roger N Gunn

Keyword(s):

Graphical Method ◽

Quantitative Estimation ◽

Specific Binding ◽

Volume Of Distribution ◽

Distribution Volume ◽

Emission Tomography ◽

Reference Region ◽

Site Specific ◽

Positron Emission ◽

Regional Estimates

Quantitative estimation of neuroreceptor occupancy by exogenous drugs using positron emission tomography is based on the reduction in the total volume of distribution ( VT) of site-specific radioligands after drug administration. An estimate of the distribution volume of free and nonspecifically bound radioligand ( VND) is also required to distinguish specific from total binding. However, a true reference region, devoid of specific binding, is often not available. We present a transformation of a graphical method, originally introduced by Lassen, using regional estimates of VT alone to determine occupancy, together with an extension that does not require baseline data.

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Reference Region Automatic Extraction in Dynamic [11C]PIB

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2013.133 ◽

2013 ◽

Vol 33 (11) ◽

pp. 1725-1731 ◽

Cited By ~ 15

Author(s):

Yoko Ikoma ◽

Paul Edison ◽

Anil Ramlackhansingh ◽

David J Brooks ◽

Federico E Turkheimer

Keyword(s):

Gray Matter ◽

Specific Binding ◽

Amyloid Plaque ◽

Blood Pool ◽

Binding Potential ◽

Automatic Extraction ◽

Reference Region ◽

Supervised Clustering ◽

Plaque Deposition ◽

Positron Emission

The positron emission tomography (PET) radiotracer [11C]Pittsburgh Compound B (PIB) is a marker of amyloid plaque deposition in brain, and binding potential is usually quantified using the cerebellum as a reference where the specific binding is negligible. The use of the cerebellum as a reference, however, has been questioned by the reported cerebellar [11C]PIB retention in familial Alzheimer's disease (AD) subjects. In this work, we developed a supervised clustering procedure for the automatic extraction of a reference region in [11C]PIB studies. Supervised clustering models each gray matter voxel as the linear combination of three predefined kinetic classes, normal and lesion gray matter, and blood pool, and extract reference voxels in which the contribution of the normal gray matter class is high. In the validation with idiopathic AD subjects, supervised clustering extracted reference voxels mostly in the cerebellum that indicated little specific [11C]PIB binding, and total distribution volumes of the extracted region were lower than those of the cerebellum. Next, the methodology was applied to the familial AD cohort where the cerebellar amyloid load had been demonstrated previously, resulting in higher binding potential compared with that obtained with the cerebellar reference. The supervised clustering method is a useful tool for the accurate quantification of [11C]PIB studies.

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On the Role of Transferrin in 67Ga Uptake by Tumor Cells

Nuklearmedizin ◽

10.1055/s-0038-1629447 ◽

1988 ◽

Vol 27 (04) ◽

pp. 151-153

Author(s):

P. Thouvenot ◽

F. Brunotte ◽

J. Robert ◽

L. J. Anghileri

Keyword(s):

Specific Binding ◽

Subcellular Fractionation ◽

Animal Blood ◽

Tumor Bearing ◽

Cell Structures ◽

The Difference ◽

Sarcoma Cells ◽

In Vitro Uptake

In vitro uptake of 67Ga-citrate and 59Fe-citrate by DS sarcoma cells in the presence of tumor-bearing animal blood plasma showed a dramatic inhibition of both 67Ga and 59Fe uptakes: about ii/io of 67Ga and 1/5o of the 59Fe are taken up by the cells. Subcellular fractionation appears to indicate no specific binding to cell structures, and the difference of binding seems to be related to the transferrin chelation and transmembrane transport differences

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The pharmacokinetics of [18F]UCB-H revisited in the healthy non-human primate brain

EJNMMI Research ◽

10.1186/s13550-021-00777-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Sébastien Goutal ◽

Martine Guillermier ◽

Guillaume Becker ◽

Mylène Gaudin ◽

Yann Bramoullé ◽

...

Keyword(s):

Slow Component ◽

Specific Binding ◽

Compartment Model ◽

Brain Regions ◽

Volume Of Distribution ◽

Pharmacokinetic Data ◽

Limited Information ◽

Positron Emission ◽

Human Primate

Abstract Background Positron Emission Tomography (PET) imaging of the Synaptic Vesicle glycoprotein (SV) 2A is a new tool to quantify synaptic density. [18F]UCB-H was one of the first promising SV2A-ligands to be labelled and used in vivo in rodent and human, while limited information on its pharmacokinetic properties is available in the non-human primate. Here, we evaluate the reliability of the three most commonly used modelling approaches for [18F]UCB-H in the non-human cynomolgus primate, adding the coupled fit of the non-displaceable distribution volume (VND) as an alternative approach to improve unstable fit. The results are discussed in the light of the current state of SV2A PET ligands. Results [18F]UCB-H pharmacokinetic data was optimally fitted with a two-compartment model (2TCM), although the model did not always converge (large total volume of distribution (VT) or large uncertainty of the estimate). 2TCM with coupled fit K1/k2 across brain regions stabilized the quantification, and confirmed a lower specific signal of [18F]UCB-H compared to the newest SV2A-ligands. However, the measures of VND and the influx parameter (K1) are similar to what has been reported for other SV2A ligands. These data were reinforced by displacement studies using [19F]UCB-H, demonstrating only 50% displacement of the total [18F]UCB-H signal at maximal occupancy of SV2A. As previously demonstrated in clinical studies, the graphical method of Logan provided a more robust estimate of VT with only a small bias compared to 2TCM. Conclusions Modeling issues with a 2TCM due to a slow component have previously been reported for other SV2A ligands with low specific binding, or after blocking of specific binding. As all SV2A ligands share chemical structural similarities, we hypothesize that this slow binding component is common for all SV2A ligands, but only hampers quantification when specific binding is low.

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Development of 18F-Labeled Radiotracers for PET Imaging of the Adenosine A2A Receptor: Synthesis, Radiolabeling and Preliminary Biological Evaluation

International Journal of Molecular Sciences ◽

10.3390/ijms22052285 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2285

Author(s):

Thu Hang Lai ◽

Susann Schröder ◽

Magali Toussaint ◽

Sladjana Dukić-Stefanović ◽

Mathias Kranz ◽

...

Keyword(s):

Specific Binding ◽

Brain Slices ◽

Total Activity ◽

Biological Evaluation ◽

Adenosine A2a Receptor ◽

Positron Emission ◽

A2a Receptor ◽

Adenosine A2a

The adenosine A2A receptor (A2AR) represents a potential therapeutic target for neurodegenerative diseases. Aiming at the development of a positron emission tomography (PET) radiotracer to monitor changes of receptor density and/or occupancy during the A2AR-tailored therapy, we designed a library of fluorinated analogs based on a recently published lead compound (PPY). Among those, the highly affine 4-fluorobenzyl derivate (PPY1; Ki(hA2AR) = 5.3 nM) and the 2-fluorobenzyl derivate (PPY2; Ki(hA2AR) = 2.1 nM) were chosen for 18F-labeling via an alcohol-enhanced copper-mediated procedure starting from the corresponding boronic acid pinacol ester precursors. Investigations of the metabolic stability of [18F]PPY1 and [18F]PPY2 in CD-1 mice by radio-HPLC analysis revealed parent fractions of more than 76% of total activity in the brain. Specific binding of [18F]PPY2 on mice brain slices was demonstrated by in vitro autoradiography. In vivo PET/magnetic resonance imaging (MRI) studies in CD-1 mice revealed a reasonable high initial brain uptake for both radiotracers, followed by a fast clearance.

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Tumor Uptake of Triazine Dendrimers Decorated with Four, Sixteen, and Sixty-Four PSMA-Targeted Ligands: Passive versus Active Tumor Targeting

Biomolecules ◽

10.3390/biom9090421 ◽

2019 ◽

Vol 9 (9) ◽

pp. 421 ◽

Cited By ~ 3

Author(s):

Jongdoo Lim ◽

Bing Guan ◽

Kien Nham ◽

Guiyang Hao ◽

Xiankai Sun ◽

...

Keyword(s):

Specific Binding ◽

Quantitative Imaging ◽

Molecular Size ◽

Tumor Uptake ◽

Competitive Binding Assay ◽

The Core ◽

Positron Emission ◽

Pentanedioic Acid

Various glutamate urea ligands have displayed high affinities to prostate specific membrane antigen (PSMA), which is highly overexpressed in prostate and other cancer sites. The multivalent versions of small PSMA-targeted molecules are known to be even more efficiently bound to the receptor. Here, we employ a well-known urea-based ligand, 2-[3-(1,3-dicarboxypropyl)-ureido] pentanedioic acid (DUPA) and triazine dendrimers in order to study the effect of molecular size on multivalent targeting in prostate cancer. The synthetic route starts with the preparation of a dichlorotriazine bearing DUPA in 67% overall yield over five steps. This dichlorotriazine reacts with G1, G3, and G5 triazine dendrimers bearing a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) group for 64Cu-labeling at the core to afford poly(monochlorotriazine) intermediates. Addition of 4-aminomethylpiperidine (4-AMP) and the following deprotection produce the target compounds, G1-(DUPA)4, G3-(DUPA)16, and G5-(DUPA)64. These targets include 4/16/64 DUPA groups on the surface and a DOTA group at the core, respectively. In vitro cell assay using PC3-PIP (PSMA positive) and PC3-FLU (PSMA negative) cells reveals that G1-(DUPA)4 has the highest PC3-PIP to PC3-FLU uptake ratio (10-fold) through the PSMA-mediated specific uptake. While G5-(DUPA)64 displayed approximately 12 times higher binding affinity (IC50 23.6 nM) to PC3-PIP cells than G1-(DUPA)4 (IC50 282.3 nM) as evaluated in a competitive binding assay, the G5 dendrimer also showed high non-specific binding to PC3-FLU cells. In vivo uptake of the 64Cu-labeled dendrimers was also evaluated in severe combined inmmunodeficient (SCID) mice bearing PC3-PIP and PC3-FLU xenografts on each shoulder, respectively. Interestingly, quantitative imaging analysis of positron emission tomograph (PET) displayed the lowest tumor uptake in PC3-PIP cells for the midsize dendrimer G3-(DUPA)16 (19.4 kDa) (0.66 ± 0.15%ID/g at 1 h. p.i., 0.64 ± 0.11%ID/g at 4 h. p.i., and 0.67 ± 0.08%ID/g at 24 h. p.i.). Through the specific binding of G1-(DUPA)4 to PSMA, the smallest dendrimer (5.1 kDa) demonstrated the highest PC3-PIP to muscle and PC3-PIP to PC3-FLU uptake ratios (17.7 ± 5.5 and 6.7 ± 3.0 at 4 h p.i., respectively). In addition, the enhanced permeability and retention (EPR) effect appeared to be an overwhelming factor for tumor uptake of the largest dendrimer G5-(DUPA)64 as the uptake was at a similar level irrelevant to the PSMA expression.

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Automated Synthesis of Fluorine-18 Labeled CXCR4 Ligand via the Conjugation with Nicotinic Acid N-Hydroxysuccinimide Ester (6-[18F]SFPy)

Molecules ◽

10.3390/molecules25173924 ◽

2020 ◽

Vol 25 (17) ◽

pp. 3924

Author(s):

Falguni Basuli ◽

Xiang Zhang ◽

Tim E. Phelps ◽

Elaine M. Jagoda ◽

Peter L. Choyke ◽

...

Keyword(s):

Nicotinic Acid ◽

Specific Binding ◽

Automated Synthesis ◽

Bone Marrow Niche ◽

Positron Emission ◽

Straightforward Method ◽

Radiochemical Yields ◽

Chemokine Receptor 4

The C-X-C motif chemokine receptor 4 (CXCR4) is a seven-transmembrane G protein-coupled receptor that is overexpressed in numerous diseases, particularly in various cancers and is a powerful chemokine, attracting cells to the bone marrow niche. Therefore, CXCR4 is an attractive target for imaging and therapeutic purposes. The goal of this study is to develop an efficient, reproducible, and straightforward method to prepare a fluorine-18 labeled CXCR4 ligand. 6-[18F]Fluoronicotinic acid-2,3,5,6-tetrafluorophenyl ester (6-[18F]FPy-TFP) and nicotinic acid N-hydroxysuccinimide ester (6-[18F]SFPy) have been prepared using ‘fluorination on the Sep-Pak’ method. Conjugation of 6-[18F]SFPy or 6-[18F]FPy-TFP with the alpha-amino group at the N terminus of the protected T140 precursor followed by deprotection, yielded the final product 6-[18F]FPy-T140. The overall radiochemical yields were 6–17% (n = 15, decay-corrected) in a 90-min radiolabeling time with a radiochemical purity >99%. 6-[18F]FPy-T140 exhibited high specific binding and nanomolar affinity for CXCR4 in vitro, indicating that the biological activity of the peptide was preserved. For the first time, [18F]SFPy has been prepared using ‘fluorination on the Sep-Pak’ method that allows rapid automated synthesis of 6-[18F]FPy-T140. In addition to increased synthetic efficiency, this construct binds with CXCR4 in high affinity and may have potential as an in vivo positron emission tomography (PET) imaging agent. This radiosynthesis method should encourage wider use of this PET agent to quantify CXCR4 in both research and clinical settings.

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Comparison of pulsed versus continuous convective flow for central nervous system tissue perfusion

Journal of Neurosurgery ◽

10.3171/2012.9.jns12506 ◽

2012 ◽

Vol 117 (6) ◽

pp. 1150-1154 ◽

Cited By ~ 7

Author(s):

Edjah K. Nduom ◽

Stuart Walbridge ◽

Russell R. Lonser

Keyword(s):

White Matter ◽

Continuous Infusion ◽

Gray Matter ◽

Convective Flow ◽

Tissue Injury ◽

Tissue Perfusion ◽

Volume Of Distribution ◽

Histological Evidence ◽

The Mean ◽

The Difference

Object Although pulsatile and continuous infusion paradigms have been described for convective delivery of drugs, the effectiveness and properties of each flow paradigm are unknown. To determine the effectiveness and properties of pulsatile and continuous convective infusion paradigms, the authors compared these convective flow methods in the gray and white matter of primates. Methods Six primates (Macaca mulatta) underwent convective infusion of Gd-DPTA (5 mM) into the cerebral gray matter (thalamus) or white matter (frontal lobe) using pulsed (intermittent pulses of 15 μl/min) or continuous (1 μl/min) convective flow. Results were assessed by clinical MRI and histological analyses. Results Distribution of Gd-DTPA infusate in gray and white matter by pulsed and continuous flow was clearly identified using MRI, which revealed that both convective flow methods demonstrated an increase in the volume of distribution (Vd) with increasing volume of infusion (Vi) in the surrounding gray and white matter. Although the mean (± SD) gray matter Vd:Vi ratio for the pulsed infusions (4.2 ± 0.5) was significantly lower than the mean Vd:Vi ratio for continuous infusions (5.4 ± 0.5; a 22% difference [p = 0.0006]), the difference between pulsed (3.8 ± 0.4) and continuous (4.3 ± 1.2) infusions in white matter was not significantly different (p = 0.3). Pulsed infusions were associated with more leakback (12.3% ± 6.4% of Vi) than continuous infusions (3.9% ± 7.8%), although this difference was not significant (p = 0.2). All animals tolerated the infusions and there was no histological evidence of tissue injury at the infusion sites. Conclusions Although pulsed and continuous infusion flow paradigms can be safely and effectively used for convective delivery into both gray and white matter, continuous infusion is associated with a higher Vd:Vi ratio than pulsatile infusion in gray matter. High rates of infusion (15 μl/min) can be used to deliver infusate without any significant leakback and without any clinical or histological evidence of injury.

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Relationship between CO and transit times for dye and thermal indicators in central circulation

Journal of Applied Physiology ◽

10.1152/jappl.1986.60.4.1363 ◽

1986 ◽

Vol 60 (4) ◽

pp. 1363-1372 ◽

Cited By ~ 19

Author(s):

P. V. Carlile ◽

R. C. Beckett ◽

B. A. Gray

Keyword(s):

Cardiac Tissue ◽

Volume Of Distribution ◽

Right Atrial ◽

Dilution Method ◽

Measuring Instruments ◽

Thermal Indicator ◽

Transit Times ◽

Time Element ◽

The Difference

We investigated two factors that may influence the estimation of lung water by the thermal-dye double-indicator-dilution method: 1) changes in cardiac output (CO), and 2) thermal equilibration with cardiac tissue. In theory, the difference between mean transit times of thermal and dye indicators (delta MTT) is proportional to the extravascular volume of distribution of the thermal indicator (VODev) and inversely related to CO. The delta MTT also includes a time element DT due to the difference in response times of the measuring instruments such that delta MTT = VODev/CO + DT. In nine anesthetized dogs we recorded 286 aortic thermal and dye curves following left atrial (LA) and right atrial (RA) injections as CO was increased from 2.35 to 6.65 ml X s-1 X kg-1 by isoproterenol infusion, and a regression of delta MTT on CO-1 was performed. DT was measured in vitro for comparison with the y-intercept. In six of nine dogs the slope of the regression for LA injections was not different from zero, indicating that there is no measurable volume of distribution for thermal indicator in cardiac tissue. For RA injections the relationship between delta MTT and CO-1 was linear in all experiments, with an average correlation coefficient of 0.97 +/- 0.01 (SE), indicating that the VODev was constant over a threefold increase in CO. Although the in vitro measurement of DT agreed closely with the average of the y-intercepts of the regressions, small between-subject differences in DT can lead to apparent flow-related changes in extravascular thermal volume computed in the conventional fashion using the in vitro estimate of DT.

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