INTRODUCTION:

Although flortaucipir F-18 displays low levels of background binding throughout the brain, it does display off-target binding to monoamine oxidase MAO-A and MAO-B, as well as to regions containing high levels of melanin, neuromelanin, and iron It was approved by the FDA on May 28, 2020, for sale by Avid Radiopharmaceuticals under the name TAUVID™ and is the first FDA-approved molecule for imaging aggregated tau protein in the brain.

Flortaucipir (¹⁸F), sold under the brand name Tauvid, is a radioactive diagnostic agent indicated for use with positron emission tomography (PET) imaging to image the brain. The most common adverse reactions include headache, injection site pain and increased blood pressure. Two proteins–tau and amyloid – are recognized as hallmarks of Alzheimer's disease. In people with Alzheimer's disease, pathological forms of tau proteins develop inside neurons in the brain, creating neurofibrillary tangles. After flortaucipir (¹⁸F) is administered intravenously, it binds to sites in the brain associated with this tau protein misfolding. The brain can then be imaged with a PET scan to help identify the presence of tau pathology^[1,2,3]

Structure

IUPAC Name:

2-(¹⁸F)fluoro-5-{5H-pyrido[4,3-b]indol-7-yl}pyridine

Indication:

Flortaucipir F-18 is a radioactive agent indicated for positron emission tomography (PET) imaging of aggregated tau neurofibrillary tangles (NFTs) in adult patients under evaluation for Alzheimer's disease. Flortaucipir F-18 is not indicated for use in patients under evaluation for chronic traumatic encephalopathy. ^[2,3]

Pharmacodynamics:

Flortaucipir F-18 is a radioactive molecule that binds to and accumulates in tau NFT deposits allowing for imaging detection; however, non-specific binding and other factors allow for the possibility of misdiagnosis. As Flortaucipir F-18 is a radioactive substance, standard precautionary measures for protecting both patients and health care workers are advised. The safety and efficacy of flortaucipir F-18 in patients being evaluated for chronic traumatic encephalopathy are unknown and hence is not recommended.^[2,3]

Mechanism of action:

Alzheimer's disease is a progressive neurodegenerative disease characterized by the build-up of hyperphosphorylated tau protein aggregates. Hyperphosphorylated tau forms dimers termed paired helical filaments (PHFs), which aggregate further to form neurofibrillary tangles (NFTs) associated with neurodegeneration and severity of Alzheimer's symptoms.

Flortaucipir F-18 is a small molecule that contains radioactive ¹⁸F, which decays by positron emission to ¹⁸O with a half-life of 109.8 minutes. As a small relatively lipophilic molecule, flortaucipir F-18, following intravenous injection, quickly passes through systemic circulation, crosses the blood-brain barrier, and binds to NFTs. Once bound, the ensuing radioactive decay emits pairs of 511 keV gamma photons useful in diagnostic imaging. The pattern and intensity of emission during imaging is used in the diagnosis of Alzheimer's disease^[1,2,3]

Absorption

Flortaucipir F-18 is administered as an intravenous bolus injection, and peak brain uptake in mice of 4.16% ID/g is achieved by 2 minutes. Fast transfer from the peripheral circulation to the brain was corroborated by human studies that demonstrated peak SUV in gray matter >2 across subjects approximately 5 minutes after administration.

Pharmacokinetic studies in humans suggest that equilibrium is achieved by 55 minutes (Logan DVR) and by 80 - 100 minutes (SUVR), and current guidelines recommend initiating imaging approximately 80 minutes after initial administration^[4.5]

Volume of distribution:

Flortaucipir F-18 injected into mice accumulates primarily in the kidneys (14.99±0.39 %ID/g at five minutes and 5.52±0.91% ID/g at 30 minutes post-injection) and liver (4.44±0.16/5.99±0.42 %ID/g at five/30 minutes, respectively). It is able to cross the blood-brain barrier, with relatively high penetration early (4.43±0.91 %ID/g at five minutes) and low residual penetration later (0.62±0.06 %ID/g at 30 minutes). Detectable amounts of Flortaucipir F-18 are found in the systemic circulation, as well as in muscle and bone.^[1,2,3]

Metabolism:

Initial studies in mice described the parent compound and four uncharacterized metabolites, one of which, termed metabolite 1, is presumed to be [¹⁸F] fluoride. Plasma radioactivity corresponded only to the parent compound and metabolite 1. All metabolites were detected in the liver while all metabolites except metabolite 2 were found in the kidneys.^[2,3]

Route of elimination:

The major route of elimination for Flortaucipir F-18 is via the kidneys

Half life

Flortaucipir F-18 plasma half-life was calculated at 17.0 ± 4.2 minutes; correction for metabolite half-life yielded a biexponential distribution with half-lives of 18.1±5.8 and 2.4±0.5 minutes.^[4,5]

Toxicity

Toxicity information regarding Flortaucipir F-18 is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as headaches and increased blood pressure. Symptomatic and supportive measures are recommended.^[6,7,8]

Uses:

Flortaucipir (¹⁸F) is a radioactive diagnostic agent for adults with cognitive impairment who are being evaluated for Alzheimer's disease. It is indicated for positron emission tomography (PET) imaging of the brain to estimate the density and distribution of aggregated tau neurofibrillary tangles (NFTs), a primary marker of Alzheimer's disease

Flortaucipir (¹⁸F) is not indicated for use in the evaluation of people for chronic traumatic encephalopathy (CTE).^[4,5,7,8]

Categories:

ContrastMedia, Compounds used in a research, industrial, or household setting Diagnostic Uses of Chemicals.^[4,5,6,7]

Experimental Properties:

Property	Value
logP	1.67
Predicted Properties
Property	Value
Water Solubility	0.0111 mg/mL
logP	3.52
pKa (Strongest Acidic)	13.03
pKa (Strongest Basic)	8.13
Polar Surface Area	41.57 Å²
Bioavailability	1

CONCLUSION:

Flortaucipir F-18, also known as ¹⁸F-T807 and ¹⁸F-AV-1451, is a small indole molecule synthesized with a radioactive fluorine isotope. It is used as a marker in positron emission tomography (PET) imaging of patients suspected of having Alzheimer's disease. After crossing the blood-brain barrier, flortaucipir F-18 binds to aggregated tau protein, a hallmark of Alzheimer's disease whose incidence correlates well with disease progression. Although flortaucipir F-18 displays low levels of background binding throughout the brain, it does display off-target binding to monoamine oxidase MAO-A and MAO-B, as well as to regions containing high levels of melanin, neuromelanin, and iron It was approved by the FDA on May 28, 2020, for sale by Avid Radiopharmaceuticals under the name TAUVID™ and is the first FDA-approved molecule for imaging aggregated tau protein in the brain

ACKNOWLEDGEMENT:

We are very thankful to Secretary Shri.Manojkumarji Kawadiya for providing us facility and support completion of this work.

REFERENCES:

1. www, drug bank.com

2. "FDA Approves First Drug to Image Tau Pathology in Patients Being Evaluated for Alzheimer's Disease". U.S. Food and Drug Administration (FDA). 28 May 2020. Retrieved 28 May 2020. This article incorporates text from this source, which is in the public domain.

3. Tauvid (flortaucipir F 18 injection), for intravenous use" (PDF). U.S. Food and Drug Administration (FDA). Retrieved 29 May 2020.

4. Drug Trial Snapshot: Tauvid". U.S. Food and Drug Administration (FDA). 28 May 2020. Retrieved 10 June 2020.

5. "Lilly Receives U.S. FDA Approval of TAUVID (flortaucipir F 18 injection) for Use in Patients Being Evaluated for Alzheimer's Disease". Eli Lilly (Press release). 28 May 2020. Retrieved 28 May 2020 – via PR Newswire.

6. Tauvid: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Retrieved 29 May 2020.

7. Wang YT, Edison P: Tau Imaging in Neurodegenerative Diseases Using Positron Emission Tomography. Curr Neurol Neurosci Rep. 2019 Jun 6;19(7):45. doi: 10.1007/s11910-019-0962-7. [PubMed:31172290].

8. Vermeiren C, Motte P, Viot D, Mairet-Coello G, Courade JP, Citron M, Mercier J, Hannestad J, Gillard M: The tau positron-emission tomography tracer AV-1451 binds with similar affinities to tau fibrils and monoamine oxidases. Mov Disord. 2018 Feb;33(2):273-281. doi: 10.1002/mds.27271. Epub 2017 Dec 26. [PubMed:29278274].

Received on 25.06.2020 Revised on 22.08.2020

Asian J. Pharm. Res. 2021; 11(1):60-62.

DOI: 10.5958/2231-5691.2021.00012.5