Flutafuranol (18F): A Comprehensive Review of a Promising Amyloid-β PET Imaging Agent for Alzheimer's Disease

1. Introduction to Flutafuranol (18F)

Overview

Flutafuranol (18F) is an investigational diagnostic radiopharmaceutical agent designed for use in positron emission tomography (PET) imaging. It is a fluorine-18 (18F) labeled molecular probe specifically developed for the in vivo visualization and quantification of amyloid-β (Aβ) plaques in the human brain.[1] The accumulation of Aβ plaques is a primary neuropathological hallmark of Alzheimer's disease (AD), a progressive neurodegenerative disorder and the most common cause of dementia.[1]

The ability to accurately detect and measure Aβ plaque burden in vivo is of paramount importance in the field of AD research and clinical practice. Amyloid PET imaging serves multiple critical roles: it aids in the early and differential diagnosis of AD from other forms of dementia, facilitates the stratification of patients for clinical trials targeting Aβ pathology, enables the monitoring of disease progression, and helps assess the pharmacodynamic effects of anti-amyloid therapeutic interventions.[3]

Rationale for Development

The development of flutafuranol (18F) was driven by the need to overcome certain limitations associated with earlier amyloid PET tracers. The pioneering amyloid PET tracer, 11C-Pittsburgh Compound B (11C-PiB), while demonstrating excellent imaging properties, is limited by the short 20-minute physical half-life of carbon-11. This necessitates an on-site cyclotron for its production, restricting its widespread clinical and research applicability.[19]

The incorporation of fluorine-18, with its longer half-life of approximately 110 minutes, allows for centralized production of flutafuranol (18F) and subsequent distribution to PET imaging centers lacking their own cyclotrons. This significantly enhances the logistical feasibility for broader clinical use and multi-center research studies.[3]

Furthermore, while first-generation 18F-labeled amyloid tracers (e.g., florbetapir, flutemetamol, florbetaben) increased accessibility, some exhibited higher non-specific binding to white matter in the brain. This non-specific binding can complicate image interpretation and reduce the sensitivity for detecting subtle or early-stage Aβ pathology.[3] Flutafuranol (18F) was engineered as a "second-generation" 18F tracer with the aim of combining the favorable imaging characteristics of 11C-PiB, particularly its low non-specific white matter binding, with the practical advantages of the 18F radioisotope.[19] The successful development of such an agent is critical for advancing the understanding of AD pathogenesis, improving diagnostic accuracy, and accelerating the development of effective treatments.

2. Chemical Properties and Synthesis Highlights

Flutafuranol (18F) is characterized by a specific chemical structure and a set of identifiers that distinguish it in scientific literature and databases.

• Chemical Name (IUPAC): The International Union of Pure and Applied Chemistry (IUPAC) name for the 18F-labeled compound is 2-[2-(18F)fluoro-6-(methylamino)pyridin-3-yl]-1-benzofuran-5-ol.[8] Its non-radioactive isotopologue, containing fluorine-19, is named 2-[2-fluoro-6-(methylamino)pyridin-3-yl]-1-benzofuran-5-ol.[31]
• Synonyms: Flutafuranol (18F) is widely known in research and development by several synonyms, most prominently [18F]NAV4694 and [18F]AZD4694. It also holds the United States Adopted Name (USAN) Flutafuranol F 18 and the International Nonproprietary Name (INN) flutafuranol (18F).[1]
• Molecular Formula: The molecular formula for flutafuranol (18F) is C14​H1118​FN2​O2​. The non-radioactive (19F) form is C14​H11​FN2​O2​.[7]
• Molecular Weight: The molecular weight of the non-radioactive (19F) flutafuranol is approximately 258.25 g/mol.[30] The 18F-labeled version has a slightly lower molecular weight due to the isotopic difference between 18F and 19F.
• CAS Number:
• Flutafuranol (19F, non-radioactive): 1054629-49-0.[31]
• Flutafuranol (18F): 1211333-21-9.[7]
• Structural Features: Flutafuranol is a benzofuran derivative.[6] Its chemical structure was rationally designed to be an analog of 11C-PiB, a well-established amyloid PET tracer, with the intention of retaining PiB's favorable Aβ plaque binding characteristics while incorporating the more clinically practical 18F radioisotope.[13] This structural similarity is a key aspect of its design, aiming to leverage the known desirable imaging properties of PiB, such as high affinity for Aβ plaques and low non-specific binding to white matter.
• Key Identifiers:
• PubChem CID: 24896605 is the PubChem Compound Identifier for the non-radioactive flutafuranol.[31] The KEGG database entry D10706 for "Flutafuranol F 18 (USAN)" links to PubChem CID 254741667.[38] It is common for different database entries or isotopically labeled versions to have distinct CIDs.
• ChemSpider ID: 28530673 is associated with flutafuranol.[36]
• UNII (Unique Ingredient Identifier): 785H5FQN20 is assigned to Flutafuranol F 18 [8], while G5K506J69E is assigned to the non-18F flutafuranol.[31]
• ChEMBL ID: CHEMBL2048308 corresponds to flutafuranol.[31]
• Synthesis Highlights: The radiosynthesis of flutafuranol (18F) involves the nucleophilic incorporation of the 18F fluoride ion into a suitable precursor molecule, followed by purification steps to ensure high radiochemical purity and specific activity for PET imaging applications.[3] The 18F radioisotope, a positron emitter with a physical half-life of approximately 109.8 minutes, is typically produced in a cyclotron.[3]

Table 1: Chemical and Physical Properties of Flutafuranol (18F)

Property	Value	Reference(s)
IUPAC Name (18F)	2-[2-(18F)fluoro-6-(methylamino)pyridin-3-yl]-1-benzofuran-5-ol	8
Common Synonyms	[18F]NAV4694, [18F]AZD4694, Flutafuranol F 18 (USAN)	1
CAS Number (18F)	1211333-21-9	30
Molecular Formula (18F)	C14​H1118​FN2​O2​	30
Approx. Mol. Weight (18F)	~258 g/mol (slightly less than 19F version)	31
Key Structural Class	Benzofuran derivative	7
PubChem CID (18F)	254741667 (per KEGG for Flutafuranol F 18)	38
UNII (18F)	785H5FQN20	30

This consolidated chemical information underscores the specific identity of flutafuranol (18F) as a diagnostic agent designed with structural features intended to optimize its performance in amyloid PET imaging.

3. Mechanism of Action and Pharmacodynamics

Flutafuranol (18F) functions as a PET imaging agent by selectively binding to Aβ plaques in the brain, which are a key neuropathological feature of AD.[1] The amyloid-beta precursor protein (APP) is the parent protein from which Aβ peptides are derived through proteolytic cleavage; thus, APP is indirectly related to the target of flutafuranol (18F).[7]

Binding Affinity and Selectivity

In vitro studies have demonstrated that flutafuranol (18F) (often referred to as AZD4694 in these studies) possesses a high binding affinity for Aβ fibrils, with a reported equilibrium dissociation constant (Kd) of 2.3 ± 0.3 nM.[13] This strong affinity is essential for a PET tracer, as it ensures robust binding to the target even at the low tracer concentrations typically used in PET imaging, thereby facilitating sensitive detection and clear image contrast.

A critical characteristic of flutafuranol (18F) is its selectivity.

• Aβ vs. Tau: Flutafuranol (18F) is specifically designed as an amyloid PET tracer. The available literature consistently distinguishes amyloid tracers from tau tracers (e.g., [18F]flortaucipir, [18F]MK-6240), which are used to visualize neurofibrillary tangles, another hallmark pathology of AD.[1] While direct quantitative comparisons of flutafuranol (18F)'s binding affinity for Aβ versus tau are not detailed in the provided snippets, its development and characterization firmly place it within the class of Aβ-selective ligands.
• Aβ Isoforms: The provided information does not specify differential binding affinities of flutafuranol (18F) for various Aβ isoforms (e.g., Aβ40, Aβ42) or different aggregation states (e.g., oligomers vs. fibrils), beyond its established affinity for fibrillar Aβ plaques.[1]
• Off-Target Binding: A significant advantage of flutafuranol (18F) is its reported low non-specific binding, especially to white matter, when compared to some other 18F-labeled amyloid tracers.[6] This characteristic is crucial for improving image quality, enhancing the signal-to-noise ratio, and facilitating more accurate quantification of Aβ burden, particularly in regions adjacent to white matter or in cases with low plaque density. Information regarding specific off-target binding to other sites like MAO or sigma receptors for flutafuranol (18F) is not detailed in the provided snippets, unlike for some tau tracers which have shown such interactions.[28] The emphasis for flutafuranol (18F) remains on its favorable low non-specific binding profile.

Mechanism of PET Signal Generation

The diagnostic utility of flutafuranol (18F) in PET imaging stems from the radioactive decay of its 18F label. Fluorine-18 is a positron-emitting isotope. Upon administration, flutafuranol (18F) distributes in the brain and binds to Aβ plaques. The emitted positrons travel a short distance in tissue before annihilating with an electron, resulting in the production of two 511 keV gamma photons that travel in nearly opposite directions. These coincident gamma photons are detected by the PET scanner, allowing for the three-dimensional reconstruction of the tracer's distribution. The intensity of the PET signal in different brain regions thus reflects the local concentration of flutafuranol (18F) and, by inference, the density of Aβ plaques.[1]

4. Preclinical Evaluation

The preclinical development of flutafuranol (18F) (AZD4694/NAV4694) provided foundational evidence for its potential as an Aβ PET imaging agent.

In vitro Studies

In vitro experiments were crucial in establishing the fundamental binding characteristics of the compound. These studies demonstrated that AZD4694 possesses a high affinity for Aβ fibrils, with a Kd value reported as 2.3 ± 0.3 nM.[14] This strong binding affinity is a prerequisite for a successful PET tracer, as it indicates a high likelihood of the tracer binding to its target even at the low concentrations used in imaging.

Autoradiography studies using [3H]AZD4694 on postmortem human AD brain tissue further corroborated its selectivity. These studies showed that the tracer selectively labeled Aβ deposits located in the grey matter, with significantly lower non-displaceable binding observed in white matter regions that are typically devoid of plaques.[19] This distinction between grey matter (target) and white matter (non-target) binding is a critical indicator of a tracer's ability to provide clear and interpretable images.

In vivo Animal Model Studies

Following promising in vitro results, flutafuranol was evaluated in animal models. Administration of unlabeled AZD4694 to rats demonstrated favorable pharmacokinetic properties for a PET radioligand, including rapid entry into the brain and subsequent fast clearance from normal brain tissue.[19] Such kinetics are desirable as they contribute to a good signal-to-noise ratio by minimizing background signal from unbound tracer in healthy tissue.

Ex vivo binding studies were conducted in aged Tg2576 mice, a transgenic model that develops Aβ pathology. After intravenous administration of [3H]AZD4694, selective and reversible binding to Aβ deposits was observed. Notably, plaque-bound [3H]AZD4694 could still be detected 80 minutes post-injection, indicating sufficient retention at the target site for imaging purposes.[19] Furthermore, [18F]flutafuranol has been successfully used to visualize amyloid plaques in the McGill-R-Thy1-APP rat model of AD.[26]

Collectively, these preclinical findings were highly encouraging. They demonstrated that flutafuranol (18F) possesses high affinity for Aβ plaques, exhibits selectivity for these plaques over normal brain tissue (particularly white matter), and has appropriate pharmacokinetic characteristics (brain penetration and clearance) in relevant animal models. This body of evidence provided a strong rationale for advancing flutafuranol (18F) into human clinical trials.

5. Pharmacokinetics in Humans

The pharmacokinetic profile of flutafuranol (18F) in humans has been investigated to understand its absorption, distribution, metabolism, and elimination, which are critical for its utility as a PET imaging agent.

Absorption and Distribution

Flutafuranol (18F) is administered intravenously (IV) as a bolus injection.[1] Following IV administration, the tracer rapidly enters the brain.[3] Studies with 18F-AZD4694 (flutafuranol (18F)) have shown that radioactivity appears quickly in the brain, with specific binding in amyloid-laden regions becoming apparent and peaking around 27 minutes post-injection in AD patients. In contrast, control subjects exhibit low and homogeneously distributed brain radioactivity.[2] The cerebellum is typically used as a reference region in quantitative analyses due to its characteristically low Aβ plaque burden.[2]

A key advantage of flutafuranol (18F) is its low non-specific binding to white matter, which distinguishes it from some other 18F-labeled amyloid tracers and contributes to clearer image contrast and more reliable quantification of cortical Aβ.[6]

Metabolism

Human studies indicate that flutafuranol (18F) undergoes rapid metabolism after IV administration, a characteristic shared with other amyloid PET radioligands.[2] Approximately 50% of the tracer is metabolized within 8–9 minutes, with about 10% of the parent compound remaining unchanged by the end of typical PET scan durations.[2] The resulting radioactive metabolites are more polar than the parent flutafuranol (18F) molecule. This increased polarity is significant because it generally limits their ability to cross the blood-brain barrier (BBB).[2] The observation that the ratio of brain radioactivity to metabolite-corrected plasma radioactivity remains stable or non-increasing in the later phases of PET scans supports the interpretation that these polar metabolites do not significantly enter the brain or interfere with the imaging of Aβ plaques by the parent compound.[2] This metabolic profile is advantageous for quantitative PET imaging, as it simplifies kinetic modeling and enhances the accuracy of Aβ plaque burden assessment.

Elimination

Flutafuranol (18F) demonstrates rapid clearance from normal (non-Aβ-laden) brain tissue.[3] The physical half-life of the 18F isotope is approximately 110 minutes.[3] The effective half-life of the tracer in the body and its specific routes of excretion (e.g., renal, hepatobiliary) are not explicitly detailed for flutafuranol (18F) in the provided snippets. However, for many 18F-labeled PET tracers, particularly those with lipophilic characteristics that undergo hepatic metabolism, hepatobiliary excretion is a common pathway. For instance, studies with the amyloid tracer [18F]FACT showed high uptake in the gallbladder and intestines, indicative of this excretion route.[64]

6. Human Radiation Dosimetry

The assessment of radiation dosimetry is a critical component of the safety evaluation for any radiopharmaceutical. For flutafuranol (18F), a typical intravenous radioactive dose administered in clinical trials is approximately 8.1 mCi (300 MBq).[1]

Detailed human radiation dosimetry data for flutafuranol (18F) (NAV4694/AZD4694), including specific effective dose and organ-specific absorbed doses calculated using standardized methodologies like MIRD (Medical Internal Radiation Dose) or OLINDA/EXM, are not explicitly provided in the summarized research snippets.[3] An early study by AstraZeneca (D2750C00001) included a whole-body dosimetry scanning component in healthy volunteers to estimate a safe dose of [18F]AZD4694, but the specific dosimetry results from this component are not available in the provided materials.[39]

However, dosimetry data from other 18F-labeled amyloid PET tracers can provide a general context for the expected radiation exposure:

• [18F]Florbetapir (Amyvid): An injected dose of 370 MBq (10 mCi) results in an effective dose of 7.0 mSv (equivalent to 19 µSv/MBq). Organs receiving the highest absorbed doses include the gallbladder wall, upper large intestine wall, liver, and small intestine.[81]
• [18F]FACT (an earlier experimental tracer, not flutafuranol): The average effective dose estimated from human PET data was 18.6 ± 3.74 µSv/MBq. The highest absorbed doses were observed in the gallbladder, liver, small intestine, and upper and lower large intestine.[64]
• Other 18F-Amyloid Tracers (reported ranges):
• 18F-AV-45 (florbetapir): 13 and 19.3 µSv/MBq
• 18F-GE067 (flutemetamol): 33.8 µSv/MBq
• 18F-BAY94-9172 (florbetaben): 14.7 µSv/MBq.[64]

The radiation doses associated with these diagnostic PET procedures are generally considered to be within acceptable limits for medical imaging. The consistent pattern of high tracer accumulation in the hepatobiliary system (liver, gallbladder, intestines) across various amyloid PET tracers suggests that this is a primary route of excretion for these types of compounds. While specific values for flutafuranol (18F) are awaited from dedicated dosimetry studies or full trial publications, its profile is anticipated to be comparable to other 18F-labeled amyloid PET agents.

Table 2: Representative Human Radiation Dosimetry for 18F-Labeled Amyloid PET Tracers

Tracer Name (Example)	Typical Injected Dose	Effective Dose (µSv/MBq)	Critical Organ(s) & Absorbed Dose (µGy/MBq)	Reference(s)
[18F]Florbetapir	370 MBq (10 mCi)	19	Gallbladder (143), Upper Large Intestine (74), Liver (64)	81
[18F]FACT	~161 MBq	18.6 ± 3.74	Gallbladder (333 ± 251), Liver (77.5 ± 14.5), Small Intestine (33.6 ± 30.7)	64
[18F]Flutemetamol	Not specified	33.8	Not specified in snippet	64
[18F]Florbetaben	Not specified	14.7	Not specified in snippet	64

Note: This table presents data for comparator tracers as detailed dosimetry for flutafuranol (18F) was not available in the provided snippets.

7. Clinical Development and Diagnostic Performance

Flutafuranol (18F), under its various developmental names ([18F]AZD4694, [18F]NAV4694), has undergone extensive clinical evaluation in Phase I, II, and III trials to assess its safety and efficacy as an Aβ PET imaging agent.[1]

Overview of Clinical Trial Program

A key pivotal study is NCT01886820, a Phase 3 trial titled "A Phase 3 Clinical Trial to Evaluate the Efficacy and Safety of [18F]NAV4694 PET for Detection of Cerebral Beta-Amyloid When Compared With Postmortem Histopathology." This trial, sponsored by Navidea Biopharmaceuticals (rights later acquired by Lantheus), was designed to enroll up to 275 end-of-life individuals to directly compare in vivo PET imaging findings with postmortem neuropathological assessment of Aβ plaques, which is considered the gold standard for confirming AD pathology.[34] The primary outcome measures for such a trial would typically be sensitivity and specificity of the PET scan in detecting Aβ pathology as confirmed by histopathology.

Other notable clinical trials include:

• NCT00991419: A completed Phase 2 study sponsored by AstraZeneca that compared [18F]AZD4694 with [11C]PiB in AD patients and healthy volunteers.[7] This trial provided early evidence of the comparable imaging characteristics of [18F]AZD4694 and [11C]PiB.
• NCT01812213: A Phase 2 trial sponsored by Navidea Biopharmaceuticals investigating [18F]NAV4694 in subjects with Mild Cognitive Impairment (MCI) to predict progression to AD. This trial was reported as terminated.[7]
• NCT01680588: A Phase 2 trial by Navidea Biopharmaceuticals evaluating the efficacy and safety of [18F]NAV4694 in subjects with probable AD.[34]

Flutafuranol (18F) has also been utilized as an amyloid PET biomarker in numerous academic and industry-led investigational therapeutic trials for AD, such as the AHEAD 3-45 study evaluating lecanemab.[1] It is also a tracer used in large observational studies like the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Australian Imaging, Biomarkers and Lifestyle (AIBL) study.[99]

PET Imaging Protocols

Standardized PET imaging protocols are crucial for ensuring consistency and comparability of results across different studies and sites.

• Patient Preparation: General guidelines for PET imaging apply. Patients are typically instructed regarding medications and fasting if necessary, though specific requirements for flutafuranol (18F) are not extensively detailed beyond standard PET practices.[71] Sedation is not routinely required but may be considered on a case-by-case basis.[72]
• Radiotracer Administration and Dosage: Flutafuranol (18F) is administered as an intravenous bolus injection.[1] A typical injected dose is around 8.1 mCi (300 MBq).[1]
• Image Acquisition Parameters: PET scans are typically acquired 40–70 minutes or 50–70 minutes post-injection for flutafuranol (18F)/NAV4694, which is considered an optimal window for deriving SUVRs.[43] Dynamic scanning for 60-90 minutes can also be performed for kinetic modeling.[50]
• Image Analysis and Interpretation:
• Reference Region: The cerebellar cortex (or cerebellar grey matter) is consistently used as the reference region for SUVR calculations with flutafuranol (18F), owing to its typically low Aβ plaque burden.[6]
• SUVR Calculation: SUVRs are derived by dividing the mean tracer uptake in cortical regions of interest (e.g., frontal, parietal, temporal, cingulate cortices, or a global cortical composite) by the mean uptake in the cerebellar reference region.[6]
• Centiloid Scale: To standardize quantitative amyloid PET measures across different tracers and imaging sites, SUVR values can be converted to the Centiloid (CL) scale. The conversion equation for 18F-NAV4694 SUVR (using whole cerebellum as reference, imaged 50-70 min post-injection) to Centiloids is reported as: CL=100×(SUVRNAV4694​−1.028)/1.174.[43] This standardization is crucial for comparing data from different studies and for establishing universal thresholds for amyloid positivity.
• SUVR Threshold for Amyloid Positivity: A study by Therriault et al. (2020) investigated optimal SUVR cutoffs for 18F-AZD4694 using various methods. Good convergence was found around an SUVR of 1.55 (using cerebellar grey matter as reference) when comparing clinical classification, visual PET reads, Gaussian mixture modeling, and CSF Aβ42/Aβ40 ratios.[5] This threshold demonstrated reliable discriminative accuracy and can be valuable in clinical interpretation, especially for borderline cases or to arbitrate inter-reader variability in visual assessments.

Diagnostic Efficacy

Flutafuranol (18F) has demonstrated high affinity and selectivity for Aβ plaques in vitro and in vivo.[1] Clinical studies have shown that PET imaging with flutafuranol (18F) can clearly distinguish between individuals with AD and healthy controls based on cortical tracer uptake.[3]

The definitive assessment of sensitivity and specificity for detecting Aβ pathology relies on correlation with postmortem neuropathological examination. The Phase 3 trial NCT01886820 was specifically designed for this purpose.[87] While the final histopathology-correlated sensitivity and specificity data from this pivotal trial are not detailed in the provided snippets [29], earlier studies and developer communications have consistently suggested favorable sensitivity and specificity for Aβ plaque detection.[40] For example, [18F]Flutafuranol has been described as having "reasonable sensitivity and specificity in Aβ visualization".[40] The successful completion and positive outcome of NCT01886820, demonstrating strong correlation with autopsy findings, would be a critical milestone for regulatory approval and widespread clinical adoption of flutafuranol (18F).

Comparison with Other Amyloid PET Tracers

Flutafuranol (18F) ([18F]AZD4694/NAV4694) has been directly compared to [11C]PiB in human studies. These head-to-head comparisons have shown that [18F]AZD4694 exhibits imaging characteristics nearly identical to those of [11C]PiB. This includes similar reversible binding kinetics, a comparable dynamic range of neocortical SUVR values, and, importantly, similarly low non-specific binding in white matter.[19] An excellent linear correlation (r=0.99) between the neocortical SUVRs obtained with [18F]AZD4694 and [11C]PiB has been reported.[27]

When converted to the Centiloid scale, [18F]NAV4694 has shown slightly higher Aβ binding signal and lower variance compared to [11C]PiB in young controls, which could be advantageous for detecting early Aβ deposition and for tracking small changes in Aβ load over time in longitudinal studies.[43]

Compared to other 18F-labeled amyloid tracers such as florbetapir, flutemetamol, and florbetaben, a key distinguishing feature of flutafuranol (18F) is its consistently reported lower non-specific white matter binding.[6] This characteristic is considered a significant advantage as it leads to improved image clarity, better contrast between grey matter (where plaques are primarily located) and white matter, and potentially more accurate quantification of Aβ burden, especially in cases with low to moderate plaque density.[3]

Table 3: Comparative Overview of Flutafuranol (18F) and Other Selected Amyloid PET Tracers

Feature	Flutafuranol (18F) ([18F]NAV4694)	[11C]PiB	[18F]Florbetapir (Amyvid)	[18F]Flutemetamol (Vizamyl)	[18F]Florbetaben (Neuraceq)
Radionuclide	18F	11C	18F	18F	18F
Half-life	~110 min	~20 min	~110 min	~110 min	~110 min
Aβ Binding Affinity (Kd)	~2.3 nM	High (nM range)	Moderate-High (nM range)	Moderate-High (nM range)	Moderate-High (nM range)
White Matter Binding	Low, similar to [11C]PiB	Low	Higher than [11C]PiB/NAV4694	Higher than [11C]PiB/NAV4694	Higher than [11C]PiB/NAV4694
Image Clarity	High contrast	High contrast	Potentially lower due to WM binding	Potentially lower due to WM binding	Potentially lower due to WM binding
Regulatory Approval	Investigational (Phase 3)	Research Use Only	Approved (FDA, EMA)	Approved (FDA, EMA)	Approved (FDA, EMA)
Reference(s)	19	19	5	5	5

This comparative profile highlights flutafuranol (18F)'s potential to offer PiB-like imaging quality with the logistical benefits of an 18F label.

8. Safety and Tolerability Profile

The safety and tolerability of flutafuranol (18F) are critical for its potential use as a diagnostic agent. Based on the available information from clinical studies, flutafuranol (18F) appears to be generally safe and well-tolerated by subjects.[1]

General Tolerability and Adverse Events

In clinical trials, [18F]NAV4694 (flutafuranol (18F)) has demonstrated a good safety profile.[3] A study specifically examining the effect of ligand mass dose of [18F]AZD4694 (another name for flutafuranol (18F)) reported "no safety signals between or within mass doses" in a cohort of healthy elderly volunteers and AD patients.[68]

While detailed, large-scale pooled analyses of adverse events specifically for flutafuranol (18F) are not extensively covered in the provided snippets, the general adverse event profile for 18F-labeled PET radiopharmaceuticals is typically mild and transient. Common reactions, if they occur, are often related to the intravenous injection itself (e.g., minor pain, swelling, or redness at the injection site) or mild, short-lived systemic effects such as headache, dizziness, or fatigue.[77] For context, Flortaucipir F-18, a tau PET tracer, has reported common side effects including injection site reactions, headache, dizziness, fatigue, and nausea.[77]

Radiation Exposure

The primary safety consideration inherent to all PET procedures, including those with flutafuranol (18F), is the exposure of the patient to ionizing radiation.[1] The injected dose of flutafuranol (18F) is carefully controlled, typically around 8.1 mCi (300 MBq), to ensure that the radiation exposure remains within diagnostically acceptable limits and adheres to the ALARA (As Low As Reasonably Achievable) principle.[8] While specific human radiation dosimetry figures for flutafuranol (18F) are not detailed in the provided snippets, the exposure is expected to be comparable to other 18F-based PET imaging agents used in neurology.

Contraindications and Precautions

Standard contraindications and precautions for PET radiopharmaceuticals generally apply to flutafuranol (18F).

• Pregnancy and Breastfeeding: Flutafuranol (18F) should not be used in pregnant or breastfeeding women due to the potential risks of radiation exposure to the fetus or infant.[1]
• Pre-existing Medical Conditions: Clinical trial protocols often exclude individuals with certain pre-existing medical conditions that might interfere with the scan or pose additional risks. Examples from trials using flutafuranol (18F) or similar agents include active HIV infection, recent cancer (unless part of the study), significant bleeding disorders, recent stroke or seizures, or certain unstable psychiatric conditions.[1]
• Implants/Devices: Patients with certain metallic implants or medical devices (e.g., pacemakers, aneurysm clips) may be contraindicated for the PET scan or an accompanying MRI scan, if performed.[1]

The overall safety profile of flutafuranol (18F) appears favorable and consistent with other 18F-labeled PET diagnostic agents. The main consideration remains the managed exposure to ionizing radiation, which is a standard aspect of nuclear medicine procedures.

9. Regulatory Status and Commercial Development

Flutafuranol (18F), also known by its developmental codes [18F]AZD4694 and [18F]NAV4694, is currently an investigational diagnostic agent. As of the information available in the provided research snippets, it has not yet received marketing approval from major regulatory authorities such as the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), or Japan's Pharmaceuticals and Medical Devices Agency (PMDA) for routine clinical use.[3] The agent is in late-stage clinical development, specifically Phase 3 clinical trials.[7]

Developer History and Current Commercial Rights

The development of flutafuranol (18F) has involved several pharmaceutical entities:

• It was originally developed by AstraZeneca under the designation [18F]AZD4694.[32]
• Subsequently, Navidea Biopharmaceuticals advanced its development, referring to it as [18F]NAV4694.[32]
• The rights were later acquired by Meilleur Technologies, Inc..[52]
• In a significant development in July 2024, Lantheus Holdings announced its acquisition of Meilleur Technologies, thereby securing worldwide exclusive rights to [18F]NAV4694 (flutafuranol (18F)).[52]
• Cerveau Technologies, Inc. has also been associated with the development of Flutafuranol F-18, with AstraZeneca listed as an active and originator organization for Flutafuranol F-18 under Cerveau's projects.[52] Lantheus acquired Cerveau Technologies in 2023, primarily for its tau PET imaging agent MK-6240.[84]

Lantheus' Strategic Positioning

Lantheus' acquisition of NAV-4694 is a strategic move to bolster its position in the neurology diagnostic space, particularly for Alzheimer's disease. NAV-4694, as a β-amyloid PET imaging agent, complements Lantheus' other clinical-stage asset, MK-6240 ([18F]florquinitau), which is an F18-labeled PET imaging agent targeting tau neurofibrillary tangles.[83]

This dual-pronged approach, targeting both key pathological hallmarks of AD (amyloid plaques and tau tangles), aligns with the evolving understanding of AD as a biological continuum and the increasing emphasis on biomarker-based diagnosis and staging, as highlighted by recent NIA-AA guidelines.[62] Lantheus aims to provide a comprehensive PET diagnostic portfolio to guide the use and assess the impact of emerging disease-modifying therapies for AD.[62] The company anticipates that having best-in-class tracers for both amyloid and tau will be crucial for patient selection and monitoring of these novel treatments.

Regulatory Submissions and Future Outlook

As of the latest information in the provided snippets (up to May 2025), there are no specific dates mentioned for New Drug Application (NDA) or Marketing Authorisation Application (MAA) submissions for flutafuranol (18F)/NAV4694 to the FDA, EMA, or PMDA.[13] Lantheus has announced plans to file an NDA with the FDA for its tau tracer, MK-6240, in the third quarter of 2025.[83] The regulatory trajectory for NAV-4694 will depend on the outcomes of its ongoing Phase 3 development program, particularly the pivotal histopathology correlation study (NCT01886820). Successful completion of these trials and positive data will be prerequisites for regulatory submissions.

The successful commercialization of flutafuranol (18F) would significantly contribute to the diagnostic armamentarium for AD, especially given the increasing number of amyloid-targeting therapies entering clinical practice, which often require PET imaging for patient eligibility and treatment monitoring.

10. Conclusion

Flutafuranol (18F), also known as [18F]NAV4694 or [18F]AZD4694, is an investigational second-generation fluorine-18 labeled positron emission tomography (PET) radiopharmaceutical designed for the in vivo imaging of amyloid-β (Aβ) plaques in the human brain. Its development was driven by the need for an Aβ tracer combining the favorable imaging characteristics of [11C]PiB (high affinity for Aβ plaques, low non-specific white matter binding) with the practical advantages of the longer-lived 18F isotope, facilitating broader clinical and research accessibility.[3]

Preclinical studies have demonstrated flutafuranol (18F)'s high binding affinity for Aβ fibrils (Kd ≈ 2.3 nM) and selectivity for Aβ plaques in grey matter with minimal non-displaceable binding in white matter.[14] Animal models confirmed its ability to rapidly enter the brain, bind to Aβ deposits, and clear from normal tissue, supporting its progression to human trials.[19]

In humans, flutafuranol (18F) exhibits rapid brain uptake and metabolism into polar metabolites that do not significantly cross the blood-brain barrier, which is advantageous for clear imaging.[2] Head-to-head comparisons with [11C]PiB have shown nearly identical imaging characteristics and a strong correlation in quantitative Aβ burden assessment, with flutafuranol (18F) potentially offering slightly higher Aβ binding and lower variance when standardized using the Centiloid scale.[19] Its lower white matter binding compared to some other 18F-amyloid tracers is a notable advantage for image interpretation and quantification.[6] A standardized SUVR threshold of approximately 1.55 (using cerebellar grey matter as reference) has been proposed for defining Aβ positivity with [18F]AZD4694.[5]

Flutafuranol (18F) has demonstrated a good safety profile in clinical trials, consistent with other PET radiopharmaceuticals, with the primary consideration being managed radiation exposure.[1] Human radiation dosimetry is expected to be within acceptable limits for diagnostic procedures, with hepatobiliary excretion likely being a significant route, similar to other 18F-amyloid tracers.[64]

Currently, flutafuranol (18F) remains an investigational agent, undergoing Phase 3 clinical development. Its worldwide exclusive rights are now held by Lantheus Holdings, which aims to integrate it into a comprehensive Alzheimer's disease diagnostic portfolio alongside a tau PET imaging agent.[52] The future clinical utility and regulatory approval of flutafuranol (18F) will heavily depend on the outcomes of ongoing pivotal trials, particularly those correlating in vivo PET findings with postmortem neuropathology (e.g., NCT01886820).

The advent of disease-modifying therapies for Alzheimer's disease, many of which target Aβ pathology, underscores the growing need for accurate, reliable, and accessible biomarkers like flutafuranol (18F). If successfully validated and approved, flutafuranol (18F) is well-positioned to become a valuable tool in the diagnostic workup of cognitive impairment, aiding in early and accurate diagnosis of AD, patient selection for targeted therapies, and monitoring of treatment efficacy. Its favorable imaging characteristics, combined with the practicality of 18F labeling, make it a promising candidate for widespread clinical application in the evolving landscape of Alzheimer's disease management.

11. References

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• [30] Pharmacompass. Flutafuranol (18F).
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• [35] MedKoo. Flutafuranol.
• [34] Medpath. Flutafuranol (18F) ([18F]NAV4694).
• [53] Brain Communications. (Reference to 18F-flortaucipir, not flutafuranol).
• [1] ClinicalTrials.EU. FLUTAFURANOL (18F): A Diagnostic Tool for Alzheimer's Disease.
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• [52] Patsnap Synapse. Cerveau Technologies, Inc. - Drug pipelines, Patents, Clinical trials.
• [33] PharmaKB. Flutafuranol F 18.
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• [2] Patsnap Synapse. What is Flutafuranol F-18 used for?
• [77] Patsnap Synapse. What are the side effects of Flortaucipir F-18? (Refers to a tau tracer).
• [104] PMC. UB-311, a Novel UBITh ® Amyloid β Peptide Vaccine for Alzheimer's Disease. (General AD context).
• [107] PMC. 18F PET with flutemetamol for the early diagnosis of Alzheimer's. (Reference to flutemetamol).
• [114] SNMMI. FDA Approves F-18 Flurpiridaz, Nuclear Cardiology's First New Radiotracer in Nearly 3 Decades. (Not directly relevant).
• [10] SNMMI. Amyloid and Tau AUC FINAL.pdf.
• [59] Journal of Nuclear Medicine. Selection of Optimal Quantification Metric in Static Prostate Cancer Imaging... (Not directly relevant, general PET methods).
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• [3] OpenMedScience. Unlocking the Potential of [F-18]NAV-4694 in Alzheimer's Diagnosis.
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• [106] ClinicalTrials.gov Protocol. Longitudinal Early-onset Alzheimer's Disease Study (LEADS). (Uses amyloid tracers).
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• [5] Journal of Nuclear Medicine. Updated Appropriate Use Criteria for Amyloid and Tau PET. (General AUC guidelines).
• [83] Lantheus Press Release. Lantheus Announces Alzheimer's Disease Radiodiagnostic MK-6240 Meets Co-Primary Endpoints... (Mentions NAV-4694).
• [105] PMC. Safety and Tolerability of Intravenous Liposomal GM1... (Not relevant).
• [106] ClinicalTrials.gov Protocol. Longitudinal Early-onset Alzheimer's Disease Study (LEADS)..[106]
• [13] PMC. Amyloid beta plaque accumulation with longitudinal [18F]AZD4694 PET..[13]
• [107] PMC. 18F PET with flutemetamol for the early diagnosis of Alzheimer's..[107]
• [61] ADNI. ADNI4 In Clinic Protocol_v1.0_20220712.pdf. (Mentions NAV4694 imaging parameters).
• [115] MSAC.gov.au. 1643 Redacted Application Form.pdf. (Mentions NAV4694 characteristics).
• [27] ResearchGate. Head-to-head comparison of11C-PiB and18F-AZD4694 (NAV4694) for b-amyloid imaging in aging and dementia.
• [116] ResearchGate. Comparison of 11C-PiB and 18F-florbetaben for Aβ imaging... (Comparison of other tracers).
• [5] Journal of Nuclear Medicine. Updated Appropriate Use Criteria for Amyloid and Tau PET..[5]
• [4] PMC. Updated appropriate use criteria for amyloid and tau PET....[5]
• [8] NCATS Inxight Drugs. FLUTAFURANOL F-18..[8]
• [79] PMC. Human biodistribution and radiation dosimetry for the tau tracer [18F]Florzolotau... (Dosimetry for a tau tracer).
• [10] SNMMI. Updated Appropriate Use Criteria for Amyloid and Tau PET..[5]
• [11] ResearchGate. [F-18]Flutemetamol amyloid-beta PET imaging compared with [C-11]PIB... (Reference to flutemetamol).
• [1] ClinicalTrials.EU. FLUTAFURANOL (18F): A Diagnostic Tool for Alzheimer's Disease..[1]
• [7] Patsnap Synapse. Flutafuranol F-18..[7]
• [83] Lantheus Press Release. Lantheus Announces Alzheimer's Disease Radiodiagnostic MK-6240....[83]
• [84] Radiology Business. Lantheus to seek approval for new Alzheimer's PET imaging agent in Q3.
• [99] PMC. Positron emission tomography harmonization in the Alzheimer's Disease Neuroimaging Initiative...
• [100] AIBL. Dementia in Australia - The AIBL study. (Presentation slides mentioning NAV4694).
• [8] NCATS Inxight Drugs. FLUTAFURANOL F-18..[8]
• [85] FirstWord Pharma. Lantheus Announces Alzheimer's Disease Radiodiagnostic MK-6240....[83]
• [86] Lantheus Press Release. Lantheus Acquires NAV-4694...
• [1] ClinicalTrials.EU. FLUTAFURANOL (18F): A Diagnostic Tool for Alzheimer's Disease..[1]
• [8] NCATS Inxight Drugs. FLUTAFURANOL F-18..[8]
• [5] Journal of Nuclear Medicine. Updated Appropriate Use Criteria for Amyloid and Tau PET..[5]
• [12] PMC. Updated appropriate use criteria for amyloid and tau PET....[5]
• [80] PubMed. Radiation dosimetry of [18F]16alpha-fluoroestradiol (FES). (Dosimetry for a different tracer).
• [28] PubMed. Head-to-head comparison of (11)C-PiB and (18)F-AZD4694 (NAV4694) for β-amyloid imaging...
• [98] PMC. Amyloid PET in the Differential Diagnosis of Dementias... (General context, mentions NCT01886820).
• [87] Navidea Press Release. Navidea Biopharmaceuticals Initiates Enrollment in Global Phase 3 Clinical Trial of NAV4694...
• [3] OpenMedScience. Unlocking the Potential of [F-18]NAV-4694 in Alzheimer's Diagnosis..[3]
• [62] NeurologyLive. Future Plans for Lantheus' Next-Generation Amyloid-ß PET Imaging Agent NAV-4694..[62]
• [83] Lantheus Press Release. Lantheus Announces Alzheimer's Disease Radiodiagnostic MK-6240....[83]
• [84] Radiology Business. Lantheus to seek approval for new Alzheimer's PET imaging agent in Q3..[84]
• [63] Journal of Nuclear Medicine. Converting NAV4694 and PiB to Centiloids.
• [44] Journal of Nuclear Medicine. Converting NAV4694 and PiB to Centiloids..[63]
• [4] PMC. Updated appropriate use criteria for amyloid and tau PET....[5]
• [56] University of Toronto Thesis. (Mentions MK-6240 and APN-1607 off-target binding).
• [80] PubMed. Radiation dosimetry of [18F]16alpha-fluoroestradiol (FES)..[80]
• [3] OpenMedScience. Unlocking the Potential of [F-18]NAV-4694 in Alzheimer's Diagnosis..[3]
• [98] ResearchGate. Amyloid imaging in Alzheimer's disease: A potential new era of personalized medicine. (Mentions NCT01886820).
• [29] ResearchGate. Head-to-head comparison of11C-PiB and18F-AZD4694 (NAV4694)....[27]
• [34] Medpath. Flutafuranol (18F) ([18F]NAV4694)..[34]
• [7] Patsnap Synapse. Flutafuranol F-18..[7]
• [85] Lantheus Press Release. Lantheus Announces Alzheimer's Disease Radiodiagnostic MK-6240....[83]
• [84] Radiology Business. Lantheus to seek approval for new Alzheimer's PET imaging agent in Q3..[84]
• [13] PMC. Amyloid beta plaque accumulation with longitudinal [18F]AZD4694 PET..[13]
• [14] Journal of Nuclear Medicine. Determining Amyloid-β Positivity Using 18F-AZD4694 PET Imaging.
• [35] MedKoo. Flutafuranol..[35]
• [6] PubMed. Determining Amyloid-β Positivity Using 18F-AZD4694 PET Imaging..[14]
• [36] Wikidata. flutafuranol.
• [117] New Drug Approvals. (General contrast agent info).
• [5] Journal of Nuclear Medicine. Updated Appropriate Use Criteria for Amyloid and Tau PET..[5]
• [7] Patsnap Synapse. Flutafuranol F-18..[7]
• [57] PMC. Off-Target Binding in 18F-Flortaucipir PET Imaging: A Review of the Evidence. (Review of a tau tracer).
• [28] PubMed. Head-to-head comparison of (11)C-PiB and (18)F-AZD4694 (NAV4694)....[28]
• [64] MHLW Grants. Biodistribution and radiation dosimetry of the 18F-labelled amyloid imaging probe ([18F]FACT)... (Dosimetry for [18F]FACT).
• [65] PMC. Biodistribution and radiation dosimetry of the 18F-labelled amyloid imaging probe ([18F]FACT)....[64]
• [98] PMC. Amyloid PET in the Differential Diagnosis of Dementias....[98]
• [87] Navidea Press Release. Navidea Biopharmaceuticals Initiates Enrollment in Global Phase 3 Clinical Trial of NAV4694....[87]
• [34] Medpath. Flutafuranol (18F) ([18F]NAV4694)..[34]
• [1] ClinicalTrials.EU. FLUTAFURANOL (18F): A Diagnostic Tool for Alzheimer's Disease..[1]
• [86] Lantheus Press Release. Lantheus Acquires NAV-4694....[86]
• [88] Lantheus Holdings Press Release. Lantheus Holdings Submits New Drug Application to the U.S. FDA for PyL™... (Not about NAV4694).
• [15] SNMMI. SNMMI and the Alzheimer's Association Release Updated Appropriate Use Criteria for Amyloid and Tau PET Imaging.
• [16] PMC. Amyloid-PET Centiloid Scale: Validation and Application.
• [36] Wikidata. flutafuranol..[36]
• [37] Tohoku Repository. (Mentions [18F]flutafuranol and ChemSpider).
• [8] NCATS Inxight Drugs. FLUTAFURANOL F-18..[8]
• [7] Patsnap Synapse. Flutafuranol F-18..[7]
• [65] PMC. Biodistribution and radiation dosimetry of the 18F-labelled amyloid imaging probe ([18F]FACT)....[64]
• [66] AstraZeneca Clinical Trials. Positron emission tomography (PET) study with [18F]AZD4694... (Study D2750C00001).
• [42] ResearchGate. Amyloid imaging in Alzheimer's disease: A potential new era of personalized medicine. (Mentions NCT01886820).
• [40] ACS Publications. Head-to-Head Comparison of [18F]Florbetazine, [18F]91, and [11C]PiB for β-Amyloid PET Imaging in Alzheimer's Disease. (Mentions [18F]Flutafuranol).
• [1] ClinicalTrials.EU. FLUTAFURANOL (18F): A Diagnostic Tool for Alzheimer's Disease..[1]
• [34] Medpath. Flutafuranol (18F) ([18F]NAV4694)..[34]
• [86] Lantheus Press Release. Lantheus Acquires NAV-4694....[86]
• [17] SNMMI. SNMMI/EANM Standard for Amyloid PET Imaging of the Brain.
• [10] SNMMI. Updated Appropriate Use Criteria for Amyloid and Tau PET..[5]
• [36] Wikidata. flutafuranol..[36]
• [37] Tohoku Repository..[37]
• [8] NCATS Inxight Drugs. FLUTAFURANOL F-18..[8]
• [1] ClinicalTrials.EU. FLUTAFURANOL (18F): A Diagnostic Tool for Alzheimer's Disease..[1]
• [65] PMC. Biodistribution and radiation dosimetry of the 18F-labelled amyloid imaging probe ([18F]FACT)....[64]
• [64] MHLW Grants. Biodistribution and radiation dosimetry of the 18F-labelled amyloid imaging probe ([18F]FACT)....[64]
• [42] ResearchGate. Amyloid imaging in Alzheimer's disease: A potential new era of personalized medicine..[42]
• [89] ACS Publications. Head-to-Head Comparison of [18F]Florbetazine, [18F]91, and [11C]PiB....[40]
• [67] MedRxiv. (Not directly relevant to flutafuranol).
• [68] Journal of Nuclear Medicine. Effect of ligand mass dose on binding of the β-amyloid specific radioligand [18F]AZD4694 (NAV4694).
• [43] Journal of Nuclear Medicine. Converting NAV4694 and PiB to Centiloids..[63]
• [44] Journal of Nuclear Medicine. Converting NAV4694 and PiB to Centiloids..[63]
• [39] PubMed. Clinical validation of 18F-AZD4694, an amyloid-β-specific PET radioligand..[50]
• [66] AstraZeneca Clinical Trials. Positron emission tomography (PET) study with [18F]AZD4694....[66]
• [40] ACS Publications. Head-to-Head Comparison of [18F]Florbetazine, [18F]91, and [11C]PiB....[40]
• [41] LUME UFRGS. (Mentions NCT01886820).
• [69] JPAD. (General AD therapy review).
• [70] CTAD Alzheimer. (General AD biomarker review).
• [71] SNMMI Journal of Nuclear Medicine Technology. (General PET/CT info).
• [72] SNMMI Journal of Nuclear Medicine Supplemental Data. (General PET protocol info).
• [18] ResearchGate. 18F-Fluoroazabenzoxazoles as potential amyloid plaque PET tracers... (Mentions [18F]MK-3328).
• [19] ResearchGate. Characterization of AZD4694, a novel fluorinated Aβ plaque....[19]
• [40] ACS Publications. Head-to-Head Comparison of [18F]Florbetazine, [18F]91, and [11C]PiB....[40]
• [41] LUME UFRGS..[41]
• [27] ResearchGate. Head-to-head comparison of11C-PiB and18F-AZD4694 (NAV4694)....[27]
• [19] ResearchGate. Characterization of AZD4694, a novel fluorinated Aβ plaque....[19]
• [71] SNMMI Journal of Nuclear Medicine Technology..[71]
• [72] SNMMI Journal of Nuclear Medicine Supplemental Data..[72]
• [20] European Journal of Nuclear Medicine and Molecular Imaging. Impact of simulated reduced injected dose on the assessment of amyloid PET scans. (Focuses on flutemetamol and florbetaben).
• [41] LUME UFRGS..[41]
• [27] ResearchGate. Head-to-head comparison of11C-PiB and18F-AZD4694 (NAV4694)....[27]
• [19] ResearchGate. Characterization of AZD4694, a novel fluorinated Aβ plaque....[19]
• [71] SNMMI Journal of Nuclear Medicine Technology..[71]
• [72] SNMMI Journal of Nuclear Medicine Supplemental Data..[72]
• [21] ResearchGate. First-in-human evaluation of 18 F-SMBT-1, a novel 18 F-labeled MAO-B PET tracer... (Not directly relevant).
• [20] ResearchGate. Impact of simulated reduced injected dose on the assessment of amyloid PET scans..[20]
• [41] LUME UFRGS..[41]
• [27] ResearchGate. Head-to-head comparison of11C-PiB and18F-AZD4694 (NAV4694)....[27]
• [19] ResearchGate. Characterization of AZD4694, a novel fluorinated Aβ plaque....[19]
• [71] SNMMI Journal of Nuclear Medicine Technology..[71]
• [72] SNMMI Journal of Nuclear Medicine Supplemental Data..[72]
• [21] ResearchGate. First-in-human evaluation of 18 F-SMBT-1....[21]
• [20] ResearchGate. Impact of simulated reduced injected dose on the assessment of amyloid PET scans..[20]
• [22] Tohoku University Repository. (List of publications, some PET related).
• [73] ResearchGate. Preclinical Safety Evaluation and Human Dosimetry of [18F]MK-6240... (Dosimetry for a tau tracer).
• [74] Journal of Nuclear Medicine. (General PET info).
• [45] ResearchGate. Amyloid tracers binding sites in autosomal dominant and sporadic Alzheimer's disease. (General Aβ binding).
• [46] ResearchGate. Amyloid, tau, and astrocyte pathology in autosomal-dominant Alzheimer's disease variants... (General AD pathology).
• [42] ResearchGate. Amyloid imaging in Alzheimer's disease: A potential new era of personalized medicine..[42]
• [40] ACS Publications. Head-to-Head Comparison of [18F]Florbetazine, [18F]91, and [11C]PiB....[40]
• [47] ResearchGate. Uncertainties in Anti-Amyloid monoclonal antibody therapy... (General AD therapy).
• [48] ResearchGate. Design, Current States, and Challenges of Nanomaterials in Anti-Neuroinflammation... (Not directly relevant).
• [110] Navidea Annual Report 2014. (Historical, Lymphoseek focus).
• [101] MDPI. Nuclear Medicine Imaging in Dementia Syndrome: A Narrative Review.
• [102] Science.gov. (General PET scanning info).
• [5] Journal of Nuclear Medicine. Updated Appropriate Use Criteria for Amyloid and Tau PET..[5]
• [23] Journal of Nuclear Medicine. Amyloid Imaging Taskforce Appropriate Use Criteria.
• [90] Journal of Nuclear Medicine. Amyloid beta plaque accumulation with longitudinal [18F]AZD4694 PET..[13]
• [91] NIH Reporter. ADNI4: PET Core. (Mentions NAV4694).
• [49] ResearchGate. (Image of AZD4694 structure).
• [14] Journal of Nuclear Medicine. Determining Amyloid-β Positivity Using 18F-AZD4694 PET Imaging..[14]
• [50] Journal of Nuclear Medicine. Clinical Validation of 18F-AZD4694, an Amyloid-β–Specific PET Radioligand..[50]
• [51] PMC. Amyloid PET tracers: a patent review. (General review).
• [24] Exploration of Targeted Anti-tumor Therapy. PET Radiopharmaceuticals for Alzheimer's Disease and Parkinson's Disease Diagnosis...
• [25] Exploration of Targeted Anti-tumor Therapy..[24]
• [73] ResearchGate. Preclinical Safety Evaluation and Human Dosimetry of [18F]MK-6240....[73]
• [75] ResearchGate. Design, Current States, and Challenges of Nanomaterials....[48]
• [118] PubChem. Flutafuranol F 18. (Site inaccessible).
• [38] KEGG. Flutafuranol F 18 (USAN)..[38]
• [30] Pharmacompass. Flutafuranol (18F)..[30]
• [27] ResearchGate. Head-to-head comparison of11C-PiB and18F-AZD4694 (NAV4694)....[27]
• [19] ResearchGate. Characterization of AZD4694, a novel fluorinated Aβ plaque....[19]
• [50] Journal of Nuclear Medicine. Clinical Validation of 18F-AZD4694....[50]
• [109] EMA. (General EMA search page).
• [92] ClinicalTrials.gov. NCT01886820. (Site inaccessible).
• [93] ClinicalTrials.gov. NCT00991419. (Site inaccessible).
• [94] ClinicalTrials.gov. (Site inaccessible).
• [108] FDA Drugs@FDA. (Site inaccessible).
• [109] EMA..[109]
• [118] PubChem. Flutafuranol F 18. (Site inaccessible).
• [95] ClinicalTrials.gov. (Site inaccessible).
• [103] PubMed. NCT01886820. (Site inaccessible).
• [111] FDA Press Announcements. (General FDA news).
• [112] EMA News. (General EMA news).
• [6] PubMed. Determining Amyloid-β Positivity Using 18F-AZD4694 PET Imaging..[6]
• [118] PubChem. Flutafuranol F 18. (Site inaccessible).
• [6] PubMed. Determining Amyloid-β Positivity Using 18F-AZD4694 PET Imaging..[6]
• [92] ClinicalTrials.gov. NCT01886820. (Site inaccessible).
• [92] ClinicalTrials.gov. NCT01886820. (Site inaccessible).
• [96] ClinicalTrials.gov. (Site inaccessible).
• [119] EMA EPAR Vizamyl. (Dosimetry for flutemetamol).
• [81] FDA Label Amyvid. (Dosimetry for florbetapir).
• [92] ClinicalTrials.gov. NCT01886820. (Site inaccessible).
• [39] PubMed. Clinical validation of 18F-AZD4694....[39]
• [92] ClinicalTrials.gov. NCT01886820. (Site inaccessible).
• [39] PubMed. Clinical validation of 18F-AZD4694....[39]
• [39] PubMed. Clinical validation of 18F-AZD4694....[39]
• [97] ClinicalTrials.gov. NCT01886820. (Site inaccessible).
• [39] PubMed. Clinical validation of 18F-AZD4694....[39]
• [39] PubMed. Clinical validation of 18F-AZD4694....[39]
• [92] ClinicalTrials.gov. NCT01886820. (Site inaccessible).

The report will be structured as per the outline, with detailed elaboration of each point using the cited snippets. The focus will be on synthesizing the information into a coherent narrative, explaining the scientific context and implications of the findings. Tables will be created as suggested. The language will be formal and technical.# Flutafuranol (18F): A Comprehensive Review of a Promising Amyloid-β PET Imaging Agent for Alzheimer's Disease

1. Introduction to Flutafuranol (18F)

Overview

Flutafuranol (18F) is an investigational positron emission tomography (PET) radiopharmaceutical. It is a fluorine-18 (18F) labeled ligand specifically designed for the in vivo detection and quantification of amyloid-β (Aβ) plaques in the human brain.[1] The presence of Aβ plaques is a defining neuropathological characteristic of Alzheimer's disease (AD), a progressive neurodegenerative disorder and the most common cause of dementia.[1]

PET imaging using amyloid-specific tracers like flutafuranol (18F) enables the non-invasive assessment of Aβ pathology. This capability is critical for improving early and differential diagnosis of dementia, facilitating the stratification of patients for enrollment in clinical trials of Aβ-targeting therapies, and monitoring the therapeutic efficacy of such treatments.[3] The ability to visualize and quantify Aβ plaques in vivo has transformed the landscape of AD research, allowing for the study of disease mechanisms in living individuals and the evaluation of interventions aimed at modifying this core pathology.

Rationale for Development

Flutafuranol (18F) was developed to address limitations associated with earlier amyloid PET tracers. The pioneering amyloid PET tracer, 11C-Pittsburgh Compound B (11C-PiB), while demonstrating excellent imaging properties, is limited by the short 20-minute physical half-life of carbon-11. This necessitates an on-site cyclotron for its production, restricting its widespread clinical and research applicability.[19]

The incorporation of fluorine-18, with its longer half-life of approximately 110 minutes, allows for centralized production of flutafuranol (18F) and subsequent distribution to PET imaging centers lacking their own cyclotrons. This significantly enhances the logistical feasibility for broader clinical use and multi-center research studies.[3]

Furthermore, while first-generation 18F-labeled amyloid tracers (e.g., florbetapir, flutemetamol, florbetaben) increased accessibility, some exhibited higher non-specific binding to white matter in the brain. This non-specific binding can complicate image interpretation and reduce the sensitivity for detecting subtle or early-stage Aβ pathology.[3] Flutafuranol (18F) was engineered as a "second-generation" 18F tracer with the aim of combining the favorable imaging characteristics of 11C-PiB, particularly its low non-specific white matter binding, with the practical advantages of the 18F radioisotope.[19] The development trajectory of amyloid PET tracers reflects a continuous effort to balance diagnostic accuracy with practical clinical utility. Flutafuranol (18F) embodies this by aiming to combine the favorable low white matter binding profile, similar to 11C-PiB, with the superior logistical advantages of 18F-labeling. This combination is crucial for enabling large-scale, multi-center clinical trials and for the potential widespread adoption of amyloid PET in clinical dementia evaluations. The successful development of such an agent is critical for advancing the understanding of AD pathogenesis, improving diagnostic accuracy, and accelerating the development of effective treatments.

2. Chemical Properties and Synthesis Highlights

Flutafuranol (18F) is characterized by a specific chemical structure and a set of identifiers that distinguish it in scientific literature and databases.

• Chemical Name (IUPAC): The International Union of Pure and Applied Chemistry (IUPAC) name for the 18F-labeled compound is 2-[2-(18F)fluoro-6-(methylamino)pyridin-3-yl]-1-benzofuran-5-ol.[8] Its non-radioactive isotopologue, containing fluorine-19, is named 2-[2-fluoro-6-(methylamino)pyridin-3-yl]-1-benzofuran-5-ol.[31]
• Synonyms: Flutafuranol (18F) is widely known in research and development by several synonyms, most prominently [18F]NAV4694 and [18F]AZD4694. Other identifiers include Flutafuranol F 18 (USAN) and Flutafuranol (18F) (INN) [[1], S_

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