An In-Depth Analysis of Alovudine F-18 ([18F]FLT) as a Radiopharmaceutical for Oncologic Imaging

Executive Summary

Alovudine F-18, more commonly known in the scientific literature as 3'-deoxy-3'-[$^{18}$F]fluorothymidine or [$^{18}$F]FLT, is an investigational small molecule radiopharmaceutical designed for the non-invasive imaging of cellular proliferation using Positron Emission Tomography (PET). As an isotopologue of the antiviral drug alovudine, its developmental history is bifurcated, originating from a therapeutic agent whose clinical progression was halted due to significant toxicity. However, when administered at tracer-level doses for diagnostic imaging, [$^{18}$F]FLT exhibits an excellent safety profile, a critical distinction that underpins its modern application.

The primary mechanism of [$^{18}$F]FLT involves its active transport into cells and subsequent phosphorylation by thymidine kinase 1 (TK1), an enzyme whose expression is tightly regulated and significantly upregulated during the S-phase of the cell cycle. This enzymatic trapping leads to the accumulation of the radiotracer in proliferating tissues, providing a quantitative surrogate for the rate of DNA synthesis via the salvage pathway. Unlike its metabolic counterpart, 2-deoxy-2-[$^{18}$F]fluoro-D-glucose ([$^{18}$F]FDG), which measures glucose metabolism, [$^{18}$F]FLT offers a more direct and specific assessment of tumor proliferation, a fundamental hallmark of cancer. This specificity allows it to better distinguish malignant tissue from sites of inflammation or infection, a significant limitation of [$^{18}$F]FDG.

Despite its specificity, the clinical utility of [$^{18}$F]FLT is nuanced. It generally exhibits lower tumor-to-background contrast than [$^{18}$F]FDG, and its high physiological uptake in the bone marrow and liver restricts its application for assessing disease in these regions. Conversely, its low background signal in the central nervous system makes it a superior agent for imaging high-grade gliomas. Extensive clinical investigation across a range of malignancies—including lung, breast, hematologic, and brain cancers—has demonstrated its value as a pharmacodynamic biomarker for monitoring early response to therapy, particularly for cytostatic agents like cyclin-dependent kinase (CDK) inhibitors.

Currently, [$^{18}$F]FLT remains an investigational agent. Its progression into broader clinical use has been significantly enabled by regulatory innovations, such as the establishment of a centralized, multi-center Investigational New Drug (IND) application by the Society of Nuclear Medicine (SNM), which has streamlined its use in large-scale clinical trials. This report provides a comprehensive analysis of [$^{18}$F]FLT, detailing its physicochemical properties, developmental history, complex pharmacology, radiopharmaceutical profile, and its evolving role in clinical oncology, ultimately positioning it as a powerful, specialized tool for precision medicine and drug development.

Compound Identification and Physicochemical Properties

A precise and unambiguous identification of the molecular entity is foundational to any rigorous scientific analysis. Alovudine F-18 is known by several names and identifiers across various chemical, medical, and regulatory databases. This section consolidates this information to provide a definitive profile of the compound.

Nomenclature and Identification

The compound is most frequently referred to in scientific and clinical literature as Fluorothymidine F-18, or by the acronym [$^{18}$F]FLT.[1] The name Alovudine F-18 is also used, particularly in databases like DrugBank, to denote the fluorine-18 radiolabeled isotopologue of the drug alovudine.[1]

• Systematic (IUPAC) Name: The formal chemical name, which describes the molecule's structure with stereochemistry, is 1--5-methylpyrimidine-2,4-dione.[2]
• Synonyms: A wide array of synonyms exists due to its development across different fields. These include, but are not limited to: [$^{18}$F]Fluorothymidine, 18F-3'-Fluoro-3'-deoxythymidine, 3'-deoxy-3'-($^{18}$F)fluorothymidine, ($^{18}$F)FLT, FLT F-18, and [$^{18}$F]FLUDEOXYTHYMIDINE.[1] The comprehensive list of synonyms is crucial for conducting exhaustive literature searches and cross-referencing information between disparate data sources.
• Key Identifiers: The molecule is uniquely cataloged in major scientific databases through specific codes:
• CAS Number: 287114-80-1.[1] This number is the standard identifier for chemical substances.
• DrugBank ID: DB14930.[2] This identifier links the compound to a rich repository of drug and target information.
• UNII (Unique Ingredient Identifier): 2X1K91UT6N.[1] This is used by regulatory bodies like the FDA for substance registration.
• Other Identifiers: Additional codes include PubChem CID 9878109, ChEMBL ID CHEMBL5314940, and NCI Thesaurus Code C49093, which facilitate integration with various bioinformatics and chemoinformatics platforms.[2]

Chemical Structure and Properties

Alovudine F-18 is a small molecule classified as a pyrimidine 2',3'-dideoxyribonucleoside.[6] It is a structural analogue of thymidine, where the hydroxyl group at the 3' position of the deoxyribose sugar is replaced by a fluorine-18 radioisotope.

• Molecular Formula: $C_{10}H_{13}^{18}FN_{2}O_{4}$.[1] The formula explicitly includes the $^{18}$F isotope.
• Molecular Weight: The average molecular weight is approximately 244.22 g/mol.[1] Some databases report a value of 243.22 g/mol, which reflects calculations based on the specific isotopic mass of $^{18}$F rather than the average atomic weight of fluorine.[2] The monoisotopic mass is 243.088469 Da.[2]
• Structural Representations: The precise three-dimensional structure and connectivity are captured by standard chemical notations:
• SMILES (Simplified Molecular Input Line Entry System): CC1=CN(C(=O)NC1=O)[C@H]2C[C@@H]([C@H](O2)CO)[18F].[1] This text-based format encodes the molecular structure, including stereochemistry.
• InChI (International Chemical Identifier): InChI=1S/C10H13FN2O4/c1-5-3-13(10(16)12-9(5)15)8-2-6(11)7(4-14)17-8/h3,6-8,14H,2,4H2,1H3,(H,12,15,16)/t6-,7+,8+/m0/s1/i11-1.[2] The final layer, /i11-1, specifically denotes that the fluorine atom (atom 11) is the $^{18}$F isotope.
• InChIKey: UXCAQJAQSWSNPQ-ZIVQXEJRSA-N.[2] This hashed version of the InChI is used for database indexing and searching.
• Computed Physicochemical Properties: Computational models predict key properties that influence the molecule's pharmacokinetic behavior. It is a relatively polar molecule, with a predicted water solubility of 79.2 mg/mL and a negative XLogP3 value of -0.3, indicating hydrophilicity.[2] It has 2 hydrogen bond donors and 5 hydrogen bond acceptors, with a polar surface area of 78.9 Ų.[2] These properties are consistent with a molecule that requires active transport to cross cell membranes rather than passive diffusion.

Table 1: Compound Identification and Key Properties of Alovudine F-18 / [18F]FLT
Preferred Name	Fluorothymidine F-18 / [18F]FLT
IUPAC Name	1--5-methylpyrimidine-2,4-dione
CAS Number	287114-80-1
DrugBank ID	DB14930
UNII	2X1K91UT6N
Molecular Formula	$C_{10}H_{13}^{18}FN_{2}O_{4}$
Molar Mass	~244.22 g/mol
SMILES String	CC1=CN(C(=O)NC1=O)[C@H]2C[C@@H]([C@H](O2)CO)[18F]
InChIKey	UXCAQJAQSWSNPQ-ZIVQXEJRSA-N

Developmental Trajectory: A Tale of Two Molecules

The history of [$^{18}$F]FLT is unique among radiopharmaceuticals, as its identity is inextricably linked to its non-radioactive analogue, alovudine. Understanding the separate and distinct developmental paths of these two molecules—one a failed therapeutic, the other a promising diagnostic—is essential for appreciating the safety profile, clinical context, and regulatory journey of [$^{18}$F]FLT.

Alovudine (Fluorothymidine): The Antiviral Precursor

In the late 1980s and early 1990s, the compound 3'-fluoro-3'-deoxythymidine, known as alovudine (or FLT), was developed by Medivir as a potential antiviral agent for the treatment of Human Immunodeficiency Virus (HIV) infection.[13] Its mechanism of action was analogous to other nucleoside reverse transcriptase inhibitors (NRTIs) like zidovudine (AZT). As a dideoxynucleoside analogue of thymidine, alovudine is converted intracellularly to its 5'-triphosphate metabolite, which then acts as a competitive inhibitor of the HIV reverse transcriptase enzyme. Lacking the 3'-hydroxyl group necessary for phosphodiester bond formation, its incorporation into the growing viral DNA strand results in premature chain termination, thereby halting viral replication.[12]

Early clinical trials demonstrated that alovudine possessed potent anti-HIV activity, significantly reducing viral load in patients, even those with resistance to other NRTIs.[15] However, its clinical development was ultimately terminated in 2005 during Phase II trials due to an unacceptable toxicity profile.[13] The therapeutic doses required for antiviral efficacy were associated with severe, dose-dependent adverse effects. Prominent among these were hematological toxicities, including significant anemia and leukopenia.[15] Most alarmingly, the trials were halted following the unexpected death of two subjects from hepatic failure.[16] This severe toxicity profile led to the discontinuation of alovudine's development as a therapeutic drug.

[18F]FLT: Rebirth as an Oncologic Imaging Agent

The failure of alovudine as a therapeutic did not end the story of the fluorothymidine molecule. Instead, it was repurposed for an entirely different application in oncology, based on a fundamental principle of nuclear medicine: the tracer principle. This principle dictates that a substance can be used to trace a biological process if it is administered in such a minute quantity that it does not perturb the process it is intended to measure.

The critical distinction between the failed drug and the successful imaging agent lies in the administered dose. The therapeutic trials of alovudine involved daily administration of milligram-level quantities (e.g., doses of 0.125 mg/kg) over weeks or months to achieve a pharmacological effect.[15] In stark contrast, a PET scan with [$^{18}$F]FLT involves a single intravenous injection containing a total mass of the compound in the microgram range (typically less than 10 µg).[16] This represents a dose that is thousands of times lower than the toxic pharmacological dose, rendering it pharmacologically inert and devoid of the toxicities observed with alovudine.[17]

The rationale for developing [$^{18}$F]FLT stemmed from the limitations of the most common oncologic PET tracer, [$^{18}$F]FDG. While [$^{18}$F]FDG is an excellent marker of the elevated glucose metabolism found in most cancers, its uptake is not specific to malignancy and can be high in areas of inflammation or infection, leading to false-positive results.[20, 21, 22, 23] Researchers sought a tracer that could image a more specific hallmark of cancer: uncontrolled cellular proliferation. Because the salvage pathway for DNA synthesis is highly active in dividing cells, a radiolabeled thymidine analogue like [$^{18}$F]FLT was an ideal candidate.[22, 24] Pioneering research in the late 1990s and early 2000s demonstrated that [$^{18}$F]FLT uptake in tumors correlated strongly with TK1 activity and established proliferation markers like Ki-67, validating its potential as a non-invasive biomarker of proliferation.[1]

The history of alovudine's toxicity has cast a long shadow, creating a potential for confusion and a non-technical barrier to the clinical adoption of [$^{18}$F]FLT. A clinician or regulator unfamiliar with the nuances of radiopharmacology might associate the name "fluorothymidine" with the severe adverse events reported in the HIV trials. This historical context necessitates that any discussion of [$^{18}$F]FLT's safety must explicitly and forcefully articulate the distinction between a therapeutic and a tracer dose, presenting the robust safety data for the imaging agent in direct contrast to the toxicity data of the failed drug.

Regulatory Landscape and Pathway to Clinical Use

[$^{18}$F]FLT is currently classified as an investigational diagnostic radiopharmaceutical. It has not received marketing approval from the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA) for routine clinical use and is therefore restricted to clinical trials and research settings.[26]

The regulatory pathway for [$^{18}$F]FLT in the United States has been characterized by a series of innovative steps that have facilitated its widespread investigation. Initially, its use was confined to a few academic institutions that had the resources to file and maintain their own single-site Investigational New Drug (IND) applications with the FDA.[28] This model severely limited the scale of research. A major breakthrough came when the National Cancer Institute (NCI) established a master FLT IND. This allowed more than 20 different research entities to cross-reference the NCI's master file, significantly reducing the regulatory burden and broadening access to the tracer for NCI-sponsored trials.[18]

The most pivotal regulatory development occurred in 2009, when the FDA approved a centralized, multi-center IND sponsored by the Society of Nuclear Medicine (SNM).[28] This was a landmark decision for the field of molecular imaging. The short half-life of fluorine-18 (approx. 110 minutes) necessitates that PET radiopharmaceuticals be produced locally or regionally, often at academic centers. This reality leads to minor variations in synthesis methods and equipment across different sites.[28] Requiring a single, standardized manufacturing process for a multi-center trial would be logistically prohibitive. The SNM's centralized IND addressed this challenge by proposing a novel regulatory framework: the FDA agreed to base its acceptance of the tracer on the final product meeting a unified set of quality and purity specifications, rather than on the specific manufacturing process used to create it.[28] This pragmatic and flexible approach removed a major bottleneck, enabling the launch of large-scale, multi-center clinical trials and facilitating the use of [$^{18}$F]FLT as a pharmacodynamic biomarker in therapeutic drug development by pharmaceutical companies.[28]

In Europe, the regulatory status is less centralized. While the EMA provides overarching guidelines for the clinical evaluation of radiopharmaceuticals, there is no specific marketing authorization for [$^{18}$F]FLT.[32] Its use is governed by national regulations and is confined to research protocols and clinical trials approved by local ethics committees and regulatory bodies.

Molecular Pharmacology and Pharmacokinetics

The clinical utility of [$^{18}$F]FLT is dictated by its precise interactions with cellular machinery and its behavior within the human body. Its mechanism of action provides a window into the DNA salvage pathway, while its pharmacokinetic profile defines its strengths and limitations as an imaging agent.

Mechanism of Action: Imaging the Salvage Pathway

The accumulation of [$^{18}$F]FLT in proliferating tissues is a multi-step process that exploits the cellular machinery for DNA synthesis.

• Cellular Transport: As a hydrophilic nucleoside analogue, [$^{18}$F]FLT does not freely diffuse across the lipid bilayer of the cell membrane. Its entry into the cell is an active process mediated by specialized protein channels. The primary transporter responsible for [$^{18}$F]FLT influx is the human equilibrative nucleoside transporter 1 (hENT1).[23] The expression and membrane localization of this transporter can be a key determinant of tracer uptake.
• Rate-Limiting Step and Intracellular Trapping: The defining step in the mechanism of [$^{18}$F]FLT is its phosphorylation by the enzyme thymidine kinase 1 (TK1).[1, 21, 26, 37, 38] TK1 is a key enzyme in the nucleoside salvage pathway, which recycles thymidine from the extracellular environment for DNA synthesis. The expression and activity of TK1 are tightly linked to the cell cycle, with levels increasing dramatically during the S-phase (synthesis phase) when DNA replication occurs.[23, 24, 38] TK1 converts [$^{18}$F]FLT into [$^{18}$F]FLT-monophosphate. This phosphorylated product carries a negative charge, which prevents it from crossing back out of the cell membrane, effectively trapping the radioactivity inside the cell.[2] While further phosphorylation to diphosphate and triphosphate forms can occur, the initial phosphorylation by TK1 is the rate-limiting step for retention.[40] Thus, the intensity of the PET signal is considered a direct surrogate for TK1 activity and, by extension, the rate of cellular proliferation.
• Lack of DNA Incorporation: A crucial feature of [$^{18}$F]FLT is the substitution of the 3'-hydroxyl group with a fluorine-18 atom. The 3'-hydroxyl group is essential for the formation of the phosphodiester bond that links nucleotides together in a DNA strand. Because [$^{18}$F]FLT lacks this group, it cannot be incorporated into DNA by DNA polymerases.[1] It acts as a chain terminator. This means the PET signal reflects the "front-end" activity of the salvage pathway (i.e., TK1 activity) rather than the final step of DNA incorporation itself.

Pharmacokinetics and Biodistribution

The movement and disposition of [$^{18}$F]FLT throughout the body determine its patterns of uptake on a PET scan and define its clinical applications.

• Administration and Distribution: [$^{18}$F]FLT is administered as a single bolus intravenous injection.[38, 44, 45] Following injection, it distributes throughout the body via the bloodstream. A key characteristic is its inability to effectively cross the intact blood-brain barrier, which results in very low background radioactivity in the normal brain parenchyma.[2, 19, 39] This is a major advantage over [$^{18}$F]FDG for neuro-oncology applications, as the high glucose metabolism of the normal brain creates a high-background environment that can obscure tumors on an [$^{18}$F]FDG PET scan.
• Physiological Biodistribution: The whole-body distribution of [$^{18}$F]FLT is dominated by uptake in tissues with high rates of normal cellular proliferation and in organs involved in its metabolism and excretion.
• Bone Marrow: The highest physiological uptake is observed in the red bone marrow, which is a site of constant hematopoietic cell division.[2]
• Liver: The liver also demonstrates high uptake, as it is the primary site of [$^{18}$F]FLT metabolism.[2]
• The high physiological uptake in the liver and bone marrow represents a fundamental limitation of [$^{18}$F]FLT. It makes the tracer unsuitable for reliably detecting or monitoring tumors located in or near the liver (e.g., liver metastases) and complicates the assessment of bone marrow involvement by hematologic malignancies or the evaluation of chemotherapy-induced myelosuppression.[19, 23, 47, 48] This biodistribution profile effectively defines the clinical niches where [$^{18}$F]FLT is most useful—namely, in anatomical regions with low physiological proliferation, such as the brain, lung, and soft tissues.
• Metabolism and Excretion: [$^{18}$F]FLT is relatively stable in vivo and is not a substrate for thymidine phosphorylase, the enzyme that rapidly degrades thymidine.[26] Its main metabolic fate is conjugation with glucuronic acid in the liver to form [$^{18}$F]FLT-glucuronide.[19, 49] This hydrophilic metabolite is not transported into cells and is cleared from the bloodstream. For quantitative kinetic modeling of [$^{18}$F]FLT uptake, it is essential to measure the fraction of tracer in the blood that remains as the parent compound over time and use this "metabolite-corrected arterial input function" in the calculations.[35, 38] The primary route of excretion for both unchanged [$^{18}$F]FLT and its glucuronide metabolite is via the kidneys into the urine. Consequently, high levels of radioactivity are seen in the renal system and accumulate in the urinary bladder.[37]

Pharmacodynamics: Linking Tracer Uptake to Biological Effect

The pharmacodynamic utility of [$^{18}$F]FLT lies in its ability to non-invasively measure changes in tumor proliferation in response to therapy.

• Correlation with Proliferation Markers: The validity of [$^{18}$F]FLT as a proliferation biomarker is firmly established by numerous studies demonstrating a strong, statistically significant positive correlation between its uptake (quantified by the Standardized Uptake Value, or SUV) and the Ki-67 labeling index, the gold-standard immunohistochemical marker for cellular proliferation, across a wide range of cancers including lung cancer, lymphoma, and gliomas.[16]
• Modulation by Therapeutics: The change in [$^{18}$F]FLT uptake following cancer therapy is highly dependent on the mechanism of action of the therapeutic agent. This dual nature makes it a sophisticated pharmacodynamic tool.
• Response to Cytostatic Agents: For therapies that work by inducing cell cycle arrest (cytostatic effect), such as cyclin-dependent kinase (CDK) 4/6 inhibitors (e.g., palbociclib, ribociclib), the expected response is a decrease in [$^{18}$F]FLT uptake. By halting progression through the cell cycle, these drugs reduce the proportion of cells in the S-phase, leading to downregulation of TK1 expression and consequently, reduced tracer trapping.[50, 51, 52] A drop in [$^{18}$F]FLT SUV can therefore serve as an early indicator of successful anti-proliferative effect.
• Response to Thymidylate Synthase (TS) Inhibitors: A more complex and fascinating pharmacodynamic response is observed with inhibitors of thymidylate synthase (TS), such as 5-fluorouracil (5-FU) or its prodrug capecitabine. TS is the key enzyme in the de novo DNA synthesis pathway. When this pathway is blocked, cancer cells attempt to compensate by upregulating the salvage pathway. This compensatory response involves increasing the expression and activity of both the hENT1 transporter and TK1.[35] The result is a paradoxical increase in [$^{18}$F]FLT uptake, often termed a "flare," which occurs shortly after the administration of a TS inhibitor.[35, 53] In this context, an increase in [$^{18}$F]FLT uptake does not indicate treatment failure (i.e., increased proliferation), but rather successful *target engagement* by the TS inhibitor. This makes [$^{18}$F]FLT a unique tool for confirming that a TS inhibitor has reached its target and exerted its intended biochemical effect in vivo.

This mechanistic duality underscores that the interpretation of a change in [$^{18}$F]FLT PET imaging is not universally straightforward. Unlike [$^{18}$F]FDG, where a decrease in uptake almost always signals a positive treatment response, the interpretation of an [$^{18}$F]FLT scan requires a priori knowledge of the therapeutic agent's mechanism of action. This complexity is both a powerful asset for nuanced drug development studies and a potential pitfall if the tracer is used without appropriate context in a general clinical setting.

Radiopharmaceutical Profile: Synthesis and Dosimetry

The practical implementation of [$^{18}$F]FLT PET imaging depends on its reliable and efficient production as a radiopharmaceutical and a thorough understanding of its radiation safety profile in humans.

Radiosynthesis of [18F]FLT

The production of [$^{18}$F]FLT is a multi-step process that begins with the generation of the radionuclide and concludes with a purified, sterile product suitable for intravenous injection.

• Radionuclide Production: The positron-emitting radionuclide fluorine-18 ($^{18}$F) is produced using a medical cyclotron. The most common nuclear reaction is the proton bombardment of oxygen-18-enriched water ([¹⁸O]H₂O), denoted as $ ^{18}O(p,n)^{18}F$. This process yields aqueous [¹⁸F]fluoride ion with a high specific activity and a physical half-life of approximately 109.7 minutes.[25] The relatively long half-life (compared to carbon-11, for example) allows for complex chemical synthesis, quality control, and distribution to nearby imaging centers.
• Radiolabeling Chemistry: The most prevalent method for synthesizing [$^{18}$F]FLT is a two-step, one-pot nucleophilic aromatic substitution reaction, which is often automated on commercial synthesis modules.[57]

1. Fluorination: The aqueous [¹⁸F]fluoride is first dried and activated. This is achieved by adding a phase transfer catalyst, typically a combination of potassium carbonate and a cryptand such as Kryptofix 2.2.2, followed by azeotropic distillation with acetonitrile.[25] The resulting anhydrous, highly reactive [¹⁸F]fluoride complex is then reacted with a protected precursor molecule in a dipolar aprotic solvent (e.g., acetonitrile) at an elevated temperature (e.g., 120 °C).[54] The precursor is a thymidine derivative with a good leaving group (e.g., tosylate, mesylate, or, more efficiently, nosylate) at the 3' position and protecting groups on the 5'-hydroxyl and 3-N positions to prevent side reactions.[58] The [¹⁸F]fluoride displaces the leaving group to form the radiolabeled, protected intermediate.
2. Deprotection: The protecting groups are then removed, typically via acidic hydrolysis by adding hydrochloric acid (HCl) and heating (e.g., 110 °C for 5 minutes).[57] This step yields the final [$^{18}$F]FLT product.

• Purification and Quality Control: The crude reaction mixture contains the desired [$^{18}$F]FLT product along with unreacted precursor, chemical byproducts, and residual reagents. This mixture must be purified to meet stringent standards for human administration. Early methods relied on High-Performance Liquid Chromatography (HPLC), which is effective but can be time-consuming and complex.[58, 59] More recent and efficient methods utilize a series of solid-phase extraction (SPE) cartridges. This approach is more amenable to automation, reduces synthesis time, and can be readily implemented on commercial synthesis modules designed for [$^{18}$F]FDG production.[57] The final product is formulated in a sterile, injectable solution (e.g., normal saline with a small amount of ethanol for stabilization).[58] Rigorous quality control tests are performed on each batch to confirm its identity, radiochemical purity (typically >99%), pH, sterility, and absence of pyrogens before it is released for patient use.[18]

Radiation Dosimetry and Safety Profile

Understanding the radiation dose delivered to the patient is a critical aspect of safety for any radiopharmaceutical. Dosimetry for [$^{18}$F]FLT has been well-characterized through human imaging studies.

• Human Dosimetry: The radiation-absorbed doses to various organs and the total body effective dose have been calculated using standardized methods (MIRD formalism). The data show that for a typical administration, the effective dose equivalent (EDE) is approximately 0.028 mSv/MBq for a standard male and 0.033 mSv/MBq for a standard female, assuming a single bladder voiding at 6 hours post-injection.[37]
• Critical Organs: The organs that receive the highest radiation-absorbed dose are those involved in the tracer's excretion and metabolism, as well as tissues with high physiological proliferation. In descending order of dose received, these are:

1. Urinary Bladder Wall: Receives the highest dose due to the accumulation of excreted radioactivity in the urine.[37]
2. Liver: The primary site of metabolism.[37]
3. Kidneys: Involved in filtering the tracer from the blood.[37]
4. Red Bone Marrow: A site of high physiological cell turnover.[37]

• Safety and Adverse Effects: The overall radiation risk associated with a diagnostic [$^{18}$F]FLT PET scan is considered to be within accepted limits and is comparable to that of other commonly performed nuclear medicine procedures, including [$^{18}$F]FDG PET.[37, 43] In numerous clinical trials involving tracer-level doses, [$^{18}$F]FLT has been shown to be safe and well-tolerated.[17, 60] No significant adverse events directly attributable to the radiopharmaceutical itself have been reported. One study noted an asymptomatic rise in blood pressure in one subject, which was attributed to discomfort from the imaging procedure rather than the tracer.[17] Minor, transient decreases in hematocrit and hemoglobin have also been observed, but these were attributed to the intravenous hydration given during the scan and not to a pharmacological effect of [$^{18}$F]FLT.[17] The primary contraindications for an [$^{18}$F]FLT scan are pregnancy and breastfeeding, due to the unknown effects of radiation on a developing fetus or nursing infant.[61]

Table 2: Summary of Radiation Dosimetry for [18F]FLT in Standard Adults	Absorbed Dose (mGy/MBq)	Absorbed Dose (mGy/MBq)
Organ	Male	Female
Bladder Wall	0.179	0.174
Liver	0.045	0.064
Kidneys	0.035	0.042
Red Marrow	0.024	0.033
Effective Dose Equivalent	0.028 mSv/MBq	0.033 mSv/MBq
Source: 37

Clinical Utility in Positron Emission Tomography (PET)

The clinical value of [$^{18}$F]FLT is defined by its ability to provide unique biological information about tumors, particularly in contexts where the standard-of-care tracer, [$^{18}$F]FDG, has limitations. Its role is not as a universal replacement for [$^{18}$F]FDG, but as a specialized tool for specific oncologic questions related to proliferation and therapeutic response.

Comparative Analysis: [18F]FLT versus [18F]FDG

A direct comparison between [$^{18}$F]FLT and [$^{18}$F]FDG highlights their complementary nature.

• Biological Process Imaged: The most fundamental difference lies in the biological pathway each tracer interrogates. [$^{18}$F]FDG measures glucose transport and phosphorylation by hexokinase, reflecting metabolic activity.[19, 21][$^{18}$F]FLT measures nucleoside transport and phosphorylation by thymidine kinase 1, reflecting DNA synthesis and cellular proliferation.[2]
• Imaging Characteristics: In most tumor types, [$^{18}$F]FDG provides images with higher tumor uptake and superior tumor-to-background contrast. The mean Standardized Uptake Value (SUV) for [$^{18}$F]FDG is often significantly higher than for [$^{18}$F]FLT in the same lesion.[19, 22, 63] This means that small or moderately proliferative tumors may be more conspicuous on an [$^{18}$F]FDG scan.
• Specificity for Malignancy: [$^{18}$F]FLT generally exhibits higher specificity for malignancy. The high glucose metabolism measured by [$^{18}$F]FDG is not unique to cancer; it is also a feature of activated immune cells. Consequently, [$^{18}$F]FDG avidly accumulates in sites of infection and inflammation, which can lead to false-positive findings that mimic or obscure cancer.[2, 19, 23, 64] While [$^{18}$F]FLT uptake in inflammatory cells is significantly lower, it is not entirely absent, as some degree of proliferation can occur in immune responses. Nonetheless, its ability to differentiate tumor from inflammation is a key advantage.[16]

Table 3: Comparative Profile of [18F]FLT vs. [18F]FDG
Feature	[18F]FLT	[18F]FDG
Biological Process Imaged	Cellular Proliferation (DNA Salvage Pathway)	Glucose Metabolism
Key Enzyme	Thymidine Kinase 1 (TK1)	Hexokinase
Typical Tumor SUV	Lower to Moderate	Moderate to High
Specificity vs. Inflammation	High (low uptake in inflammation)	Low (high uptake in inflammation)
Main Limitation	High background in bone marrow/liver; lower signal	Low specificity vs. inflammation; high brain background
Key Advantage	High specificity for proliferation; low brain background	High sensitivity; widely available; robust signal
Primary Clinical Application	Monitoring anti-proliferative therapy; neuro-oncology	Staging, restaging, monitoring metabolic therapy response

Applications in Major Malignancies

Clinical trials have explored the use of [$^{18}$F]FLT across a spectrum of cancers, defining its potential role in each disease context.

• Central Nervous System (CNS) Tumors: This is arguably the most promising clinical application for [$^{18}$F]FLT. The normal brain has very high glucose metabolism, creating a high-background environment that makes it difficult to delineate tumors with [$^{18}$F]FDG. In contrast, normal brain tissue has a very low proliferation rate and thus exhibits minimal [$^{18}$F]FLT uptake.[19, 25] This results in excellent tumor-to-background contrast for high-grade gliomas. Studies have shown that [$^{18}$F]FLT uptake correlates strongly with the Ki-67 proliferation index and is a more sensitive marker for recurrent high-grade tumors than [$^{18}$F]FDG. Furthermore, the intensity of [$^{18}$F]FLT uptake has been shown to be a powerful independent predictor of tumor progression and patient survival.[6]
• Lung Cancer: [$^{18}$F]FLT has been extensively studied in non-small cell lung cancer (NSCLC) for diagnosis, staging, and therapy response assessment. Its uptake correlates well with proliferation markers and can provide early evidence of response to treatment.[20, 24] However, its overall performance compared to [$^{18}$F]FDG has been mixed. Some studies have found that while [$^{18}$F]FLT is more specific, [$^{18}$F]FDG remains a better overall predictor of progression-free and overall survival in patients treated with certain therapies.[6]
• Breast Cancer: In breast cancer, [$^{18}$F]FLT PET is being investigated primarily as a tool for monitoring response to systemic therapies. It has shown particular promise in evaluating the effects of CDK4/6 inhibitors (like ribociclib) and chemotherapy (like paclitaxel). A decrease in [$^{18}$F]FLT uptake can be detected very early in the treatment course, serving as a non-invasive pharmacodynamic biomarker that may predict eventual clinical benefit.[6]
• Hematologic Malignancies: The application of [$^{18}$F]FLT in diseases like lymphoma and leukemia is complex. While it can effectively visualize highly proliferative lymphoma lesions and has been used to assess changes in bone marrow after chemotherapy, its utility is hampered by the high physiological uptake in healthy bone marrow.[1, 23, 44, 69, 70] This high background can mask diffuse bone marrow infiltration at baseline, making it less suitable for initial staging compared to [$^{18}$F]FDG. Its role may be more focused on monitoring response in extramedullary sites or using advanced quantitative methods to discern therapeutic effects within the marrow itself.[6]

Role in Monitoring Therapeutic Response

The most significant potential for [$^{18}$F]FLT lies in its application as a biomarker for assessing treatment response, particularly in the context of modern targeted therapies and drug development.

• Early Response Assessment: A key advantage of functional imaging with PET is the ability to detect biological changes in a tumor long before they manifest as changes in size on anatomical imaging like CT or MRI. [$^{18}$F]FLT PET can detect a shutdown in proliferation within days or weeks of initiating an effective cytostatic therapy.[1] This could allow clinicians to identify non-responders early and switch them to a more effective treatment, personalizing therapy and avoiding the toxicity and cost of ineffective regimens.
• Pharmacodynamic Biomarker in Drug Development: [$^{18}$F]FLT is increasingly being integrated into early-phase (Phase 0, I, and II) clinical trials of novel anti-cancer drugs. In this setting, it serves as a non-invasive pharmacodynamic biomarker to provide proof-of-concept that a new drug is engaging its target and exerting the intended biological effect (e.g., inhibiting proliferation) in human tumors.[8] This can help in selecting the optimal biological dose for further studies and can accelerate the drug development process by providing early go/no-go decisions.[28]
• Predicting Clinical Outcomes: Several studies have demonstrated that the magnitude of the change in [$^{18}$F]FLT uptake early in the course of treatment is predictive of long-term clinical outcomes. A significant decrease in [$^{18}$F]FLT SUV after one or two cycles of therapy has been correlated with improved progression-free survival (PFS) and overall survival (OS) in various cancers, positioning it as a powerful prognostic biomarker.[25]

Synthesis and Strategic Recommendations

Alovudine F-18, or [$^{18}$F]FLT, has been established as a robust and specific PET radiotracer for imaging cellular proliferation. Its journey from a failed therapeutic concept to a sophisticated diagnostic tool highlights the critical importance of the tracer principle in nuclear medicine. While not a universal replacement for [$^{18}$F]FDG, it occupies several crucial niches in clinical oncology and drug development. A strategic assessment of its current status reveals clear limitations that must be acknowledged, as well as promising future directions that could lead to its broader clinical integration.

Current Limitations and Clinical Challenges

Despite its strengths, several challenges currently limit the widespread clinical adoption of [$^{18}$F]FLT.

• Lower Signal Intensity: Compared to [$^{18}$F]FDG, [$^{18}$F]FLT generally produces a lower uptake signal in tumors. This can make the detection of small-volume or slowly proliferating lesions challenging and may result in lower overall sensitivity for initial tumor detection compared to [$^{18}$F]FDG.[19]
• Unfavorable Biodistribution: The high physiological uptake in the liver and, most significantly, the bone marrow, fundamentally restricts its clinical utility. It is not a suitable agent for assessing liver metastases, primary bone marrow malignancies, or for routine whole-body staging where bone involvement is a key question.[19]
• Complexity of Interpretation: The pharmacodynamic response of [$^{18}$F]FLT is highly dependent on the mechanism of the co-administered therapy. The paradoxical "flare" phenomenon with TS inhibitors, while a powerful tool for experts, introduces a layer of complexity that could lead to misinterpretation in a general clinical setting if the treating physician is not fully aware of the underlying pharmacology.[35]
• Logistical and Financial Hurdles: As an investigational agent, [$^{18}$F]FLT is not commercially available on a wide scale. Its use is limited to academic centers with the necessary cyclotron and radiochemistry infrastructure to produce it on-site under an IND. Furthermore, without FDA approval, reimbursement from payers is not standardized, creating a significant financial barrier to its routine use outside of funded clinical trials.

Future Research Directions and Potential for Clinical Integration

The future of [$^{18}$F]FLT in oncology will likely involve a focused strategy to leverage its unique strengths while mitigating its weaknesses.

• Refining Clinical Niches: The most direct path to clinical integration is to generate definitive evidence for its superiority in specific, well-defined clinical scenarios. The strongest evidence to date is in neuro-oncology for grading high-grade gliomas and differentiating recurrence from treatment effects. Further large-scale trials should focus on solidifying this application. Another key niche is as the preferred biomarker for monitoring response to therapies with a purely cytostatic mechanism, such as CDK inhibitors, where metabolic changes may be less pronounced.
• Multi-Tracer and Multi-Modal Imaging: The future of molecular imaging lies in providing a more complete biological profile of a tumor. Research protocols combining [$^{18}$F]FLT PET with [$^{18}$F]FDG PET (to assess both proliferation and metabolism) or with tracers for other hallmarks of cancer, such as hypoxia (e.g., [$^{18}$F]FMISO), could provide a multi-parametric snapshot of tumor biology. This comprehensive view could be invaluable for understanding tumor heterogeneity and predicting response to combination therapies.[69]
• Integration into Adaptive Clinical Trials: [$^{18}$F]FLT is ideally suited for use as an early decision-making tool in adaptive trial designs. An [$^{18}$F]FLT PET scan performed after a short course of a novel anti-proliferative agent could rapidly stratify patients into "responder" and "non-responder" cohorts. Non-responders could then be immediately switched to an alternative therapy, optimizing patient outcomes and increasing the efficiency of the trial.
• Pathway to Regulatory Approval: The ultimate goal for clinical integration is regulatory approval. The centralized IND model has paved the way for the necessary large, multi-center trials. The path forward requires the oncologic imaging community to design and execute pivotal trials that demonstrate that the use of [$^{18}$F]FLT imaging to guide treatment decisions leads to improved patient outcomes (e.g., improved survival, reduced toxicity) in a specific clinical indication. Success in a well-chosen niche, such as glioma management, could provide the foundation for its first New Drug Application (NDA) and subsequent broader adoption.

In conclusion, [$^{18}$F]FLT stands as a testament to successful scientific repurposing. It is a highly specific and powerful tool for visualizing a core process of cancer biology. While its limitations preclude it from being a universal oncologic tracer, its strengths in specific clinical contexts and its indispensable role as a pharmacodynamic biomarker in drug development secure its place as a key agent in the advancement of precision oncology.

Appendices

Appendix A: Comprehensive List of Synonyms and Identifiers

• Synonyms: (18F) FLT, (18F)-FLT, (18F)FLT, (F-18)FLT, 18F-3'-Fluoro-3'-deoxythymidine, 18F-FLT, 3'-Deoxy-3'-(18F) Fluorothymidine, 3'-Deoxy-3'-($^{18}$F)fluorothymidine, 3'-Deoxy-3'-[18F]fluorothymidine, Alovudine (18F) Injection, Alovudine F-18, F-18 Fluorothymidine, FLT F-18, Fluorothymidine (18f), Fluorothymidine F 18, FLUOROTHYMIDINE (18F), FLUOROTHYMIDINE F-18, Thymidine, 3'-deoxy-3'-($^{18}$F)fluoro-, [$^{18}$F]FLT, [$^{18}$F]Fluorothymidine, [$^{18}$F]FLUDEOXYTHYMIDINE.
• Identifiers:
• CAS: 287114-80-1
• DrugBank: DB14930
• UNII: 2X1K91UT6N
• PubChem CID: 9878109
• ChEMBL ID: CHEMBL5314940
• NCI Thesaurus Code: C49093
• CompTox Dashboard (EPA): DTXSID90182869
• Wikidata: Q22908453

Appendix B: Summary of Key Clinical Trials

Table 4: Overview of Significant Clinical Trials for [18F]FLT
Identifier	Trial Title/Objective	Condition(s) Studied	Phase	Status	Source(s)
NCT02819024	Dexamethasone Effects in Patients With Refractory NSCLC Using FLT PET	Stage IV Non-Small Cell Lung Cancer (NSCLC)	Not Available	Unknown	6
NCT00880074	FLT-PET in Predicting Response to Chemotherapy in Patients With Advanced Malignancies	Cancer	Phase 1	Completed	8
NCT03422731	Multi-modality Imaging and Biospecimen Collection in AML Patients Undergoing TBI	Acute Myeloid Leukemia (AML), Acute Lymphoblastic Leukemia (ALL)	Phase 0 (Early Phase 1)	Recruiting	6
NCT01480583	GRN1005 Alone or in Combination With Trastuzumab in Breast Cancer Patients With Brain Metastases	Brain Metastases, Breast Cancer	Phase 2	Completed	10
NCT02392429	Early Assessment of Treatment Response in AML Using FLT PET/CT Imaging	Acute Myeloid Leukemia (AML)	Phase 2	Not specified	44
NCI-2019-06638	[18F]Fluorothymidine PET/CT Imaging for Monitoring Treatment Response in Metastatic Breast Cancer	Metastatic Breast Cancer	Not specified	Closed	45
NCT01244737	Phase 2 Study of [18F]FLT for PET Imaging of Brain Tumors in Children	Brain Neoplasms	Phase 2	Completed	65
NCT03276676	[18F]Fluciclovine and [18F]FLT PET/CT Assessment of Primary High-Grade Brain Tumors	High-Grade Brain Tumors	Not specified	Not specified	66
NCI-2014-00861	18F-FLT PET/CT to Spare Bone Marrow in Gynecologic Cancers Undergoing Radiation	Gynecologic Cancers	Early Phase 1	Not specified	47
NCT00757549	FLT and FDG PET Scans in Evaluating Response to Cetuximab, Cisplatin, and Radiation	Advanced Head and Neck Cancer	Not specified	Not specified	73

Works cited

1. Fluorothymidine (18F) - Wikipedia, accessed October 24, 2025, https://en.wikipedia.org/wiki/Fluorothymidine_(18F)
2. Fluorothymidine F-18 | C10H13FN2O4 | CID 9878109 - PubChem, accessed October 24, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Fluorothymidine-F-18
3. UNII - 2X1K91UT6N, accessed October 24, 2025, https://precision.fda.gov/uniisearch/srs/unii/2x1k91ut6n
4. CAS No : 287114-80-1 | Product Name : Alovudine (18F) Injection - Pharmaffiliates, accessed October 24, 2025, https://www.pharmaffiliates.com/en/287114-80-1-alovudine-18f-injection-pa014010000.html
5. Fluorothymidine F-18 | API DMFs | US Drug Master File (DMF, accessed October 24, 2025, https://www.pharmacompass.com/us-drug-master-files-dmfs/fluorothymidine-f-18
6. Alovudine F-18 | MedPath, accessed October 24, 2025, https://trial.medpath.com/drug/0b06cd555ba29825/alovudine-f-18
7. Product Index - AA Blocks, accessed October 24, 2025, https://www.aablocks.com/prods/name/A?page=106
8. Alovudine F-18 Completed Phase 1 Trials for Cancer Diagnostic | DrugBank Online, accessed October 24, 2025, https://go.drugbank.com/drugs/DB14930/clinical_trials?conditions=DBCOND0020966&phase=1&purpose=diagnostic&status=completed
9. ALOVUDINE F-18 - precisionFDA, accessed October 24, 2025, https://precision.fda.gov/ginas/app/ui/substances/b2da9e0c-f72b-4980-9e98-9c674f7b3e55
10. Alovudine F-18 Completed Phase 2 Trials for Brain Metastases / Breast Cancer Treatment, accessed October 24, 2025, https://go.drugbank.com/drugs/DB14930/clinical_trials?conditions=DBCOND0029546%2CDBCOND0028036&phase=2&purpose=treatment&status=completed
11. ALOVUDINE F-18 - gsrs, accessed October 24, 2025, https://gsrs.ncats.nih.gov/ginas/app/ui/substances/b2da9e0c-f72b-4980-9e98-9c674f7b3e55
12. Alovudine: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed October 24, 2025, https://go.drugbank.com/drugs/DB06198
13. Alovudine - Wikipedia, accessed October 24, 2025, https://en.wikipedia.org/wiki/Alovudine
14. gsrs.ncats.nih.gov, accessed October 24, 2025, https://gsrs.ncats.nih.gov/ginas/app/ui/substances/b2da9e0c-f72b-4980-9e98-9c674f7b3e55#:~:text=Chemical%20Structure,-Stereochemistry&text=Cc1cn(%5BC%40H%5D2C,O)%5BnH%5Dc1%3DO
15. Antiviral activity of low-dose alovudine in antiretroviral-experienced patients: Results from a 4-week randomized, double-blind, placebo-controlled dose-ranging trial - ResearchGate, accessed October 24, 2025, https://www.researchgate.net/publication/6367120_Antiviral_activity_of_low-dose_alovudine_in_antiretroviral-experienced_patients_Results_from_a_4-week_randomized_double-blind_placebo-controlled_dose-ranging_trial
16. (PDF) [18F]FLT-PET in oncology: Current status and opportunities - ResearchGate, accessed October 24, 2025, https://www.researchgate.net/publication/8162740_18FFLT-PET_in_oncology_Current_status_and_opportunities
17. NCI-Sponsored Trial for the Evaluation of Safety and Preliminary Efficacy of FLT as a Marker of Proliferation in Patients with Recurrent Gliomas - NIH, accessed October 24, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4465245/
18. NCI-Sponsored Trial for the Evaluation of Safety and Preliminary Efficacy of 3′-Deoxy-3′-[18F] fluorothymidine (FLT) as a Marker of Proliferation in Patients with Recurrent Gliomas, accessed October 24, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4739628/
19. PET Imaging with 18F-FLT and Thymidine Analogs: Promise and ..., accessed October 24, 2025, https://jnm.snmjournals.org/content/44/9/1432
20. deoxy-3'-(18)F-fluorothymidine PET responses to pharmacologic inhibition of the c-MET receptor in preclinical tumor models - PubMed, accessed October 24, 2025, https://pubmed.ncbi.nlm.nih.gov/21764800/
21. Molecular Imaging with 3′-deoxy-3′[(18)F]-Fluorothymidine (18F-FLT) PET/CT for Early Response to Targeted Therapies in Sarcomas: A Pilot Study - MDPI, accessed October 24, 2025, https://www.mdpi.com/2075-4418/10/3/125
22. [18F]FLT-PET in oncology: current status and opportunities - PubMed, accessed October 24, 2025, https://pubmed.ncbi.nlm.nih.gov/15565331/
23. Emerging Role of [18F]FLT PET/CT in Lymphoid Malignancies: A Review of Clinical Results, accessed October 24, 2025, https://www.mdpi.com/2038-8330/16/1/4
24. In Vivo Validation of 3′deoxy-3′-[18F]fluorothymidine ([18F]FLT) as a Proliferation Imaging Tracer in Humans | Clinical Cancer Research - AACR Journals, accessed October 24, 2025, https://aacrjournals.org/clincancerres/article/8/11/3315/289067/In-Vivo-Validation-of-3-deoxy-3-18F
25. Imaging Proliferation in Brain Tumors with 18 F-FLT PET: Comparison with 18 F-FDG, accessed October 24, 2025, https://jnm.snmjournals.org/content/46/6/945
26. [18F]fluorothymidine - SNMMI, accessed October 24, 2025, https://snmmi.org/common/Uploaded%20files/Web/Centers/PET%20Center%20of%20Excellence/FLT_07-11-12%20Final.pdf
27. 18F-fluorodeoxyglucose (FDG) PET or 18F-fluorothymidine (FLT) PET to assess early response to aromatase inhibitors (AI) in women with ER+ operable breast cancer in a window-of-opportunity study, accessed October 24, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8381552/
28. Radiology Today Magazine - News, accessed October 24, 2025, https://www.radiologytoday.net/news/rtdaily3132009.shtml
29. GE Medical Systems Partners with the National Cancer Institute on Groundbreaking Molecular Imaging Drug Trial, accessed October 24, 2025, https://www.gehealthcare.com/about/newsroom/press-releases/ge-medical-systems-partners-national-cancer-institute-groundbreaking-molecular?npclid=botnpclid
30. FDA approves SNM app for 18-FLT - Radiology Business, accessed October 24, 2025, https://radiologybusiness.com/topics/medical-imaging/molecular-imaging/fda-approves-snm-app-18-flt
31. [18F]Fluciclovine and [18F]FLT PET/CT Assessment of Primary High-Grade Brain Tumors - ClinicalTrials.gov, accessed October 24, 2025, https://cdn.clinicaltrials.gov/large-docs/76/NCT03276676/Prot_SAP_002.pdf
32. Vizamyl | European Medicines Agency (EMA), accessed October 24, 2025, https://www.ema.europa.eu/en/medicines/human/EPAR/vizamyl
33. Clinical efficacy and safety: radiopharmaceuticals and diagnostic agents | European Medicines Agency (EMA), accessed October 24, 2025, https://www.ema.europa.eu/en/human-regulatory-overview/research-development/scientific-guidelines/clinical-efficacy-safety-guidelines/clinical-efficacy-safety-radiopharmaceuticals-diagnostic-agents
34. US and EU radiopharmaceutical diagnostic and therapeutic nonclinical study requirements for clinical trials authorizations and marketing authorizations, accessed October 24, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6529498/
35. Altered Tissue 3′-Deoxy-3′-[18F]Fluorothymidine ..., accessed October 24, 2025, https://aacrjournals.org/clincancerres/article/15/21/6649/74806/Altered-Tissue-3-Deoxy-3-18F-Fluorothymidine
36. Preclinical Applications of 3'-Deoxy-3'-[18F]Fluorothymidine in Oncology - A Systematic Review - PMC - NIH, accessed October 24, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC5196884/
37. 18F-Fluorothymidine radiation dosimetry in human PET imaging ..., accessed October 24, 2025, https://pubmed.ncbi.nlm.nih.gov/12960196/
38. Kinetic Analysis of 3′-Deoxy-3′-18F-Fluorothymidine (18F-FLT) in ..., accessed October 24, 2025, https://jnm.snmjournals.org/content/50/7/1028
39. Definition of fluorine F 18-fluorothymidine - NCI Drug Dictionary - National Cancer Institute, accessed October 24, 2025, https://www.cancer.gov/publications/dictionaries/cancer-drug/def/fluorothymidine-f-18
40. Metabolism of 3 '-Deoxy-3 '-[F-18]fluorothymidine in Proliferating A549 Cells: Validations for Positron Emission Tomography - AMiner, accessed October 24, 2025, https://www.cn.aminer.org/pub/53e9a1d5b7602d9702acf237
41. Deoxy-3'-[18F]fluorothymidine - Molecular Imaging and Contrast Agent Database (MICAD), accessed October 24, 2025, https://www.ncbi.nlm.nih.gov/books/NBK23373/
42. 18F-FLT and 18F-FDG PET-CT imaging in the evaluation of early therapeutic effects of chemotherapy on Walker 256 tumor-bearing rats - PMC - NIH, accessed October 24, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC5228162/
43. (PDF) 18F-Fluorothymidine radiation dosimetry in human PET ..., accessed October 24, 2025, https://www.researchgate.net/publication/10579113_18F-Fluorothymidine_radiation_dosimetry_in_human_PET_imaging_studies
44. Study Details | NCT02392429 | FLT PET/CT in Measuring Response in Patients With Previously Untreated Acute Myeloid Leukemia | ClinicalTrials.gov, accessed October 24, 2025, https://www.clinicaltrials.gov/study/NCT02392429
45. [18F]Fluorothymidine PET/CT Imaging for Monitoring Treatment Response in Patients with Metastatic Breast Cancer Undergoing Treatment with Ribociclib and Paclitaxel - NCI, accessed October 24, 2025, https://www.cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2019-06638
46. Baseline and on Treatment Biodistribution Variability of F-FLT Uptake in Patients With Advanced Melanoma - Amsterdam UMC, accessed October 24, 2025, https://pure.amsterdamumc.nl/files/142151478/Baseline-and-on-treatment-biodistribution-variability-of-18f-flt-uptake-in-patients-with-advanced-melanoma.pdf
47. 18F-FLT PET/CT in Sparing Bone Marrow in Patients With Gynecologic Cancer Undergoing Radiation Therapy - NCI, accessed October 24, 2025, https://www.cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2014-00861
48. Summary of pharmacokinetic PET variables for [ 18 F]FLT obtained from... | Download Table - ResearchGate, accessed October 24, 2025, https://www.researchgate.net/figure/Summary-of-pharmacokinetic-PET-variables-for-18-FFLT-obtained-from-the-TACs-in-vehicle_tbl1_6902168
49. Applications of PET imaging with the proliferation marker [18F]-FLT - PMC - NIH, accessed October 24, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4415691/
50. Study Details | NCT06498648 | Testing the Addition of an Anti, accessed October 24, 2025, https://www.clinicaltrials.gov/study/NCT06498648
51. 18F-FLT PET, a Noninvasive Pharmacodynamic Biomarker of Tumor Cell Proliferation, Detected Differential Response to Various Cyclin-Dependent Kinase (CDK) Inhibitors - AACR Journals, accessed October 24, 2025, https://aacrjournals.org/mct/article/24/7/1111/763170/18F-FLT-PET-a-Noninvasive-Pharmacodynamic
52. Serial [18F]Fluorothymidine (FLT)PET/CT as a Biomarker of Therapeutic Response in Pemetrexed Therapy for Non-Small Cell Lung Cancer - Clinical Trials, accessed October 24, 2025, https://cdn.clinicaltrials.gov/large-docs/38/NCT02274038/Prot_SAP_000.pdf
53. Fluorine-18 Radiochemistry, Labeling Strategies and Synthetic Routes - ACS Publications, accessed October 24, 2025, https://pubs.acs.org/doi/10.1021/bc500475e
54. Fluorine-18 Radiochemistry, Labeling Strategies and Synthetic Routes, accessed October 24, 2025, https://psec.uchicago.edu/Simulation/jacobsonf18radiochemistry.pdf
55. The Positron Emission Tomography Tracer 3'-Deoxy-3'-[18F]Fluorothymidine ([18F]FLT) Is Not Suitable to Detect Tissue Proliferation Induced by Systemic Yersinia enterocolitica Infection in Mice | PLOS One, accessed October 24, 2025, https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0164163
56. SYNTHESIS AND QUALITY CONTROL OF [18F] FLUOROTHYMIDINE Leonardo Tafas C. Nascimento1, Juliana B. Silva1, Marina B. Silveira1, Pr - INIS-IAEA, accessed October 24, 2025, https://inis.iaea.org/collection/NCLCollectionStore/_Public/45/107/45107387.pdf
57. A new precursor for the radiosynthesis of [F-18]FLT | Request PDF, accessed October 24, 2025, https://www.researchgate.net/publication/11537349_A_new_precursor_for_the_radiosynthesis_of_F-18FLT
58. Radiosynthesis of [ 18 F]-FLT. | Download Scientific Diagram - ResearchGate, accessed October 24, 2025, https://www.researchgate.net/figure/Radiosynthesis-of-18-F-FLT_fig2_6269791
59. 18F-FLT PET Imaging in Assessing Tumors and Measuring Response in Younger Patients With Brain Tumors - National Cancer Institute, accessed October 24, 2025, https://www.cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2013-00805
60. F-18 Fluorothymidine PET Imaging for Early Evaluation of Response to Therapy in Head & Neck Cancer Patients | ClinicalTrials.gov, accessed October 24, 2025, https://www.clinicaltrials.gov/study/NCT00721799
61. deoxy-2'-(18)F-fluoro-d-glucose PET/CT better assess response after 3-weeks treatment by epidermal growth factor receptor kinase inhibitor, in non-small lung cancer patients? Preliminary results - PubMed, accessed October 24, 2025, https://pubmed.ncbi.nlm.nih.gov/24997081/
62. Study Details | NCT01244737 | FLT-PET Imaging of Brain Tumors in ..., accessed October 24, 2025, https://clinicaltrials.gov/study/NCT01244737
63. Study Details | NCT03276676 | [18F]Fluciclovine and [18F]FLT PET/CT Assessment of Primary High-Grade Brain Tumors | ClinicalTrials.gov, accessed October 24, 2025, https://clinicaltrials.gov/study/NCT03276676
64. Stage IV, NSCLC Unknown Status Phase Trials for Alovudine F-18 (DB14930) - DrugBank, accessed October 24, 2025, https://go.drugbank.com/indications/DBCOND0105480/clinical_trials/DB14930?phase=&status=unknown_status
65. Study Details | NCT02608216 | [18F]FLT PET/CT in Rb+ Metastatic Breast Cancer | ClinicalTrials.gov, accessed October 24, 2025, https://clinicaltrials.gov/study/NCT02608216
66. Alovudine F-18 Recruiting Phase 0 Trials for Acute Myeloid Leukemia / Acute Lymphoblastic Leukemia (ALL) Diagnostic - DrugBank, accessed October 24, 2025, https://go.drugbank.com/drugs/DB14930/clinical_trials?conditions=DBCOND0031335%2CDBCOND0029883&phase=0&purpose=diagnostic&status=recruiting
67. Clinical Trials Using Fluorothymidine F-18 - NCI, accessed October 24, 2025, https://www.cancer.gov/research/participate/clinical-trials/intervention/fluorothymidine-f-18
68. Study Details | NCT01243333 | Multi-Tracer Positron Emission Tomography in Patients With Solid Tumors | ClinicalTrials.gov, accessed October 24, 2025, https://www.clinicaltrials.gov/study/NCT01243333
69. Study Details | NCT00757549 | 3'-Deoxy-3'-[18F] Fluorothymidine and Fludeoxyglucose F 18 PET Scans in Evaluating Response to Cetuximab, Cisplatin, and Radiation Therapy in Patients With Advanced Cancer of the Oropharynx, Larynx, or Hypopharynx | ClinicalTrials.gov, accessed October 24, 2025, https://clinicaltrials.gov/study/NCT00757549