Next Article in Journal
Performance Characteristics of Intelligent Reflecting Surface-Assisted Non-Lambertian Visible Light Communications for 6G and Beyond Internet of Things
Previous Article in Journal
Pilot Study of an Online Exercise Therapy Programme for Home Office Workers in Terms of Musculoskeletal and Mental Health
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Applied Sciences
Volume 15
Issue 20
10.3390/app152010964
applsci-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Lapatinib-Based Radioagents for Application in Nuclear Medicine

by
Przemysław Koźmiński
* and
Ewa Gniazdowska
*
Centre of Radiochemistry and Nuclear Chemistry, Institute of Nuclear Chemistry and Technology, 03-195 Warsaw, Poland
*
Authors to whom correspondence should be addressed.
Appl. Sci. 2025, 15(20), 10964; https://doi.org/10.3390/app152010964
Submission received: 9 September 2025 / Revised: 10 October 2025 / Accepted: 11 October 2025 / Published: 12 October 2025
Browse Figures
Versions Notes

Abstract

Lapatinib is an approved therapeutic agent for the treatment of HER2-positive breast cancer. It has a high affinity for the non-receptor cytoplasmic tyrosine kinases of the EGFR and HER2 receptors. It is a type II inhibitor, with Kiapp values of 3 nM and 13 nM, respectively. The dissociation rate of the lapatinib–receptor complex is notably slow compared with many other kinase inhibitors. Although the literature contains numerous reports on radiolabelled ligands for HER-family receptors, studies on radiolabelled tyrosine kinase inhibitors are far fewer, and only few focus specifically on radiolabelled lapatinib. The aim of this review is to compile and discuss the chemical and biological data on lapatinib-based radiopharmaceuticals with potential applications in the diagnosis and treatment of HER2-positive tumours.

1. Introduction

Lapatinib (GW572016) is a small molecule developed by GlaxoSmithKline (GSK) that belongs to the class of kinase inhibitors. Its structure is based on a 4-anilinoquinazoline core, which serves as the principal hinge-binding motif responsible for interaction with kinase domains. Lapatinib is a targeted therapeutic agent indicated for the treatment of advanced or metastatic HER2-positive breast cancer [1,2] in patients who have previously received standard chemotherapeutic regiments [3,4]. Lapatinib is the active substance of the drug Tykerb (marketed as Tyverb in Europe), formulated and administered as lapatinib ditosylate monohydrate (Figure 1). It is a selective dual tyrosine kinase inhibitor, targeting both the Epidermal Growth Factor Receptor (EGFR) and the Human Epidermal Growth Factor Receptor 2 (HER2) [5,6,7,8]. The predominant elimination pathway of lapatinib is via the faeces, accounting for more than 90% of the administered dose, while renal excretion plays only a minor role [9]. Lapatinib in combination with capecitabine (Capecitabine Glenmark) received approval from the U.S. Food and Drug Administration (FDA) in 2007, based on the results of a phase III clinical trial [10,11]) and from the European Medicines Agency (EMA) in 2008 for the treatment of patients with advanced and/or metastatic HER2-overexpressing breast cancer who have experienced disease progression following prior treatment with anthracyclines, taxanes, and trastuzumab [12]. In vitro studies have demonstrated that the combination of lapatinib and trastuzumab has a synergistic effect on HER2-overexpressing breast cancer cells, significantly enhancing apoptosis [13]. Further investigations using the HER2-positive SKBR3 breast cancer cell line have shown that the combination of lapatinib and radiotherapy may augment the efficacy of radiotherapy. Specifically, pretreatment with lapatinib increased radiation-induced cell death in HER2-positive breast cancer cells, while no radiosensitizing effect was observed in HER2-negative breast cancer cells or in normal human astrocytes [14].
In addition to blocking HER receptors, Lapatinib has the ability to inhibit truncated variants of HER2, known as p95HER2 receptors, which lack the extracellular binding domain recognized by trastuzumab but retain active kinase function [12,15]. This property provides lapatinib with therapeutic potential in trastuzumab-resistant tumours. Furthermore, lapatinib has been reported to interfere with signalling cascades activated by the Insulin-like Growth Factor 1 Receptor (IGF-1R). Inhibition of this pathway may contribute to the immediate suppression of cancer cell proliferation and induction of apoptosis, further broadening the drug’s antitumour activity [16].
Accurate assessment of HER2 expression plays an essential role in cancer diagnosis and treatment. HER2 overexpression serves as a clinically relevant biomarker functioning both as a prognostic factor—providing information about the likely course of the disease—and as a predictive factor indicating the likelihood of response to targeted therapy. Determining HER2 status enables effective patient stratification for HER2-directed therapies, including trastuzumab (Herceptin), a humanized IgG1 monoclonal antibody, and lapatinib (Tykerb), a dual tyrosine kinase inhibitor [17]. Currently, several methods are employed to assess the level of HER2 overexpression. The most widely used is immunohistochemistry (IHC), which is inexpensive, broadly accessible, and relatively simple to perform. However, its accuracy is limited, as the evaluation depends on the subjective assessment of staining intensity, which can complicate interpretation [18,19]. A more precise, though costlier, approach is fluorescence in situ hybridization (FISH), which enables quantification of HER2 gene copy number and provides a reliable assessment of gene amplification status [18,19,20,21]. An alternative method, chromogenic in situ hybridization (CISH), allows for the visualization of specific DNA or RNA sequences within cells or tissues using a standard bright-field microscope. This makes CISH a practical substitute for FISH, which requires access to specialized fluorescence microscopy equipment [20,21]. All of these techniques rely on the acquisition and analysis of biopsy samples.
A promising competitive non-invasive alternative to biopsy-based methods for the visualization and quantification of HER2 receptor overexpression in heterogeneous tumours, compared to the methods mentioned above, is the use of diagnostic radiopharmaceuticals containing lapatinib as a targeting vector. Depending on the radionuclide employed, radiopharmaceutical can be either diagnostic (containing radionuclides that emit gamma or beta plus radiation suitable for single-photon emission computed tomography (SPECT) or positron emission tomography (PET) imaging, respectively) or therapeutic, incorporating radionuclides that emit alpha, beta minus particles, or Auger electrons selectively destroy cells overexpressing the appropriate/target receptor. Generally, radiopharmaceuticals are radiopreparations containing radionuclides, the radiation from which is used for the diagnosis or treatment of numerous diseases, such as neurodegenerative or oncological ones. Depending on the radiopreparation’s structure (radiopharmaceutical generation), they may be simple ions (e.g., 131I− or 201Tl+) or more complex chemical forms containing a radionuclide complex attached directly or through a specially selected linker to a biologically active molecule (with high affinity for a given molecular target), acting as a vector that selectively delivers the radiopreparation to the desired target. When introduced into the body, they allow for the detection of pathological changes at a very early stage, before morphological changes are yet visible. This allows for early initiation of therapy, which largely determines the effectiveness of the entire treatment. Both diagnostic and therapeutic radiopharmaceuticals are administered to patients in such small amounts (nano- and milligrams) that they have no impact on the body and do not lead to functional disorders of the organ being studied. Radiopharmaceuticals are finding increasingly widespread use in diagnostics and targeted therapy, and research on new radiopharmaceuticals is a rapidly developing field of nuclear medicine [22].
There are numerous reports in the literature on radiopharmaceuticals acting on HER family receptors [23,24,25,26,27,28,29] alongside the publications cited in them. HER2-targeted radiopharmaceuticals [23,25] discussed in ref. [23] are monoclonal antibodies (trastuzumab and pertuzumab), antibody fragments (Fab and F(ab’)2 antibody fragments of trastuzumab and pertuzumab), nanobodies (2Rs15d, NM-02 and NM-302), affibodies (ZHER2:342 and its derivatives: ABY-002, ABY-025, ABH2, HPark2, GE-226, ADAPT6) and peptides (KCCYSL, MEGPSKCCYSLALASH, GTKSKCCYSLRRSS, CGGGLTVSPWY, CSSSLTVSPWY, SSSLTVPWY, FCGDFYACYMDV, YLFFVFER and its retro-inversion analogue, KLRLEWNR and A9 containing a fragment of trastuzumab (Fab)) labelled with different radionuclides (Tc-99m, In-111, I-123, I-124, F-18, N-13, C-11, Cu-64, Ga-68 and Zr-89). The HER3-targeted radiopharmaceuticals [24,26,27,28,29] discussed in ref. [24] are monoclonal antibodies (Mab#58, GSK2849330, lumretuzumab (RG7116, RO5479599), mAb3481, duligotuzumab (MEHD7945A)), nanobody MSB0010853 (binding to two different HER3 epitopes), affibodies (Z08698 and Z08699, (HE)3-Z08698), peptides (CLPTKFRSC, HER3P1) and the small molecule AZD8931, labelled with different diagnostic radionuclides (Tc-99m, In-111, Ga-68, Co-55, Co-57, Zr-89, C-11). HER3-targeted cancer therapy may be an alternative to the anti-EGFR and anti-HER2 resistance therapies [24].
The aim of this review is to compile and discuss the current literature on the chemical and biological aspects of radiopreparations based on the lapatinib molecule with particular emphasis on their potential application in the diagnosis and therapy of cancers characterized by HER2 overexpression.
A comprehensive literature search was conducted in PubMed, Scopus, Web of Science, and Google Scholar. The following keywords and their combinations were used: lapatinib, tyrosine kinase inhibitor, HER2 imaging, PET/SPECT imaging using radiolabelled lapatinib or its radiolabelled derivatives, radiopharmaceutical/radiotracer/radiopreparation based on lapatinib.
The search period was from January 2004 to August 2025, encompassing the period from the first regulatory approval of the drug lapatinib to the present.
Inclusion criteria included original research papers or review articles written in English describing the synthesis, physicochemical or biological characterization, or other properties of radiopreparations containing lapatinib or its derivatives labelled with various radionuclides. Exclusion criteria included articles substantively unrelated to lapatinib or its derivatives labelled with various radionuclides, such as those reporting studies focusing solely on the clinical use of non-radiolabelled lapatinib or its derivatives, conference abstracts without full text, and publications written in a language other than English.

2. Lapatinib Molecular Target

Lapatinib belongs to the family of targeted chemotherapy drugs that inhibit the activity of HER/ErbB receptor tyrosine kinases by binding to their intracellular kinase domains (the terms HER and ErbB are equivalent, with “ErbB” referring to the gene and name “HER” corresponding protein) [25]. The HER/ErbB receptor family comprises four members (HER1-4, also known as ErbB1-4). Among them, HER1, commonly referred to as the Epidermal Growth Factor Receptor (EGFR), is the best characterized and most extensively studied. Structurally all HER/ErbB family receptors contain three regions: an extracellular ligand-binding domain (receptor kinases), a single transmembrane helix, and an intracellular (non-receptor) cytoplasmic tyrosine kinase tail [12,30,31,32,33]. These tyrosine kinases (TKs) play a critical role in transmitting intracellular signals that regulate cell growth, proliferation, and differentiation. Importantly, their dysregulation or overexpression has been strongly implicated in the initiation and progression of various cancers [31,34].
Lapatinib enters the cell and binds with high affinity to the cytoplasmic tyrosine kinase domains of EGFR and HER2 receptors, thereby inhibiting receptor phosphorylation and blocking downstream signalling through the phosphoinositol-3-kinase (PI3-K) pathway, which promotes cell survival, and the Ras pathway, which drives cell proliferation (Figure 2) [6,7,8,12].
The apparent inhibition constant (Kiapp) values for lapatinib against the tyrosine kinase activity of EGFR and HER2 receptors are 3 nM and 13 nM, respectively [8]. In comparison with other inhibitors containing a 4-anilinoquinazoline scaffold—a commonly used hinge-binding motif—lapatinib is distinguished by a remarkably slow dissociation rate from the receptor–inhibitor complex, which may contribute to its sustained inhibitory effect [8].
Kinase inhibitors can act either irreversibly or reversibly. Irreversible inhibitors form covalent bonds with a reactive nucleophilic cysteine residue located near the adenosine triphosphate (ATP) binding site, thereby permanently blocking ATP access and leading to irreversible inhibition. Reversible inhibitors are classified into four main types according to the conformation of the ATP-binding pocket and the orientation of the Asp-Phe-Gly (DFG) motif [25,34]. Briefly, type I inhibitors are ATP-competitive and bind to the active conformation of the kinase, where the Asp residue of the DFG motif points inward toward the ATP-binding site; type II inhibitors bind to the inactive form of the kinase, where the Asp residue of the DFG motif adopts an outward orientation (DFG-out), enabling additional interaction with an adjacent allosteric pocket; type III inhibitors bind exclusively to an allosteric site located adjacent to the ATP-binding pocket, but without directly interacting with ATP-binding site; and type IV inhibitors bind to an allosteric pocket remote from the ATP-binding site, modulating kinase activity through long-range conformational effects.
Lapatinib is a reversible type II inhibitor that binds to the inactive (DFG-out) conformation of EGFR and HER2 receptors, engaging not only the ATP-binding site but also an adjacent allosteric pocket exposed by the conformational rearrangement of the DFG motif [8,25,34,35].

3. Radionuclide-Labelled Lapatinib Agent

The use of radioactively labelled kinase inhibitors provides the unique opportunity in oncology, neurology and neuro-oncology to quantify kinase density in tumours, assess brain penetration, and measure kinase levels in normal and pathological brain tissue. While numerous studies (both original research and reviews) have reported on ligands targeting HER family receptors labelled with various radionuclides [23,24], far fewer publications focus on radiolabelled protein kinase inhibitors [25,36], and even more limited are studies specifically investigating radiolabelled lapatinib, highlighting a gap in the current literature [36,37,38,39,40,41,42,43,44].
Concise information on published articles regarding lapatinib or its derivatives labelled with diagnostic or therapeutic radionuclides is presented in Table 1.

3.1. Lapatinib Labelled with Non-Metallic Radionuclides

The first potential radiopharmaceuticals based on lapatinib were radiopreparations labelled with non-metallic, ‘organic’, short-lived diagnostic radionuclides F-18 and C-11 as well as long-lived therapeutic radionuclide C-14. The short half-lives of F-18 (110 min) and C-11 (20 min) require the development of rapid and efficient synthetic methods for these radiopreparations. However, the obtained radiopreparations [18F]lapatinib and [11C]lapatinib (Figure 3a,b) retain the exact chemical structure of the parent molecule, lapatinib. This structural fidelity ensures that PET imaging studies using these radiolabelled derivatives accurately reflect the pharmacokinetics, biodistribution, and biological behaviour of lapatinib in vivo.
The multi-step, manual radiosynthesis of F-18-labelled lapatinib ([18F]lapatinib, Figure 3a) was described in detail by Basuli and colleagues in 2011 [37]. After purification (by the HPLC method), the radiotracer was obtained with a radiochemical yield (RCY) of 8–12%, radiochemical purity (RCP) exceeding 98%, and specific activity (SA) in the range 35–430 Ci.mmol. The synthesis was sufficiently short to allow production of [18F]lapatinib in quantities adequate for PET imaging, as well as for physicochemical and biological studies of the radiopreparation. However, the authors did not report any further physicochemical or biological evaluation of the synthesized radiocompound, leaving its in vivo behaviour and suitability for imaging uncharacterized.
Several years later, Nunes et al. developed and described in detail a novel, facile 2-step procedure for the routine preparation of [18F]lapatinib for clinical trials [38]. This method employed a pinacolyl arylboronate precursor in nucleophilic copper-mediated 18F-fluorination reaction between meta-[18F]fluorobenzylbromide and Boc-protected lapatinib (the reaction was carried out in a microwave, using K2CO3 as a catalyst, at 110 °C for 10 min). After the 18F-fluorination reaction, the Boc-group was removed using trifluoroacetic acid, and the crude product was purified using the HPLC method. This synthesis proved to be simpler, but the final radiochemical yield was not satisfactory.
The synthesis of C-11-labelled lapatinib ([11C]lapatinib, Figure 3b) was reported by Saleem et al. [39]. The studies presented in this article are registered in the European Union Clinical Trials Database, the National Institute of Health database, and the National Cancer Research Network study portfolio under the numbers EudraCT 2009-009884-76, NCT01290354 and NCRN262, respectively. The [11C]lapatinib radiotracer was prepared in a four-step synthesis, the scheme of which is presented in the article. The [11C]lapatinib was purified by HPLC, and the radiopreparation was isolated from the product-containing fraction by solid-phase extraction and filtration through a 0.2 μm Pall Tuffryn® membrane. Quality control methods for the radiopreparation administered to patients were in accordance with the European Pharmacopoeia guidelines. The radiochemical purity of the radiopreparation administered to patients was 100%, and the average mass and specific activity were 2.92 μg and 24 GBq/μmol, respectively. In vivo studies have shown that [11C]lapatinib is stable and accumulates differentially in healthy brain tissue and brain metastasis, thereby enabling the visualization of brain tumours. The authors also verified the hypothesis put forward several years earlier by Gril et al. [45] that lapatinib may prevent breast cancer metastases to the brain if treatment is initiated at an early enough stage of the disease. They also investigated whether pretreatment with therapeutic doses of lapatinib could enhance brain uptake of [11C]lapatinib. However, PET studies demonstrated that therapeutic doses of lapatinib did not increase brain penetration of the radiopharmaceutical, suggesting that prophylactic administration of lapatinib to prevent brain metastases in breast cancer patients may not be effective. In conclusion, lapatinib may play a role in the treatment of established brain metastases but not in their prevention.
In vitro and in vivo biological studies of lapatinib labelled with the therapeutic carbon radionuclide C-14 using [14C]lapatinib (supplied by GlaxoSmithKline (GSK)) were reported by Taskar et al. [40]. Generally, oral administration lapatinib was shown to distribute efficiently to multiple organs. However, due to the protective effect (efflux transport mechanism) of the blood–brain barrier (BBB), brain uptake of lapatinib was limited to less than 10% of the plasma levels. In case of brain metastases, the blood–tumour barrier (BTB) is partially compromised, which further results in variable passage of lapatinib across the BTB. The authors investigated the ability of lapatinib to reach therapeutic concentrations of the drug in the central nervous system (CNS). The radiocompound was administered either orally (100 mg/kg) or intravenously (10 mg/kg) to mice with MDA-MD-231-BR-HER2 breast cancer brain metastases. Orally, the radiopreparation was administered in a vehicle formulation consisting of 0.5% hydroxypropylmethylcellulose with 0.1% Tween 80 in water, and in the case of intravenous administration, the radiopreparation was administered in a DMSO solution diluted to 30% with 0.9% NaCl. The [14C]lapatinib circulated for 2 or 12 h following oral administration and for 30 min following intravenous administration. The authors found that the radiopreparation was completely stable during this period (more than 98% of the radioactive tracer remained intact) and that no resistance to the drug lapatinib was observed in tumour cells isolated from brains treated with lapatinib. After the circulatory period, the animals were sacrificed and the brain, blood and plasma samples as well as selected other tissues (e.g., liver, lungs, heart, kidneys) were collected to measure the accumulated radioactivity. The authors found that lapatinib concentrations in brain metastases following oral administration were on average 7-fold greater than in healthy brain after 2 h and 9 times higher after 12 h. In the case of intravenous administration of the radiopreparation, the accumulation of radiotracer in brain metastases was on average 3.2-fold greater compared to the normal brain. Based on the experimental results, the authors concluded that (i) the concentration of 14C-lapatinib in brain metastases, as opposed to the normal brain, was generally clearly elevated, highly variable and highly heterogeneous; (ii) there were no differences in the distribution of lapatinib between the centre of the metastasis and its periphery; (iii) in sites distant from the metastases, the concentrations of the radioactive agent were low and homogeneous; (iv) for all brain metastases studied, [14C]lapatinib uptake varied both within and between lesions; (v) in the vast majority of brain metastases studied (>80%), average 14Clapatinib concentration was <10–20% of that in peripheral metastases; (vi) only in a small group of brain metastases studied (about 17%) did lapatinib concentrations in the brain approach those in peripheral tumours (for effective therapy, the distribution of lapatinib should be comparable to the distribution in systemic metastases); and (vii) BTB permeability is responsible for the limited accumulation of radiopharmaceuticals in brain metastases.
In summary, the results of the work performed by Taskar’s research group indicated that the distribution of lapatinib to metastases in the central nervous system is limited and insufficient, primarily due to the permeability of the BTB.

3.2. Lapatinib Labelled with Metallic Radionuclides

One of the first reports on lapatinib labelled with the metallic radionuclides is the publication by Gniazdowska et al. [41]. The authors designed the synthesis of the [99mTc]Tc(NS3)(CN-lapatinib) radioconjugate (Figure 3c) and performed studies on the physicochemical and biological properties of the obtained radiopreparation from the point of view of its use as a diagnostic radiopharmaceutical for imaging the overexpression of the HER2 receptor. The diagnostic radionuclide cation Tc-99m was complexed by the tetradentate tripodal chelator (tris(2-mercaptoethyl)-amine; 2,2′,2″-nitrilotriethanethiol, NS3) and the monodentate isocyanobutyric acid (CN, as a bifunctional coupling agent, CN-BFCA), forming a complex with a trigonal bipyramidal structure. To verify the obtainment of the radioconjugate [99mTc]Tc(NS3)(CN-lapatinib) synthesized on the n.c.a. scale, a non-radioactive ‘cold’ reference compound Re(NS3)(CN-lapatinib) was synthesized on the milligram scale and examined using various analytical methods (EA, NMR, MS). The [99mTc]Tc(NS3)(CN-lapatinib) radioconjugate was obtained with high yield > 97%, high purity > 98%, and with specific activity within the range 25–30 GBq/mmol. Stability studies performed in the presence of a 1000-fold molar excess of histidine and cysteine and in human serum showed that the radioconjugate does not undergo ligand exchange reactions or enzymatic biodegradation. The lipophilicity value of [99mTc]Tc(NS3)(CN-lapatinib) determined in n-octanol/PBS buffer, pH 7.4, was 1.24 ± 0.04. In biological studies using a human ovarian cancer cell line (SKOV-3), the authors determined a Bmax value of 2.4 ± 0.3 nM, corresponding to an approximate number of 2.4 × 106 binding sites per cell, a dissociation constant Kd of 3.5 ± 0.4 nM, and an IC50 value of 41.2 ± 0.4 nM. An in vivo multi-organ biodistribution study in an animal model (BALB/c mice) showed generally low uptake of the radioconjugate in all organs examined (<5% ID/g), with slightly higher uptake in the liver (4–5% ID/g) than in the kidney (3–5% ID/g), indicating that clearance of the [99mTc]Tc(NS3)(CN-lapatinib) radioconjugate occurs via the hepatic and renal pathways to a comparable extent. Uptake in other organs remained at <1% ID/g. In conclusion, the authors emphasized that the [99mTc]Tc(NS3)(CN-lapatinib) radioconjugate can be easily synthesized in hospital laboratories from previously prepared lyophilized kit formulations and that this radiopreparation can be considered a promising diagnostic radiopharmaceutical for patients suffering from HER2 breast cancer and a useful tool for patient stratification for the purpose of so-called personalized therapy.
Nearly a decade later, Gokulu et al. [42] reported technetium-99m labelling of lapatinib and its derivative, a poly(lactic-co-glycolic acid) (PLGA)-encapsulated lapatinib formulation. Until this study, no reports had described im aging using a radioactively labelled encapsulated lapatinib derivative. SEM analysis showed that the LPT-PLGA nanoparticles had a spherical morphology, and their size distribution measured by DLS was 225.60 ± 1.21 nm. The novel radiopreparations [99mTc]Tc-lapatinib and [99mTc]Tc-lapatinib-PLGA were obtained by the so-called direct labelling method, involving reduction of sodium pertechnetate ([99mTc]NaTcO4 eluted from a 99Mo/99mTc generator) with SnCl2 as a reducing agent. To characterize the newly obtained radioconjugates, the authors relied solely on thin-layer radiochromatography (TLRC), which was applied for quality control, assessment of radiolabelling efficiency, and stability testing. The determined radiochemical yields of [99mTc]Tc-LPT and [99mTc]Tc-LPT-PLGA radioconjugates were 98.14 ± 1.12% and 97.68 ± 0.93%, respectively. The chromatographic separation was carried out using an n-butanol/double-distilled water/acetic acid mixture (4:2:1) as the mobile phase. After obtaining the radioconjugates, the authors tested their in vitro bioaffinity using MDA-MB-231 (human breast), HeLa (cervical) and MDAH-2774 (endometrioid ovarian cancer) cell lines. Both [99mTc]Tc-lapatinib and [99mTc]Tc-lapatinib-PLGA radioconjugates were reported to be more than 90% stable for 4 h, with lipophilicity (logP) values of −2.79 ± 0.01 and −1.09 ± 0.03, respectively, determined in n-octanol/pH 7 buffer systems. The bioaffinity of the obtained [99mTc]Tc-lapatinib and [99mTc]Tc-lapatinib-PLGA radiopreparations was tested in vitro using MDA-MB-231, HeLa, and MDAH cell lines by determining the time-dependent cellular uptake of radiocompounds in the cell lines. The cellular uptake values of [99mTc]Tc-LPT and [99mTc]Tc-LPT-PLGA after 2 h in HeLa and MDAH cells were generally higher than 15% and increased slightly in the time interval up to 4 h. Both radiopreparations showed higher uptake in HeLa and MDAH cells (approximately 15%), whereas in the MDA-MB-231 cell line, uptake remained low and comparable to that of free [99mTc]Tc (around 5%).
As the authors of this review, we feel obliged to draw the reader’s attention to numerous experimental shortcomings in the work of Gokulu et al. [42]: (i) the TLRC analyses used to demonstrate the preparation of [99mTc]Tc-lapatinib and [99mTc]Tc-lapatinib-PLGA radioconjugates are completely unreliable (Figure 5 in [42], and the caption to this figure: “TLRC chromatograms of [99mTc]NaTcO4, ([99mTc]TcO2 should be here instead of [99mTc]TcO4), [99mTc]Tc-LPT and [99mTc]Tc-LPT-PLGA” in [42]). The TLRC chromatograms of [99mTc]NaTcO4 and [99mTc]Tc-LPT are almost identical (the analyses were performed under analogous conditions); so, on what basis do the authors believe that these are two different compounds? (ii) direct labelling with Tc-99m, without additional coligands, cannot account for the dramatic reduction in lipophilicity from logP 5.1 (or 6.17, as reported by the authors) to −2.8; (iii) the reported trend in logP value between [99mTc]Tc-LPT and [99mTc]Tc-LPT-PLGA radiopreparations is unlikely, as encapsulation of lapatinib in a PLGA nanoparticle structure (Figure 4) containing many oxygen atoms (each with 2 lone electron pairs) would be expected to increase hydrophilicity (i.e., reduce logP), not increase lipophilicity (logP of −2.8 to −1.09) as claimed; (iv) no explanation was provided regarding the mode of stable coordination of the 99mTc cation within the lapatinib nanoformulation (LPT-PLGA); and (v) it is unclear whether stability studies were performed on purified radioconjugates or directly on crude reaction mixtures, which raises concerns about the reliability of the reported stability data.
The significant shortcomings mentioned above make the experimental results presented in this article unreliable, which will be discussed in more detail in the Discussion section.
Almost simultaneously, two further reports on lapatinib labelling with the metallic radionuclides Sm-153 and Ga-68 appeared in the literature [43,44].
Pham et al. presented and optimized the synthesis of [153Sm]Fe3O4@lapatinib-Sm nanoparticles and described a series of analytical techniques used to characterize the physicochemical properties of both the synthesized Fe3O4@lapatinib nanoparticles and the new radiopreparation. Additionally, they evaluated the in vivo biocompatibility and systemic toxicity of the radioconjugate in a mouse model [43]. [153Sm]Fe3O4@lapatinib-Sm nanoparticles consisted of an Fe3O4 core connected by hydrogen bonds to the surrounding lapatinib layer and Sm-153 radionuclides as a result of the formation of a complex between 153Sm+3 cation and lapatinib (Figure 3d). Under optimized labelling conditions ([153Sm]SmCl3 concentration of 10 mCi/mL, pH 7.4, a reaction time of 30 min, and temperature of 25 °C), the labelling efficiency and radiochemical purity of the [153Sm]Fe3O4@lapatinib-Sm radiopreparation were >99%. The use of gamma-emitting radionuclide 153Sm enables the use of the radiopreparation for imaging by SPECT and radiation dose assessment, while beta-minus radiation provides a targeted therapeutic effect on cancer cells. The size of [153Sm]Fe3O4@lapatinib-Sm nanoparticles measured by DLS in sodium phosphate buffer (pH 7.4) was in the range of 10 nm to 100 nm (with an average value of 27.4 nm), which makes it suitable for the construction of targeted drug delivery systems for cancer treatment. The radiochemical purity of [153Sm]Fe3O4@lapatinib-Sm nanoparticles (measured by gamma spectroscopy) was 100% for the gamma-emitting radionuclide. Stability studies of radiolabelled nanoparticles were conducted in a phosphate-buffered saline (PBS) solution (0.02 M, pH 7.4) and human serum, and a sterility assessment was performed using FTM (liquid thioglycolate medium) and SCDM (soybean casein digestion medium) over a 14-day observation period. The results showed that the radiopreparation maintained stability and sterility throughout the study, and it fully meets the requirements for radiopharmaceuticals. The authors investigated in vivo the acute toxicity of [153Sm]Fe3O4@lapatinib-Sm nanoparticles (in doses ranging from 20 to 100 mCi/kg) in an animal model (mice) using a single-dose toxicity test method and selected a dose of 20 mCi/kg as an effective and completely safe dose for further experiments on mice. At higher doses, temporary changes in some blood parameters began to occur immediately after nanoparticle injection, but most of these parameters returned to baseline levels within a 14-day observation period. The biodistribution of [153Sm]Fe3O4@lapatinib-Sm nanoparticles was investigated in BT474 (HER2+) xenograft female mice (BALB/c). At selected time points (up to 48 h post-injection), the authors determined the accumulation of radiolabelled nanoparticles in selected organs, including blood, heart, lungs, liver, stomach, spleen, kidneys, urinary bladder, and intestines. The results indicated that 0.5 h after injection, the radiolabelled nanoparticles were predominantly localized in the liver, 27.43 ± 2.17%ID/g, and blood, 8.61 ± 2.11%ID/g, while in the remaining organs, the accumulation of the radiopreparation was below 5%ID/g. Over time, nanoparticle accumulation increased in the tumour, blood, liver, stomach, spleen, kidneys, urinary bladder, and intestines, while accumulation in the heart and lungs gradually decreased. After 24 h, accumulation in the tumour significantly increased to 5.45 ± 0.37%ID/g. After 48 h, the overall accumulation of [153Sm]Fe3O4@lapatinib-Sm nanoparticles decreased in most organs, likely due to a combination of radioactive decay of 153Sm and progressive excretion of the radiopreparation from the body. The significant accumulation in the kidneys and urinary bladder may indicate that [153Sm]Fe3O4@lapatinib-Sm nanoparticles are excreted primarily through the urinary tract. The observed rapid increase in the tumour/blood accumulation ratio of tested [153Sm]Fe3O4@lapatinib-Sm radioconjugate after 48 h (five times higher than after 24 h) may indicate its high affinity to tumour cells and high specificity in the tumour microenvironment, which may constitute a basis for designing targeted anti-cancer therapies using this radiotracer.
Recently, Gong et al. published a report describing, among other aspects, the labelling of lapatinib with the radionuclide Ga-68 [44]. In this study, the authors present the potential of a multimodal approach to cancer imaging that combines PET and near-infrared (NIR) fluorescence imaging at the same time. The PET probe was lapatinib labelled with the radionuclide Ga-68, while the NIR probe was the NIR LP-S fluorescent agent, also based on lapatinib. According to the authors, this synchronized dual-probing strategy, based on the same targeting molecule with high affinity for HER2-overexpressing cells, may provide an effective diagnostic tool for detecting HER2-positive breast cancer or preoperative PET imaging, as well as for fluorescence-guided tumour surgery. The study included a detailed characterization of the physicochemical and biological properties of both the radiopharmaceutical probe [68Ga]Ga-NOTA-lapatinib and the fluorescent probe NIRF LP-S, underscoring the potential of this multimodal approach in future clinical applications.
Before designing the radiopharmaceutical probe [68Ga]Ga-NOTA-lapatinib, the authors performed a series of preliminary studies. Based on the assumption that the attachment of a PEG linker to the NOTA group would not significantly interfere with receptor interactions, they performed molecular docking analyses using the crystallographic structures of the EGFR (PDB-ID 4G5J) and HER2 (PDB-ID 3PP0). The docking studies evaluated the interactions of both lapatinib and the NOTA-lapatinib conjugate within the ATP-binding pockets of the receptors. The calculated binding energies of lapatinib and the NOTA–lapatinib conjugate with EGFR receptor were −9.2 kcal/mol and −9.0 kcal/mol, respectively, and with the HER2 receptor were −10.64 kcal/mol and −10.05 kcal/mol, respectively, indicating that the structural modification did not substantially impair binding affinity. The cytotoxicity of lapatinib, the NOTA-lapatinib conjugate, and the LP-S probe was assessed using the L02 cell line and the MTT assay. In competitive isotope assays using the HepG2 cell line, the HER2 affinity of lapatinib was found to be 15.26 nM, that of the LP-S probe was 30.54 nM, and that of the NOTA-lapatinib conjugate was 49.78 nM. The [68Ga]Ga-NOTA-lapatinib radioconjugate synthesized by the authors consisted of a lapatinib molecule conjugated with polyethylene glycol (PEG2, which increased aqueous solubility) and the chelator NOTA, which formed a complex with the 68Ga radionuclide (Figure 3e). In accordance with the nomenclature adopted by Gong et al. in their article, in our review publication, we also use the term [68Ga]Ga-NOTA-lapatinib for the discussed radioconjugate; however, in our opinion, due to the presence of the polyethylene glycol (PEG2) group between the NOTA chelator and the lapatinib molecule, it would be more correct to always indicate its presence using the term [68Ga]Ga-NOTA-PEG-lapatinib in the case of the discussed radioconjugate. Labelling of the NOTA-lapatinib conjugate with Ga-68 (pH 4, 90 °C, 10 min) and purification (using a pre-treated Sep Pak Plus Light C18 column) of the resulting [68Ga]Ga-NOTA-lapatinib radioconjugate were completed in less than 30 min, and the radiochemical purity of the radiopreparation was greater than 95% (as confirmed by TLC and/or HPLC). The log D value of the obtained radioconjugate, as determined in the standard n-octanol/PBS solution system (calculated as a ratio of radioactivity of the n-octanol layer to the radioactivity of the water layer), was 1.08 ± 0.02, which indicates the very slightly lipophilic nature of the radiocompound. Incubation of [68Ga]Ga-NOTA-lapatinib radiopreparation in PBS, murine serum, and saline at 25 °C or 37 °C and TLC analyses of the mixture samples (in the case of murine serum, protein components were precipitated with acetonitrile before analysis) showed the stability of the radiopreparation. The biological stability of the radiopharmaceutical was demonstrated by HER2 immunostaining of HepG2 tumours in HepG2 tumour-bearing mice following administration of the radiotracer. The H&E results showed that no organ damage occurred after injection of [68Ga]Ga-NOTA-lapatinib (and also LP-S), confirming the low biological toxicity and high biological safety of the radiopharmaceutical probe (and the fluorescent probe also). Static microscopic PET/MR imaging showed that both the PET probe [68Ga]Ga-NOTA-lapatinib and the fluorescent probe LP-S based on lapatinib could achieve accurate tumour localization. Cellular studies of a [68Ga]Ga-NOTA-lapatinib radioconjugate conducted using HepG2 and K562 cell lines (characterized by varying levels of HER2 expression) demonstrated rapid uptake of the radiotracer by HepG2 cells (8.93% ID/1 mio cells within 1 h of incubation and 7.48% ID/1 mio cells after 2 h) with minimal uptake observed in K562 cells (0.8% ID/1 mio cells after 30 min and 0.96% ID/1 mio cells after 2 h). These results confirm the high receptor affinity and selectivity of the radiotracer for HER2-overexpressing cells. The results of the HER2 receptor blocking study in HepG2 cells using an excess of lapatinib showed that the cellular uptake pathway of lapatinib and the [68Ga]Ga-NOTA-lapatinib radioconjugate is the same. Biodistribution studies of the [68Ga]Ga-NOTA-lapatinib radioconjugate were performed in mice bearing HepG2 and K562 tumours. After 1 h post-injection, accumulation of the radioconjugate in all examined organs was generally significantly higher in the HepG2 tumour-bearing mice group (tumour uptake was 2.53 ± 0.34%ID/g) compared with the K562 tumour-bearing mice group (0.59 ± 0.08%ID/g) and consistent with the different levels of HER2 receptor expression on HepG2 and K562 cells. The relatively high, probably non-specific accumulation of the radioconjugate in the liver (approximately 12%ID/g) and intestines (approximately 9%ID/g) is consistent with the fluorescence imaging results and indicates a predominantly hepatic excretion.
Gong et al. drew attention in their work to two potential disadvantages of using the [68Ga]Ga-NOTA-lapatinib radioconjugate as a PET probe. One is the radioconjugate’s insufficient hydrophilicity, which causes significant accumulation in the liver and intestines, negatively impacting imaging results. The second drawback is the widely varying half-lives of the radioconjugate’s component fragments. Lapatinib is characterized by a relatively long circulation time in blood of 14.2 h, which means that the radiopreparation reaches the maximum concentration approximately 4 h post-injection. This pharmacokinetic profile is suboptimal for imaging with 68Ga, whose physical half-life is only 68 min, which is already almost four half-lives of the radionuclide at the time lapatinib reaches its maximum concentration in the blood. The authors acknowledged these limitations and proposed two potential improvements: the incorporation of a longer PEG fragment to decrease the lipophilicity of the radioconjugate, and the use of a radionuclide with a longer half-life to better match the pharmacokinetics of lapatinib.

4. Discussion

Our review article discusses currently known radiopreparations based on the radiolabelled tyrosine kinase inhibitor lapatinib. Lapatinib labelled with F-18, C-11, or C-14 radionuclides creates radiopreparations structurally identical to lapatinib, but the syntheses of such radiopreparations are multi-step and cannot be performed in hospital laboratories. Labelling lapatinib with metallic radionuclides is usually a single step which can be performed in a hospital setting. In this step, the radionuclide is complexed by a chelator previously linked directly or through a linker to the lapatinib molecule.
Particularly noteworthy are the works of Taskar et al. [40], Pham et al. [43], and Gong et al. [44]. They contain descriptions of many experiments that are important from the point of view of their use as radiopharmaceuticals, descriptions of studies on physicochemical and biological properties, and often the results of SPECT or PET imaging.
The work of Gokulu et al. [42] is also noteworthy. It contains numerous minor and fundamental errors, as mentioned above. As mentioned above, the only evidence for obtaining radioconjugates was the results of the TLRC analyses. Planar chromatography techniques are simple, specific, and accurate methods for the rapid qualitative assessment of mixture composition. They are commonly used in nuclear medicine facilities to assess the efficiency of radionuclide labelling reactions during quality control of various radiopharmaceutical preparations. However, these techniques do not enable qualitative identification of chemical compounds [46]. They serve as analytical comparison methods and can only be applied to well-known chemical systems. The use of these methods requires prior evaluation of appropriate analytical conditions, namely the selection of the stationary phase and mobile phase (developing solutions), enabling optimal separation of the mixture components. The final assessment of the reaction mixture composition by planar chromatography is based on a comparison of the Rf values obtained for the sample being tested with the Rf values previously determined for the individual reagents (reactants and intermediates). Therefore, on what basis do the authors, having two identical TLRC chromatograms, one representing [99mTc]NaTcO4, believe that the second TLRC chromatogram, performed under analogous experimental conditions, represents a [99mTc]Tc-LPT ([99mTc]Tc-lapatinib) radioconjugate? Regarding the stability tests of radiopreparations, they should be performed using radiopreparations previously isolated from the reaction mixture; testing the stability of radiopreparations in the labelling reaction mixture is not reliable, because there is always an excess of a given compound in relation to the amount of radionuclide, shifting the reaction equilibrium towards the formation of a radioconjugate. To conclude, the experimental results described by the authors are not reliable and convincing, and it is uncertain whether the authors really obtained and tested [99mTc]Tc-lapatinib and [99mTc]Tc-lapatinib-PLGA radioconjugates.
Of the lapatinib-based radioconjugates discussed in this review, only radioconjugate [11C]lapatinib described in the paper by Saleem et al. [39] has undergone clinical trials. The remaining radioconjugates are radiocompounds that could be considered potential radiopharmaceuticals; however, they still require further studies to meet regulatory requirements for their clinical use.
Regulatory challenges for radiopharmaceuticals stem from their dual nature as pharmaceutical products and radioactive materials. They require essential non-clinical studies, including non-clinical pharmacology; assessment of radiation exposure and its effects; coordination of pharmacovigilance and radiation safety; and the development of quality control taking into account the specific properties of radiocompounds, especially radiopreparations containing short-lived radionuclides; toxicological studies; pharmacokinetic modelling; and imaging studies.
Furthermore, logistical requirements include the need for knowledge about new and personalized therapies, coordination of pharmacovigilance and radiological safety, and the need to provide specialized infrastructure in hospitals to ensure radiological safety for patients and staff. Due to the dynamic development of radiopharmacy, these issues are currently of interest to many researchers [47,48,49].
In summary, in our opinion, the use of lapatinib as a vector in radiopharmaceuticals has great potential and, to date, has not been exploited at all. Lapatinib is a small and biologically stable molecule with a convenient modification site (a secondary amino group from the aliphatic chain -CH2-CH2-NH-CH2- of the lapatinib molecule) for the attachment of a chelator, selected for labelling with a metallic radionuclide (e.g., theranostic 43,44,47Sc radionuclides). The use of lapatinib labelled with a therapeutic radionuclide (e.g., an alpha emitter, of course after prior diagnosis of HER2 receptor overexpression) would allow for a synergistic therapeutic effect resulting from the simultaneous destruction of cancer cells by the emitted radiation and the presence of lapatinib, which is an inhibitor of the signalling pathway leading to cancer cell proliferation (compared to the therapeutic effect of radiation, this effect will be minimal due to the nanogram amount of lapatinib).

Author Contributions

Conceptualization, E.G. and P.K.; writing—original draft preparation, E.G. and P.K.; writing—review and editing, E.G. and P.K.; visualization, E.G. and P.K.; supervision, E.G.; project administration, E.G. and P.K. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by International Atomic Energy Agency (IAEA), Research Contract No 28460, “Design, Synthesis and Evaluation Of technetium-99m Labelled Lapatinib as a Potential Radioconjugate for Breast Cancer Imaging”.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The original contributions presented in the study are included in the article, further inquiries can be directed to the corresponding author.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

ATPadenosine triphosphate
BBBblood–brain barrier
BTBblood–tumour barrier
CISHchromogenic in situ hybridization
CNScentral nervous system
DFGAsp-Phe-Gly
DLSDuckworth–Lewis–Stern method
EAelemental analysis
EGFRepidermal growth factor receptor
EMAEuropean Medicines Agency
ErbBerythroblastic leukemia viral oncogene homolog
FDAU.S. Food and Drug Administration
FISHfluorescence in situ hybridization
GSKGlaxoSmithKline
H&Ehematoxylin and eosin staining histological technique
HER2human epidermal growth factor receptor 2
HPLChigh-performance liquid chromatography
ID/gpercentage of injected dose per gram of tissue
IHCimmunohistochemistry
Kiappapparent inhibition constant
LPTlapatinib
MSmass spectrometry
n.c.a.no carrier added
NIRnear-infrared
PI3-K phosphatidylinositol 3-kinase pathway
NMRnuclear magnetic resonance
NOTA1,4,7-Triazacyclononane-1,4,7-triacetic acid
NS3tris(2-mercaptoethyl)-amine; 2,2′,2″-nitrilotriethanethiol
PETpositron emission tomography
PLGApoly(lactic-co-glycolic acid)
Rasintracellular signalling cascade pathway
RCPradiochemical purity
RCYradiochemical yield
SAspecific activity
SEMscanning electron microscopy
SPECTsingle-photon emission computed tomography
TEMtransmission electron microscopy analytical method
TKstyrosine kinases
TLRCthin-layer radiochromatography

References

  1. Fragomeni, S.M.; Sciallis, A.; Jeruss, J.S. Molecular subtypes and local-regional control of breast cancer. Surg. Oncol. Clin. N. Am. 2018, 27, 95–120. [Google Scholar] [CrossRef] [PubMed]
  2. Loibl, S.; Poortmans, P.; Morrow, M.; Denkert, C.; Curigliano, G. Breast cancer. Lancet 2021, 397, 1750–1769. [Google Scholar] [CrossRef] [PubMed]
  3. Nelson, M.H.; Dolder, C.R. Lapatinib: A novel dual tyrosine kinase inhibitor with activity in solid tumors. Ann. Pharmacother. 2006, 40, 261–269. [Google Scholar] [CrossRef] [PubMed]
  4. Johnston, S.R.; Leary, A. Lapatinib: A novel EGFR/HER2 tyrosine kinase inhibitor for cancer. Drugs Today (Barc.) 2006, 42, 441–453. [Google Scholar] [CrossRef]
  5. Kumar, R.; George, B.; Campbell, M.R.; Verma, N.; Paul, A.M.; Melo-Alvim, C.; Ribeiro, L.; Pillai, M.R.; da Costa, L.M.; Moasser, M.M. HER family in cancer progression: From discovery to 2020 and beyond. Adv. Cancer. Res. 2020, 147, 109–160. [Google Scholar] [CrossRef]
  6. Rusnak, D.W.; Alligood, K.J.; Mullin, R.J.; Spehar, G.M.; Arenas-Elliott, C.; Martin, A.M.; Degenhardt, Y.; Rudolph, S.K.; Haws, T.F., Jr.; Hudson-Curtis, B.L.; et al. Assessment of epidermal growth factor receptor (EGFR, ErbB1) and HER2 (ErbB2) protein expression levels and response to lapatinib (Tykerb, GW572016) in an expanded panel of human normal and tumour cell lines. Cell Prolif. 2007, 40, 580–594. [Google Scholar] [CrossRef]
  7. Spector, N.L.; Xia, W.; Burris, H., 3rd; Hurwitz, H.; Dees, E.C.; Dowlati, A.; O’Neil, B.; Overmoyer, B.; Marcom, P.K.; Blackwell, K.L.; et al. Study of the biologic effects of lapatinib, a reversible inhibitor of ErbB1 and ErbB2 tyrosine kinases, on tumor growth and survival pathways in patients with advanced malignancies. J. Clin. Oncol. 2005, 23, 2502–2512. [Google Scholar] [CrossRef]
  8. Wood, E.R.; Truesdale, A.T.; McDonald, O.B.; Yuan, D.; Hassell, A.; Dickerson, S.H.; Ellis, B.; Pennisi, C.; Horne, E.; Lackey, K.; et al. A unique structure for epidermal growth factor receptor bound to GW572016 (Lapatinib): Relationships among protein conformation, inhibitor off-rate, and receptor activity in tumor cells. Cancer Res. 2004, 64, 6652–6659. [Google Scholar] [CrossRef]
  9. Castellino, S.; O’Mara, M.; Koch, K.; Borts, D.J.; Bowers, G.D.; MacLauchlin, C. Human metabolism of lapatinib, a dual kinase inhibitor: Implications for hepatotoxicity. Drug Metab. Dispos. 2012, 40, 139–150. [Google Scholar] [CrossRef]
  10. Geyer, C.E.; Forster, J.; Lindquist, D.; Chan, S.; Romieu, C.G.; Pienkowski, T.; Jagiello-Gruszfeld, A.; Crown, J.; Chan, A.; Kaufman, B.; et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N. Engl.J. Med. 2006, 355, 2733–2743. [Google Scholar] [CrossRef]
  11. Morikawa, A.; Peereboom, D.M.; Thorsheim, H.R.; Samala, R.; Balyan, R.; Murphy, C.G.; Lockman, P.R.; Simmons, A.; Weil, R.J.; Tabar, V.; et al. Capecitabine and lapatinib uptake in surgically resected brain metastases from metastatic breast cancer patients: A prospective study. Neuro. Oncol. 2015, 17, 289–295. [Google Scholar] [CrossRef] [PubMed]
  12. Medina, P.J.; Goodin, S. Lapatinib: A dual inhibitor of human epidermal growth factor receptor tyrosine kinases. Clin. Ther. 2008, 30, 1426–1447. [Google Scholar] [CrossRef] [PubMed]
  13. Konecny, G.E.; Pegram, M.D.; Venkatesan, N.; Finn, R.; Yang, G.; Rahmeh, M.; Untch, M.; Rusnak, D.W.; Spehar, G.; Mullin, R.J.; et al. Activity of the dual kinase inhibitor lapatinib (GW572016) against HER-2-overexpressing and trastuzumab-treated breast cancer cells. Cancer Res. 2006, 66, 1630–1639. [Google Scholar] [CrossRef]
  14. Yu, T.; Cho, B.J.; Choi, E.J.; Park, J.M.; Kim, D.H.; Kim, I.A. Radiosensitizing effect of lapatinib in human epidermal growth factor receptor 2-positive breast cancer cells. Oncotarget 2016, 7, 79089–79100. [Google Scholar] [CrossRef]
  15. Scaltriti, M.; Rojo, F.; Ocaña, A.; Anido, J.; Guzman, M.; Cortes, J.; Di Cosimo, S.; Matias-Guiu, X.; Ramon y Cajal, S.; Arribas, J.; et al. Expression of p95HER2, a Truncated Form of the HER2 Receptor, and Response to Anti-HER2 Therapies in Breast Cancer. JNCI J. Natl. Cancer Inst. 2007, 99, 628–638. [Google Scholar] [CrossRef]
  16. Nahta, R.; Yuan, L.X.; Du, Y.; Esteva, F.J. Lapatinib induces apoptosis in trastuzumab-resistant breast cancer cells: Effects on insulin-like growth factor I signaling. Mol. Cancer Ther. 2007, 6, 667–674. [Google Scholar] [CrossRef]
  17. Van Poznak, C.; Somerfield, M.R.; Bast, R.C.; Cristofanilli, M.; Goetz, M.P.; Gonzalez-Angulo, A.M.; Hicks, D.G.; Hill, E.G.; Liu, M.C.; Lucas, W.; et al. Use of Biomarkers to Guide Decisions on Systemic Therapy for Women With Metastatic Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline. J. Clin. Oncol. 2015, 33, 2695–2704. [Google Scholar] [CrossRef]
  18. Ellis, C.M.; Dyson, M.J.; Stephenson, T.J.; Maltby, E.L. HER2 amplification status in breast cancer: A comparison between immunohistochemical staining and fluorescence in situ hybridisation using manual and automated quantitative image analysis scoring techniques. J. Clin. Pathol. 2005, 58, 710–714. [Google Scholar] [CrossRef]
  19. Sauter, G.; Lee, J.; Bartlett, J.M.; Slamon, D.J.; Press, M.F. Guidelines for human epidermal growth factor receptor 2 testing: Biologic and methodologic considerations. J. Clin. Oncol. 2009, 27, 1323–1333. [Google Scholar] [CrossRef]
  20. Tanner, M.; Gancberg, D.; Di Leo, A.; Larsimont, D.; Rouas, G.; Piccart, M.J.; Isola, J. Chromogenic in situ hybridization: A practical alternative for fluorescence in situ hybridization to detect HER-2/neu oncogene amplification in archival breast cancer samples. Am. J. Pathol. 2000, 157, 1467–1472. [Google Scholar] [CrossRef]
  21. Pedersen, M.; Rasmussen, B.B. The correlation between dual-color chromogenic in situ hybridization and fluorescence in situ hybridization in assessing HER2 gene amplification in breast cancer. Diagn. Mol. Pathol. 2009, 18, 96–102. [Google Scholar] [CrossRef]
  22. Zhang, S.; Wang, X.; Gao, X.; Chen, X.; Li, L.; Li, G.; Liu, C.; Miao, Y.; Wang, R.; Hu, K. Radiopharmaceuticals and their applications in medicine. Signal Transduct. Target Ther. 2025, 10, 1. [Google Scholar] [CrossRef] [PubMed]
  23. Ge, S.; Li, J.; Yu, Y.; Chen, Z.; Yang, Y.; Zhu, L.; Sang, S.; Deng, S. Review: Radionuclide Molecular Imaging Targeting HER2 in Breast Cancer with a Focus on Molecular Probes into Clinical Trials and Small Peptides. Molecules 2021, 26, 6482. [Google Scholar] [CrossRef] [PubMed]
  24. Molavipordanjani, S.; Hosseinimehr, S.J. The Radiolabeled HER3 Targeting Molecules for Tumor Imaging. Iran. J. Pharm. Res. 2021, 20, 141–152. [Google Scholar] [CrossRef] [PubMed]
  25. Bernard-Gauthier, V.; Bailey, J.J.; Berke, S.; Schirrmacher, R. Recent Advances in the Development and Application of Radiolabeled Kinase Inhibitors for PET Imaging. Molecules 2015, 20, 22000–22027. [Google Scholar] [CrossRef]
  26. Oude Munnink, T.H.; de Vries, E.G.; Vedelaar, S.R.; Timmer-Bosscha, H.; Schröder, C.P.; Brouwers, A.H.; Lub-de Hooge, M.N. Lapatinib and 17AAG reduce 89Zr-trastuzumab-F(ab’)2 uptake in SKBR3 tumor xenografts. Mol. Pharm. 2012, 9, 2995–3002. [Google Scholar] [CrossRef]
  27. Rosestedt, M.; Andersson, K.G.; Mitran, B.; Tolmachev, V.; Löfblom, J.; Orlova, A.; Ståhl, S. Affibody-mediated PET imaging of HER3 expression in malignant tumours. Sci. Rep. 2015, 5, 15226. [Google Scholar] [CrossRef]
  28. Da Pieve, C.; Allott, L.; Martins, C.D.; Vardon, A.; Ciobota, D.M.; Kramer-Marek, G.; Smith, G. Efficient [18F]AlF Radiolabeling of ZHER3:8698 Affibody Molecule for Imaging of HER3 Positive Tumors. Bioconjug. Chem. 2016, 27, 1839–1849. [Google Scholar] [CrossRef]
  29. Pool, M.; Kol, A.; de Jong, S.; de Vries, E.G.E.; Lub-de Hooge, M.N.; Terwisscha van Scheltinga, A.G.T. 89Zr-mAb3481 PET for HER3 tumor status assessment during lapatinib treatment. MAbs 2017, 9, 1370–1378. [Google Scholar] [CrossRef]
  30. Burden, S.; Yarden, Y. Neuregulins and their receptors: A versatile signaling module in organogenesis and oncogenesis. Neuron. 1997, 18, 847–855. [Google Scholar] [CrossRef]
  31. Kolibaba, K.S.; Druker, B.J. Protein tyrosine kinases and cancer. Biochim. Biophys. Acta 1997, 1333, F217–F248. [Google Scholar] [CrossRef] [PubMed]
  32. Riese, D.J., 2nd; Stern, D.F. Specificity within the EGF family/ErbB receptor family signaling network. Bioessays 1998, 20, 41–48. [Google Scholar] [CrossRef] [PubMed]
  33. Aertgeerts, K.; Skene, R.; Yano, J.; Sang, B.C.; Zou, H.; Snell, G.; Jennings, A.; Iwamoto, K.; Habuka, N.; Hirokawa, A.; et al. Structural analysis of the mechanism of inhibition and allosteric activation of the kinase domain of HER2 protein. J. Biol. Chem. 2011, 286, 18756–18765. [Google Scholar] [CrossRef]
  34. Wu, P.; Nielson, T.E.; Clausen, M.H. FDA-approved small-molecule kinase inhibitors. Trends Pharmacol. Sci. 2015, 36, 422–439. [Google Scholar] [CrossRef]
  35. Qiu, C.; Tarrant, M.K.; Choi, S.H.; Sathyamurthy, A.; Bose, R.; Banjade, S.; Pal, A.; Bornmann, W.G.; Lemmon, M.A.; Cole, P.A.; et al. Mechanism of activation and inhibition of the HER4/ErbB4 kinase. Structure 2008, 16, 460–467. [Google Scholar] [CrossRef]
  36. Slobbe, P.; Poot, A.J.; Windhorst, A.D.; van Dongen, G.A. PET imaging with small-molecule tyrosine kinase inhibitors: TKI-PET. Drug Discov. Today 2012, 17, 1175–1187. [Google Scholar] [CrossRef]
  37. Basuli, F.; Wu, H.; Li, C.; Shi, Z.-D.; Sulima, A.; Griffiths, G.L. A first synthesis of 18F-radiolabeled Lapatinib: A potential tracer for positron emission tomographic imaging of erbb1/erbb2 tyrosine kinase activity. J. Label. Compd. Radiopharm. 2011, 54, 633–636. [Google Scholar] [CrossRef]
  38. Nunes, P.; Zhang, Z.; Zhang, C.; Carvalho, I.; Benard, F.; Lin, K.-S. Facile synthesis of 18F-labeled Lapatinib for imaging with positron emission tomography. JNM 2018, 59 (Suppl. S1), 1055. [Google Scholar]
  39. Saleem, A.; Searle, G.E.; Kenny, L.M.; Huiban, M.; Kozlowski, K.; Waldman, A.D.; Woodley, L.; Palmieri, C.; Lowdell, C.; Kaneko, T.; et al. Lapatinib access into normal brain and brain metastases in patients with Her-2 overexpressing breast cancer. EJNMMI Res. 2015, 5, 30. [Google Scholar] [CrossRef]
  40. Taskar, K.S.; Rudraraju, V.; Mittapalli, R.K.; Samala, R.; Thorsheim, H.R.; Lockman, J.; Gril, B.; Hua, E.; Palmieri, D.; Polli, J.W.; et al. Lapatinib distribution in HER2 overexpressing experimental brain metastases of breast cancer. Pharm Res. 2012, 29, 770–781. [Google Scholar] [CrossRef]
  41. Gniazdowska, E.; Koźmiński, P.; Bańkowski, K.; Luniewski, W.; Królicki, L. Synthesis, physicochemical and biological evaluation of technetium- 99m labeled lapatinib as a novel potential tumor imaging agent of Her-2 positive breast cancer. Eur. J. Med. Chem. 2014, 87, 493–499. [Google Scholar] [CrossRef]
  42. Gokulu, S.G.; Karatay, K.B.; Bilgi, A.; Kayas, C.; Yildirim, N.; Kilcar, A.Y.; Muftuler, F.Z.B.; Terek, M.C.; Akman, L. Synthesis and in vitro evaluation of 99mTc radiolabeled lapatinib (LPT) and its PLGA formulation. J. Radioanal. Nucl. Chem. 2024, 333, 665–672. [Google Scholar] [CrossRef]
  43. Pham, T.M.; Cao, D.V.; Dang, H.H.Q.; Mai, P.M.T.; Nguyen, T.B.; Dinh, N.B.N.; Nguyen, T.K.G.; Le, T.M.H.; Doan, V.D.; Nguyen, D.T.; et al. 153Sm-labeled Fe3O4@lapatinib nanoparticles as a potential therapeutic agent for breast cancer: Synthesis, quality control, and In Vivo evaluation. J. Mater. Chem. B 2024, 12, 678–690. [Google Scholar] [CrossRef] [PubMed]
  44. Gong, J.; Li, Y.; Di, H.; Li, J.; Dong, J.; He, C.; Cao, P.; Cai, H.; He, J.; Wang, Y. Combined PET and near-infrared fluorescence probe based on lapatinib targeting HER2 for in vivo tumor imaging. Bioorg. Chem. 2025, 161, 108550. [Google Scholar] [CrossRef] [PubMed]
  45. Gril, B.; Palmieri, D.; Bronder, J.L.; Herring, J.M.; Vega-Valle, E.; Feigenbaum, L.; Liewehr, D.J.; Steinberg, S.M.; Merino, M.J.; Rubin, S.D.; et al. Effect of lapatinib on the outgrowth of metastatic breast cancer cells to the brain. J. Natl. Cancer Inst. 2008, 100, 1092–1103. [Google Scholar] [CrossRef]
  46. Koźmiński, P.; Halik, P.K.; Chesori, R.; Gniazdowska, E. Common Shortcomings in Study on Radiopharmaceutical Design Research: A Case Study of 99mTc-Labelled Methotrexate. Molecules 2021, 26, 5862. [Google Scholar] [CrossRef]
  47. Korde, A.; Mikolajczak, R.; Kolenc, P.; Bouziotis, P.; Westin, H.; Lauritzen, M.; Koole, M.; Herth, M.M.; Bardiès, M.; Martins, A.F.; et al. Practical considerations for navigating the regulatory landscape of non-clinical studies for clinical translation of radiopharmaceuticals. EJNMMI Radiopharm Chem. 2022, 19, 18. [Google Scholar] [CrossRef]
  48. Navneet, S.; Harvinder, K.; Rakesh, K.S. Radiopharmaceuticals Regulations: Current Scenario and the Way Forward. Appl. Clin. Res. Clin. Trials Regul. Aff. 2017, 4, 183–194. [Google Scholar] [CrossRef]
  49. Korde, A.; Patt, M.; Selivanova, S.V.; Scott, A.M.; Hesselmann, R.; Kiss, O.; Ramamoorthy, N.; Todde, S.; Rubow, S.M.; Gwaza, L.; et al. Position paper to facilitate patient access to radiopharmaceuticals: Considerations for a suitable pharmaceutical regulatory framework. EJNMMI Radiopharm. Chem. 2024, 9, 2. [Google Scholar] [CrossRef]
Applsci 15 10964 g001
Figure 1. Structure of lapatinib ditosylate monohydrate.
Figure 1. Structure of lapatinib ditosylate monohydrate.
Applsci 15 10964 g001
Applsci 15 10964 g002
Figure 2. Graphic illustration of the inhibitory effect of lapatinib via EGFR and HER2 receptors.
Figure 2. Graphic illustration of the inhibitory effect of lapatinib via EGFR and HER2 receptors.
Applsci 15 10964 g002
Applsci 15 10964 g003
Figure 3. Structure of radiopreparations based on the lapatinib molecule discussed in this report.
Figure 3. Structure of radiopreparations based on the lapatinib molecule discussed in this report.
Applsci 15 10964 g003
Applsci 15 10964 g004
Figure 4. Structure of poly(lactic-co-glycolic acid), x = number of units of lactic acid, y = number of units of glycolic acid.
Figure 4. Structure of poly(lactic-co-glycolic acid), x = number of units of lactic acid, y = number of units of glycolic acid.
Applsci 15 10964 g004
Table 1. Lapatinib or its derivatives labelled with diagnostic or therapeutic radionuclides.
Table 1. Lapatinib or its derivatives labelled with diagnostic or therapeutic radionuclides.
Lapatinib-Based Radiotracers
(Use in Nuclear Medicine)		Research Purpose and ConclusionsReferences
[18F]lapatinib
(PET imaging of neoplastic lesions)		Manual, multi-step radiosynthesis of 18F-labelled lapatinib dedicated to PET imaging of ErbB1/ErbB2 tyrosine kinase activity (synthesis time 140 min, RCY 8–12%, RCP > 98% and SA in the range 35–430 Ci/mmol.[37]
Facile two-step procedure for the routine radiotracer preparation for clinical trials (nucleophilic copper-mediated 18F-fluorination reaction of Boc-protected lapatinib, microwave, K2CO3 as catalyst, temperature 110 °C, 10 min). This synthesis proved to be simpler, but the final radiochemical yield was not satisfactory.[38]
[11C]lapatinib
(PET imaging of neoplastic lesions)		Clinical trials registered in the European Union Clinical Trials Database (Eudra CT 2009-009884-76), the National Institute of Health database (NCT01290354) and the National Cancer Research Network study portfolio (NCRN262):
▪
In vivo studies have shown that the radiotracer is stable and accumulates differentially in healthy brain tissue and brain metastasis, thereby enabling the visualization of brain tumours;
▪
PET studies showed that therapeutic doses of lapatinib did not increase the penetration of the radiotracer into the brain, suggesting that the use of lapatinib in breast cancer patients has a role in treating existing brain metastases but not in preventing them.
[39]
[14C]lapatinib
(treatment of neoplastic lesions)		Studies on the possibility of achieving therapeutic concentrations of lapatinib in breast cancer brain metastases after oral or intravenous administration of the radiotracer [14C]lapatinib. Experimental results showed:
  • elevated, highly variable and very heterogeneous [14C]lapatinib concentrations in brain metastases;
  • visible differences in the distribution of radiotracer between the centre of the metastasis and its periphery;
  • low and non-homogeneous concentrations of the radiotracer in sites distant from the metastases;
  • [14C]lapatinib uptake in all examined brain metastases varies both within and between lesions;
  • in the majority of cases (>80%), [14C] lapatinib delivery to breast cancer brain metastases is approximately 7–9-fold elevated compared to surrounding brain tissue but still represents only a fraction (approximately 10–20%) of the concentrations achieved in peripheral metastases;
  • only in a small group of examined brain metastases (approximately 17%) did lapatinib concentrations in the brain approach those in peripheral tumours;
  • the reason for the limited accumulation of radiopharmaceuticals in brain metastases is the permeability of the blood–tumour barrier.
[40]
[99mTc]Tc(NS3)(CN-lapatinib)
(SPECT imaging of neoplastic
lesions)
  • Synthesis and physicochemical and biological studies of a potential diagnostic radiopharmaceutical for HER2 breast cancer imaging and patient stratification for personalized therapy.
  • The radioconjugate [99mTc]Tc(NS3)(CN-lapatinib) is formed with high radiochemical yield (>97%), high radiochemical purity (>98%) and specific activity within the range 25–30 GBq/mmol;
  • the radioconjugate is stable in the presence of excess concentrations of competing ligands containing reactive SH or NH groups and in human serum;
  • the determined log p value of the [99mTc]Tc(NS3)(CN-lapatinib) radioconjugate is 1.24 ± 0.04;
  • the parameters determined in biological studies using a human ovarian cancer cell line (SKOV-3) are Kd 3.5 ± 0.4 nM, IC50 41.2 ± 0.4 nM, Bmax 2.4 ± 0.3 nM, corresponding to number of 2.4 × 106 binding sites per cell;
  • a multi-organ biodistribution study showed radioconjugate uptake in the liver of 4–5% ID/g, in the kidneys of 3–5% ID/g, and below 1% ID/g in the remaining organs tested.
[41]
[99mTc]Tc-lapatinib
[99mTc]Tc-lapatinib-PLGA
(SPECT imaging of neoplastic lesions)		Syntheses and characterization of novel radiotracers containing lapatinib and its poly(lactic-co-glycolic acid)-encapsulated formulation labelled with technetium-99m.
▪
SEM analysis showed spherical morphology of LPT-PLGA nanoparticles, and DLS analysis showed their size distribution at 225.60 ± 1.21 nm;
▪
[99mTc]Tc-LPT and [99mTc]Tc-LPT-PLGA radioconjugates were obtained by direct labelling with radiochemical yields of 98.14 ± 1.12% and 97.68 ± 0.93%, respectively, by reduction of sodium pertechnetate [99mTc]NaTcO4 with SnCl2 as a reducing agent;
▪
both [99mTc]Tc-LPT and [99mTc]Tc-LPT-PLGA radioconjugates are hydrophilic in nature, and the determined logP values are −2.79 ± 0.01 and −1.09 ± 0.03, respectively;
▪
the cellular uptake values of both [99mTc]Tc-LPT and [99mTc]Tc-LPT-PLGA radioconjugates were higher in HeLa and MDAH cells (approximately 15%), whereas in MDA-MB-231 cells, the uptake remained low and comparable to the uptake of free [99mTc]Tc (approximately 5%).
[42]
[153Sm]Fe3O4@lapatinib-Sm
(SPECT imaging and treatment of neoplastic lesions)		Synthesis and physicochemical and biological characterization of a new radiopharmaceutical [153Sm]Fe3O4@lapatinib-Sm for the diagnosis and targeted therapy of breast cancer.
  • γ radiation of 153Sm radionuclide with energy of 103 keV enabled SPECT imaging and radiation dose assessment;
  • β radiation of 153Sm radionuclide with energy of 0.81 MeV and a half-life of 1.9 days enabled targeted eradication of cancer cells smaller than a centimetre;
  • under optimized labelling conditions ([153Sm]SmCl3 concentration of 10 mCi/mL, pH 7.4, reaction time of 30 min and temperature of 25 °C), the labelling efficiency and radiochemical purity of the radiopreparation were >99%;
  • the TEM analysis showed the diameter of [153Sm]Fe3O4@lapatinib-Sm nanoparticles ranged from 10 to 40 nm;
  • stability control of the radiopreparation in PBS solution and human serum carried out for 8 days and sterility of the radiopreparation carried out for 12 days showed its stability and sterility;
  • toxicity studies of the radiopreparation in an animal model have shown that a dose of 20 mCi/kg is sufficiently effective and completely safe;
  • the biodistribution of [153Sm]Fe3O4@lapatinib-Sm nanoparticles in BT474 female xenograft mice showed time-varying (up to 48 h post-injection) accumulation of the radiopreparation in individual organs and its excretion mainly through the urinary tract;
  • increasing accumulation of the [153Sm]Fe3O4@lapatinib-Sm radioconjugate in the tumour over time and a rapidly increasing ratio of tumour and blood radioconjugate accumulation indicate its high affinity and high specificity to tumour cells.
[43]
[68Ga]Ga-NOTA-lapatinib
(PET imaging of neoplastic lesions)		Synthesis and physicochemical and biological studies of the radiopreparation [68Ga]Ga-NOTA-lapatinib intended as a radiopharmaceutical probe for a synchronized real-time imaging strategy of HER2-overexpressing tumours using both PET and near-infrared fluorescence (NIR, using the LP-S fluorescent probe based on the same target molecule—lapatinib).
  • under optimized labelling conditions (pH 4, 90 °C, 10 min), the radiochemical purity of the radiopreparation was >95%;
  • incubation of the radiopreparation in PBS, murine serum and saline at 25 °C or 37 °C showed its stability;
  • determined logP values were 1.08 ± 0.02;
  • biodistribution studies of the radioconjugate performed in HepG2 and K562 tumour-bearing mice showed visible accumulation of the radioconjugate in tumour (2.53 ± 0.34%ID/g), and high uptake in the liver (~12%ID/g) and intestines (~9%ID/g) indicated a predominantly hepatic excretion;
  • static microscopic PET/MR imaging showed that both the PET probe [68Ga]Ga-NOTA-lapatinib and the fluorescent probe LP-S based on lapatinib could achieve accurate tumour localization;
  • both probes [68Ga]Ga-NOTA-Lapatinib and LP-S have the same internalization pathway, similar metabolic cycles in cells, as well as low biological toxicity and high biological safety.
[44]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Koźmiński, P.; Gniazdowska, E. Lapatinib-Based Radioagents for Application in Nuclear Medicine. Appl. Sci. 2025, 15, 10964. https://doi.org/10.3390/app152010964

AMA Style

Koźmiński P, Gniazdowska E. Lapatinib-Based Radioagents for Application in Nuclear Medicine. Applied Sciences. 2025; 15(20):10964. https://doi.org/10.3390/app152010964

Chicago/Turabian Style

Koźmiński, Przemysław, and Ewa Gniazdowska. 2025. "Lapatinib-Based Radioagents for Application in Nuclear Medicine" Applied Sciences 15, no. 20: 10964. https://doi.org/10.3390/app152010964

APA Style

Koźmiński, P., & Gniazdowska, E. (2025). Lapatinib-Based Radioagents for Application in Nuclear Medicine. Applied Sciences, 15(20), 10964. https://doi.org/10.3390/app152010964

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop