Delving into the Latest Updates on 18F-THK-5317 with Synapse

Overview

Basic Info

Drug Type

Chemical drugs, Radiopharmaceuticals and diagnostic agent

Synonyms-

Target

TAU

Action

modulators

Mechanism

TAU modulators(Microtubule-associated protein tau modulators)

Therapeutic Areas

Nervous System Diseases

Active Indication

Alzheimer Disease

Inactive Indication-

Originator Organization

Uppsala University Hospital

Active Organization

Uppsala University Hospital

Inactive Organization-

License Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Female and male rats (n = 11-12) were cannulated via the femoral artery for continuous blood sampling. Blood sampling was performed at regular intervals after intravenous injection of [¹⁸F]THK-5317. After collection of the last blood sample, animals were sacrificed, and organs were excised. Blood from minute 5, 20 and 60 was centrifuged to obtain plasma. Radiolabeled metabolites in plasma, brain, liver and urine were analyzed by radio-thin-layer chromatography (radio-TLC).

RESULTS:

Plasma pharmacokinetics and metabolism were significantly different between female and male rats. [¹⁸F]THK-5317 plasma clearance was faster in female (0.66 ± 0.08 mL/h/kg BW) than in male (0.52 ± 0.11 mL/h/kg BW) rats (p = .005). The percentage of unmetabolized parent was significantly different between both sexes at 20 min and 60 min p.i. In the liver, a 1.6-fold higher radioactivity concentration was found in male versus female animals and in addition also the percentage of unmetabolized parent was different.

CONCLUSION:

Our results show pronounced sex differences in blood/plasma pharmacokinetics and metabolism of [¹⁸F]THK-5317 in rats. Female animals showed a faster plasma clearance compared to males. These results underline the importance of investigating both sexes and also support the notion that individual input functions or sex-specific population-based input functions are needed for kinetic modeling analyses.

ADVANCES IN KNOWLEDGE:

First preclinical study in rats showing pronounced sex differences in blood/plasma pharmacokinetics and metabolism of [¹⁸F]THK-5317.

IMPLICATIONS FOR PATIENT CARE:

Sex-specific differences might also be present in humans and thus clinical trials should have adequate sample size to account for effects in men and women separately.

01 Apr 2016·Journal of nuclear medicine : official publication, Society of Nuclear MedicineQ1 · MEDICINE

Tracer Kinetic Analysis of (S)-¹⁸F-THK5117 as a PET Tracer for Assessing Tau Pathology

Q1 · MEDICINE

Article

Author: Anders Wall ; Agneta Nordberg ; Jonas Eriksson ; Alf Thibblin ; Konstantinos Chiotis ; Jens Sörensen ; Laure Saint-Aubert ; Mark Lubberink ; Helena Wilking ; Beatrice Borg ; Margareta Sprycha ; My Jonasson ; Gunnar Antoni

METHODS:

Nine subjects (5 with AD, 4 with mild cognitive impairment) received a 90-min dynamic (S)-(18)F-THK5117 PET scan. Arterial blood was sampled for measurement of blood radioactivity and metabolite analysis. Volume-of-interest (VOI)-based analysis was performed using plasma-input models; single-tissue and 2-tissue (2TCM) compartment models and plasma-input Logan and reference tissue models; and simplified reference tissue model (SRTM), reference Logan, and SUV ratio (SUVr). Cerebellum gray matter was used as the reference region. Voxel-level analysis was performed using basis function implementations of SRTM, reference Logan, and SUVr. Regionally averaged voxel values were compared with VOI-based values from the optimal reference tissue model, and simulations were made to assess accuracy and precision. In addition to 90 min, initial 40- and 60-min data were analyzed.

RESULTS:

Plasma-input Logan distribution volume ratio (DVR)-1 values agreed well with 2TCM DVR-1 values (R(2)= 0.99, slope = 0.96). SRTM binding potential (BP(ND)) and reference Logan DVR-1 values were highly correlated with plasma-input Logan DVR-1 (R(2)= 1.00, slope ≈ 1.00) whereas SUVr(70-90)-1 values correlated less well and overestimated binding. Agreement between parametric methods and SRTM was best for reference Logan (R(2)= 0.99, slope = 1.03). SUVr(70-90)-1 values were almost 3 times higher than BP(ND) values in white matter and 1.5 times higher in gray matter. Simulations showed poorer accuracy and precision for SUVr(70-90)-1 values than for the other reference methods. SRTM BP(ND) and reference Logan DVR-1 values were not affected by a shorter scan duration of 60 min.

CONCLUSION:

SRTM BP(ND) and reference Logan DVR-1 values were highly correlated with plasma-input Logan DVR-1 values. VOI-based data analyses indicated robust results for scan durations of 60 min. Reference Logan generated quantitative (S)-(18)F-THK5117 DVR-1 parametric images with the greatest accuracy and precision and with a much lower white-matter signal than seen with SUVr(70-90)-1 images.

100 Deals associated with 18F-THK-5317

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