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1.
Mol Pharm ; 2020 Nov 30.
Artículo en Inglés | MEDLINE | ID: mdl-33253591

RESUMEN

C-X-C chemokine receptor 4 (CXCR4) is highly expressed in cancers, contributing to proliferation, metastasis, and a poor prognosis. The noninvasive imaging of CXCR4 can enable the detection and characterization of aggressive cancers with poor outcomes. Currently, no 18F-labeled CXCR4 positron emission tomography (PET) radiotracer has demonstrated imaging contrast comparable to [68Ga]Ga-Pentixafor, a CXCR4-targeting radioligand. We, therefore, aimed to develop a high-contrast CXCR4-targeting radiotracer by incorporating a hydrophilic linker and trifluoroborate radioprosthesis to LY2510924, a known CXCR4 antagonist. A carboxy-ammoniomethyl-trifluoroborate (PepBF3) moiety was conjugated to the LY2510924-derived peptide possessing a triglutamate linker via amide bond formation to obtain BL08, whereas an alkyne ammoniomethyl-trifluoroborate (AMBF3) moiety was conjugated using the copper-catalyzed [3+2] cycloaddition click reaction to obtain BL09. BL08 and BL09 were radiolabeled with [18F]fluoride ion using 18F-19F isotope exchange. Pentixafor was radiolabeled with [68Ga]GaCl3. Side-by-side PET imaging and biodistribution studies were performed on immunocompromised mice bearing Daudi Burkitt lymphoma xenografts. The biodistribution of [18F]BL08 and [18F]BL09 showed tumor uptake at 2 h postinjection (p.i.) (5.67 ± 1.25%ID/g and 5.83 ± 0.92%ID/g, respectively), which were concordant with the results of PET imaging. [18F]BL08 had low background activity, providing tumor-to-blood, -muscle, and -liver ratios of 72 ± 20, 339 ± 81, and 14 ± 3 (2 h p.i.), respectively. [18F]BL09 behaved similarly, with ratios of 64 ± 20, 239 ± 72, and 17 ± 3 (2 h p.i.), respectively. This resulted in high-contrast visualization of tumors on PET imaging for both radiotracers. [18F]BL08 exhibited lower kidney uptake (2.2 ± 0.5%ID/g) compared to [18F]BL09 (7.6 ± 1.0%ID/g) at 2 h p.i. [18F]BL08 and [18F]BL09 demonstrated higher tumor-to-blood, -muscle, and -liver ratios compared to [68Ga]Ga-Pentixafor (18.9 ± 2.7, 95.4 ± 36.7, and 5.9 ± 0.7 at 2 h p.i., respectively). In conclusion, [18F]BL08 and [18F]BL09 enable high-contrast visualization of CXCR4 expression in Daudi xenografts. Based on high tumor-to-organ ratios, [18F]BL08 may prove a valuable new tool for CXCR4-targeted PET imaging with potential for translation. The use of a PepBF3 moiety is a new approach for the orthogonal conjugation of organotrifluoroborates for 18F-labeling of peptides.

2.
Pharmaceuticals (Basel) ; 13(8)2020 Aug 17.
Artículo en Inglés | MEDLINE | ID: mdl-32824565

RESUMEN

Kinins, bradykinin and kallidin are vasoactive peptides that signal through the bradykinin B1 and B2 receptors (B1R and B2R). B2R is constitutively expressed in healthy tissues and mediates responses such as vasodilation, fluid balance and retention, smooth muscle contraction, and algesia, while B1R is absent in normal tissues and is induced by tissue trauma or inflammation. B2R is activated by kinins, while B1R is activated by kinins that lack the C-terminal arginine residue. Perturbations of the kinin system have been implicated in inflammation, chronic pain, vasculopathy, neuropathy, obesity, diabetes, and cancer. In general, excess activation and signaling of the kinin system lead to a pro-inflammatory state. Depending on the disease context, agonism or antagonism of the bradykinin receptors have been considered as therapeutic options. In this review, we summarize molecular imaging agents targeting these G protein-coupled receptors, including optical and radioactive probes that have been used to interrogate B1R/B2R expression at the cellular and anatomical levels, respectively. Several of these preclinical agents, described herein, have the potential to guide therapeutic interventions for these receptors.

3.
Cancer Lett ; 493: 31-40, 2020 Nov 28.
Artículo en Inglés | MEDLINE | ID: mdl-32763272

RESUMEN

Hypoxic tumour cells are radiation-resistant and are associated with poor therapeutic outcome. A poorly understood source of tumour hypoxia is unstable perfusion, which exposes tumour cells to varying oxygen tensions over time creating "transiently" hypoxic cells. Evidence suggests that angiotensin II type 1 receptor blockers (ARBs) can improve tumour perfusion by reducing collagen deposition from cancer associated fibroblasts (CAFs). However, the influence of ARBs on transient hypoxia and tumour radiation response is unknown. We tested how the ARBs losartan and telmisartan affected the solid tumour microenvironment, using fluorescent perfusion dyes and positron emission tomography to quantify tumour perfusion, and a combination of hypoxia markers and the hemorheological agent pentoxifylline to assess transient tumour hypoxia. We found CAF-containing tumours have reduced collagen I levels in response to telmisartan, but not losartan. Telmisartan significantly increased tumour blood flow, stabilized microregional tumour perfusion, and decreased tumour hypoxia by reducing the development of transient hypoxia. Telmisartan-treated tumours were more responsive to radiation, indicating that telmisartan reduces a therapeutically important population of transiently hypoxic tumour cells. Our findings indicate telmisartan is capable of modifying the tumour microenvironment to stabilize tumour perfusion, reduce transient hypoxia, and improve tumour radiation response.

4.
Molecules ; 25(17)2020 Aug 25.
Artículo en Inglés | MEDLINE | ID: mdl-32854201

RESUMEN

High kidney uptake is a common feature of peptide-based radiopharmaceuticals, leading to reduced detection sensitivity for lesions adjacent to kidneys and lower maximum tolerated therapeutic dose. In this study, we evaluated if the Met-Val-Lys (MVK) linker could be used to lower kidney uptake of 68Ga-labeled DOTA-conjugated peptides and peptidomimetics. A model compound, [68Ga]Ga-DOTA-AmBz-MVK(Ac)-OH (AmBz: aminomethylbenzoyl), and its derivative, [68Ga]Ga-DOTA-AmBz-MVK(HTK01166)-OH, coupled with the PSMA (prostate-specific membrane antigen)-targeting motif of the previously reported HTK01166 were synthesized and evaluated to determine if they could be recognized and cleaved by the renal brush border enzymes. Additionally, positron emission tomography (PET) imaging, ex vivo biodistribution and in vivo stability studies were conducted in mice to evaluate their pharmacokinetics. [68Ga]Ga-DOTA-AmBz-MVK(Ac)-OH was effectively cleaved specifically by neutral endopeptidase (NEP) of renal brush border enzymes at the Met-Val amide bond, and the radio-metabolite [68Ga]Ga-DOTA-AmBz-Met-OH was rapidly excreted via the renal pathway with minimal kidney retention. [68Ga]Ga-DOTA-AmBz-MVK(HTK01166)-OH retained its PSMA-targeting capability and was also cleaved by NEP, although less effectively when compared to [68Ga]Ga-DOTA-AmBz-MVK(Ac)-OH. The kidney uptake of [68Ga]Ga-DOTA-AmBz-MVK(HTK01166)-OH was 30% less compared to that of [68Ga]Ga-HTK01166. Our data demonstrated that derivatives of [68Ga]Ga-DOTA-AmBz-MVK-OH can be cleaved specifically by NEP, and therefore, MVK can be a promising cleavable linker for use to reduce kidney uptake of radiolabeled DOTA-conjugated peptides and peptidomimetics.

5.
J Nucl Med ; 2020 Aug 28.
Artículo en Inglés | MEDLINE | ID: mdl-32859704

RESUMEN

The use of an albumin binder has been shown to improve tumor uptake of prostate-specific membrane antigen (PSMA)-targeting radiotherapeutic agents. The aim of this study was to develop improved radiotherapeutic agents that combine an optimized linker and optimized albumin binders to maximize the tumor-to-kidney absorbed dose ratio. Methods: 68Ga-labeled DOTA-conjugated lysine-ureido-glutamate-based PSMA-targeting agents bearing various linkers or albumin binders were synthesized, and evaluated by PET/CT imaging and biodistribution studies in LNCaP tumor-bearing mice. The optimized linker and albumin binders were combined and the resulting derivatives were radiolabeled with 177Lu and evaluated by SPECT/CT imaging and biodistribution studies in LNCaP tumor-bearing mice. Radiation dosimetry was calculated using the OLINDA/EXM software. Results: Linker optimization revealed that [68Ga]Ga-HTK03041 bearing a tranexamic acid-9-anthrylalanine linker had the highest tumor uptake (23.1±6.11 %ID/g at 1h post-injection). Albumin binder optimization showed that [68Ga]Ga-HTK03055 and [68Ga]Ga-HTK03086 bearing the N-(4-(p-chlorophenyl)butanoyl)-Gly and N-(4-(p-methoxyphenyl)butanoyl)-Gly motifs, respectively, had relatively faster tumor accumulation (~30 %ID/g at 3H post-injection) and lower average kidney uptake (<55 %ID/g at both 1h and 3H post-injection). Combining the tranexamic acid-9-anthrylalanine linker with N-(4-(p-chlorophenyl)butanoyl)-Gly and N-(4-(p-methoxyphenyl)butanoyl)-Gly albumin-binding motifs generated HTK03121 and HTK03123, respectively. [177Lu]Lu-HTK03121 and [177Lu]Lu-HTK03123 had extremely high peak uptake (104±20.3 and 70.8±23.7 %ID/g, respectively) in LNCaP tumor xenografts, which was sustained up to 120h post-injection. Dosimetry calculation showed that compared to [177Lu]Lu-PSMA-617, [177Lu]Lu-HTK03121 and [177Lu]Lu-HTK03123 delivered 18.7- and 12.7-fold higher absorbed dose to tumor, but only 6.4- and 6.3-fold higher absorbed dose to kidneys leading to 2.9- and 2.0-fold improvement in the tumor-to-kidney absorbed dose ratios. Conclusion: With greatly enhanced tumor uptake and tumor-to-kidney absorbed dose ratio [177Lu]Lu-HTK03121 and [177Lu]Lu-HTK03123 have the potential to improve treatment efficacy using significantly lower quantities of 177Lu, and are promising candidates for clinical translation to treat metastatic castration-resistant prostate cancer.

6.
ACS Omega ; 5(19): 10767-10773, 2020 May 19.
Artículo en Inglés | MEDLINE | ID: mdl-32455196

RESUMEN

In this study, we designed and evaluated a novel α-melanocyte-stimulating hormone derivative with four N-methylations for melanocortin 1 receptor-targeted melanoma imaging with positron emission tomography (PET). The resulting peptide, DOTA-Pip-Nle4-Cyclo[Asp5-N-Me-His6-d-Phe7-N-Me-Arg8-N-Me-Trp9-N-Me-Lys10]αMSH4-10-NH2 (CCZ01099), showed high receptor selectivity, greatly improved stability, and rapid internalization. [68Ga]Ga-CCZ01099 showed clear tumor visualization and excellent tumor-to-normal tissue contrast with PET imaging in a preclinical melanoma model. Therefore, CCZ01099 is a promising compound for imaging and potentially radioligand therapy for melanoma.

7.
Cancers (Basel) ; 12(5)2020 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-32455729

RESUMEN

While the development of positron emission tomography (PET) radiopharmaceuticals closely follows that of traditional drug development, there are several key considerations in the chemical and radiochemical synthesis, preclinical assessment, and clinical translation of PET radiotracers. As such, we outline the fundamentals of radiotracer design, with respect to the selection of an appropriate pharmacophore. These concepts will be reinforced by exemplary cases of PET radiotracer development, both with respect to their preclinical and clinical evaluation. We also provide a guideline for the proper selection of a radionuclide and the appropriate labeling strategy to access a tracer with optimal imaging qualities. Finally, we summarize the methodology of their evaluation in in vitro and animal models and the road to clinical translation. This review is intended to be a primer for newcomers to the field and give insight into the workflow of developing radiopharmaceuticals.

8.
Dalton Trans ; 49(22): 7605-7619, 2020 Jun 09.
Artículo en Inglés | MEDLINE | ID: mdl-32459231

RESUMEN

The peptide is an important class of biological targeting molecule; herein, a new bifunctional octadentate non-macrocyclic H4octapa, tBu4octapa-alkyl-NHS, which is compatible with solid-phase peptide synthesis and thus useful for radiopeptide preparation, has been synthesized. To preserve denticity, the alkyl-N-hydroxylsuccinimide linker was covalently attached to the methylene-carbon on one of the acetate arms, yielding a chiral carbon center. According to density-functional theory (DFT) calculations using [Lu(octapa-alkyl-benzyl-ester)]- as a simulation model, the chirality has minimal effects on the complex geometry; regardless of the S-/R-stereochemistry, DFT calculations revealed two possible geometric isomers, distorted bicapped trigonal antiprism (DBTA) and distorted square antiprism (DSA), due to the asymmetry in the chelator. To evaluate the biological behavior of the new bifunctionalization, two well-studied PSMA (prostate-specific membrane antigen)-targeting peptidomimetics of varying hydrophobicity were chosen as proof-of-principle targeting vector molecules. Radiolabeling both bioconjugates with lutetium-177 was highly efficient at room temperature in 15 min at micromolar chelator concentration pH = 7. Both the in vitro serum challenge and the lanthanum(iii) challenge studies revealed complex lability, and notably, progressive bone accumulation was only observed with the more hydrophobic linker (i.e. H4octapa-alkyl-PSMA617). This in vivo result informs potential alterations exerted by the linker on the complex geometry and stability, with an appropriate biological targeting vector adopted for such evaluations.

9.
Molecules ; 25(8)2020 Apr 18.
Artículo en Inglés | MEDLINE | ID: mdl-32325695

RESUMEN

Losartan is widely used in clinics to treat cardiovascular related diseases by selectively blocking the angiotensin II type 1 receptors (AT1Rs), which regulate the renin-angiotensin system (RAS). Therefore, monitoring the physiological and pathological biodistribution of AT1R using positron emission tomography (PET) might be a valuable tool to assess the functionality of RAS. Herein, we describe the synthesis and characterization of two novel losartan derivatives PET tracers, [18F]fluoroethyl-losartan ([18F]FEtLos) and [18F]ammoniomethyltrifluoroborate-losartan ([18F]AMBF3Los). [18F]FEtLos was radiolabeled by 18F-fluoroalkylation of losartan potassium using the prosthetic group 2-[18F]fluoroethyl tosylate; whereas [18F]AMBF3Los was prepared following an one-step 18F-19F isotopic exchange reaction, in an overall yield of 2.7 ± 0.9% and 11 ± 4%, respectively, with high radiochemical purity (>95%). Binding competition assays in AT1R-expressing membranes showed that AMBF3Los presented an almost equivalent binding affinity (Ki 7.9 nM) as the cold reference Losartan (Ki 1.5 nM), unlike FEtLos (Ki 2000 nM). In vitro and in vivo assays showed that [18F]AMBF3Los displayed a good binding affinity for AT1R-overexpressing CHO cells and was able to specifically bind to renal AT1R. Hence, our data demonstrate [18F]AMBF3Los as a new tool for PET imaging of AT1R with possible applications for the diagnosis of cardiovascular, inflammatory and cancer diseases.

10.
Bioconjug Chem ; 2020 Apr 09.
Artículo en Inglés | MEDLINE | ID: mdl-32216377

RESUMEN

Herein, we present the syntheses and characterization of a new undecadendate chelator, H4py4pa, and its bifunctional analog H4py4pa-phenyl-NCS, conjugated to the monoclonal antibody, Trastuzumab, which targets the HER2+ cancer. H4py4pa possesses excellent affinity for 225Ac (α, t1/2 = 9.92 d) for targeted alpha therapy (TAT), where quantitative radiolabeling yield was achieved at ambient temperature, pH = 7, in 30 min at 10-6 M chelator concentration, leading to a complex highly stable in mouse serum for at least 9 d. To investigate the chelation of H4py4pa with large metal ions, lanthanum (La3+), which is the largest nonradioactive metal of the lanthanide series, was adopted as a surrogate for 225Ac to enable a series of nonradioactive chemical studies. In line with the 1H NMR spectrum, the DFT (density functional theory)-calculated structure of the [La(py4pa)]- anion possessed a high degree of symmetry, and the La3+ ion was secured by two distinct pairs of picolinate arms. Furthermore, the [La(py4pa)]- complex also demonstrated a superb thermodynamic stability (log K[La(py4pa)]- ∼ 20.33, pLa = 21.0) compared to those of DOTA (log K[La(DOTA)]- ∼ 24.25, pLa = 19.2) or H2macropa (log K[La(macropa)]- = 14.99, pLa ∼ 8.5). Moreover, the functional versatility offered by the bifunctional py4pa precursor permits facile incorporation of various linkers for bioconjugation through direct nucleophilic substitution. In this work, a short phenyl-NCS linker was incorporated to tether H4py4pa to Trastuzumab. Radiolabeling studies, in vitro serum stability, and animal studies were performed in parallel with the DOTA-benzyl-Trastuzumab. Both displayed excellent in vivo stability and tumor specificity.

11.
Inorg Chem ; 59(7): 4895-4908, 2020 Apr 06.
Artículo en Inglés | MEDLINE | ID: mdl-32175726

RESUMEN

A rigid chiral acyclic chelator H2CHXhox was synthesized and evaluated for Ga3+-based radiopharmaceutical applications; it was compared to the previously reported hexadentate H2hox to determine the effect of a backbone reinforced from adding a chiral 1S,2S-trans-cyclohexane on metal complex stability, kinetic inertness, and in vivo pharmacokinetics. NMR spectroscopy and theoretical calculation revealed that [Ga(CHXhox)]+ showed a very similar coordination geometry to that of [Ga(hox)]+, and only one isomer in solution was observed by NMR spectroscopy. Solution studies showed that the modification results in a significant improvement in the exceptionally high thermodynamic stability of [Ga(hox)]+ with a 1.56 log unit increase in stability constant (logKML = 35.91(1)). More importantly, H2CHXhox showed very fast Ga3+ complexation at physiological pH 7.4, and acid-assisted Ga3+ complex dissociation kinetic studies (pH 1) in comparison with H2hox revealed a 50-fold increase of the dissociation half-life time from 73 min to 58 h. Fluorescence microscopy imaging study confirmed its cellular uptake and accumulation in endoplasmic reticulum and mitochondria. MTT studies indicated a quite low cytotoxicity of [Ga(CHXhox)]+ over a large concentration range. Dynamic PET imaging studies showed no accumulation in muscle, lungs, bone, and brain, suggesting no release of free Ga3+ ions. [68Ga][Ga(CHXhox)]+ is cleared from the mouse via hepatobiliary and renal pathways. Compared to [68Ga][Ga(hox)]+, the increased lipophilicity of [68Ga][Ga(CHXhox)]+ enhanced heart and liver uptake and decreased kidney clearance. [67Ga][Ga(CHXhox)]+ SPECT/CT imaging and biodistribution study revealed good clearance from liver to gallbladder after 90 min and finally into feces after 5 h. No decomposition or transchelation was observed over the 5 h study. These results confirmed H2CHXhox to be an obvious improvement over H2hox and an excellent candidate in this new "ox" family for the development of radiopharmaceutical compounds.

12.
EJNMMI Res ; 10(1): 25, 2020 Mar 19.
Artículo en Inglés | MEDLINE | ID: mdl-32189151

RESUMEN

INTRODUCTION: [18F]AmBF3-TATE is a somatostatin agonist that selectively binds to somatostatin receptor subtype 2 (SSTR2). For clinical translation, pharmacokinetics, radiation dosimetry, and acute toxicity of [18F]AmBF3-TATE were assessed with good laboratory practice (GLP) standards. METHODS: ICR mice were intravenously administered 0.8-2.0 MBq of [18F]AmBF3-TATE, with one group pre-injected with 100 µg of [19F]AmBF3-TATE 30 min before radiopharmaceutical administration to assess uptake specificity. The mice were euthanized at 0.5, 1, 2, or 4 h post-injection (p.i.). Blood and tissues were collected, weighed, and counted on a gamma counter to determine percentage injected dose per gram (%ID/g). Dosimetry was calculated based on biodistribution data using the mouse and human phantoms included in OLINDA. Acute toxicity was assessed in Sprague-Dawley rats at the dose of 0.742 mg/kg [19F]AmBF3-TATE, with a 14-day observation/recovery period. Blood chemistry parameters, gross, and histopathology were evaluated. Body weight change and food consumption were monitored. The production of [18F]AmBF3-TATE was automated on a Trasis AllinOne synthesis module. RESULTS: [18F]AmBF3-TATE was cleared through the renal and hepatobiliary pathway. At 1 h p.i., the pancreas (F, 15.7 ± 3.72 and M 14.3 ± 1.61 %ID/g), stomach (F, 15.3 ± 3.63 and M, 19.0 ± 3.49 %ID/g), and lungs (F, 9.26 ± 2.24 and M, 6.17 ± 6.04 %ID/g) were the organs with the highest specific uptake. Pre-injection with [19F]AmBF3-TATE significantly reduced pancreatic uptake (F, 0.13 ± 0.03 and M, 0.18 ± 0.09 %ID/g) at 1 h p.i. For dosimetry extrapolated to the average adult human, the bladder (0.027-0.030 mGy/MBq), pancreas (0.018-0.028 mGy/MBq), and lungs (0.006-0.013 mGy/MBq) are expected to receive the highest doses. No test-item related effects were observed upon evaluation of clinical observations, body weights, food consumption, clinical pathology, gross pathology, and histopathology for acute toxicity. [18F]AmBF3-TATE was produced at activity yields of 15.6 ± 4.59 GBq, average molar activity of 435 ± 162 GBq/µmol, and radiochemical purity of 98.0 ± 1.73% with the automated synthesizer. CONCLUSION: [18F]AmBF3-TATE binds specifically to SSTR2. At 1000× clinical dose, [19F]AmBF3-TATE was well tolerated with no treatment-related adverse effects.

13.
Inorg Chem ; 59(3): 1985-1995, 2020 Feb 03.
Artículo en Inglés | MEDLINE | ID: mdl-31976659

RESUMEN

44Sc is an attractive positron-emitting radionuclide for PET imaging; herein, a new complex of the Sc3+ ion with nonmacrocyclic chelator H4pypa was synthesized and characterized with high-resolution electrospray-ionization mass spectrometry (HR-ESI-MS), as well as different nuclear magnetic resonance (NMR) spectroscopic techniques (1H, 13C, 1H-13C HSQC, 1H-13C HMBC, COSY, and NOESY). In aqueous solution (pH = 7), [Sc(pypa)]- presented two isomeric forms, the structures of which were predicted using density functional theory (DFT) calculation with a small energy difference of 22.4 kJ/mol, explaining their coexistence. [Sc(pypa)]- was found to have superior thermodynamic stability (pM = 27.1) compared to [Sc(AAZTA)]- (24.7) and [Sc(DOTA)]- (23.9). In radiolabeling, [44Sc][Sc(pypa)]- formed efficiently at RT in 15 min over a range of pH (2-5.5), resulting in a complex that is highly stable (>99%) in mouse serum over at least six half-lives of scandium-44. Similar labeling efficiency was observed with the PSMA (prostate-specific membrane antigen)-targeting H4pypa-C7-PSMA617 at pH = 5.5 (RT, 15 min), confirming negligible disturbance from the bifunctionalization on scandium-44 scavenging. Moreover, the kinetic inertness of the radiocomplex was proved in vivo. Surprisingly, the molar activity was found to have profound influence on the pharmacokinetics of the radiotracers where lower molar activity drastically reduced the background accumulations, particularly, kidney, and thus, yielded a much higher tumor-to-background contrast.


Asunto(s)
Quelantes/química , Complejos de Coordinación/química , Neoplasias Experimentales/diagnóstico por imagen , Antígeno Prostático Específico/análisis , Radioisótopos/química , Radiofármacos/química , Escandio/química , Termodinámica , Animales , Quelantes/síntesis química , Quelantes/farmacocinética , Complejos de Coordinación/síntesis química , Complejos de Coordinación/farmacocinética , Teoría Funcional de la Densidad , Humanos , Concentración de Iones de Hidrógeno , Ratones , Ratones Desnudos , Modelos Moleculares , Estructura Molecular , Tomografía de Emisión de Positrones , Radioisótopos/farmacocinética , Radiofármacos/síntesis química , Radiofármacos/farmacocinética , Escandio/farmacocinética , Distribución Tisular
14.
Chembiochem ; 21(7): 943-947, 2020 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-31621172

RESUMEN

We report a single-molecule radiotracer that can be labeled independently with 18 F-fluoride or radiometals (64 Cu, 177 Lu) in a single step. A prostate-specific membrane antigen (PSMA)-targeting ligand, armed with both an organotrifluoroborate and a metal-chelator (DOTA), was designed to optionally afford 18 F-, 64 Cu- or 177 Lu-labeled products that were injected into mice bearing prostate cancer (LNCaP) xenografts. PET/CT images and ex vivo biodistribution data show high, specific tumor uptake irrespective of which radionuclide is used, thereby demonstrating a new approach to combining, in a single molecule, 18 F-labeling capabilities for PET imaging with radiometalation for potential imaging and therapeutic applications.

15.
J Labelled Comp Radiopharm ; 63(2): 56-64, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31715025

RESUMEN

The gastrin-releasing peptide receptor (GRPR) is overexpressed in prostate cancer and other solid malignancies. Following up on our work on [68 Ga]Ga-ProBOMB1 that had better imaging characteristics than [68 Ga]Ga-NeoBOMB1, we investigated the effects of substituting 68 Ga for 177 Lu to determine if the resulting radiopharmaceuticals could be used with a therapeutic aim. We radiolabeled the bombesin antagonist ProBOMB1 (DOTA-pABzA-DIG-D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-ψ-Pro-NH2 ) with lutetium-177 and compared it with [177 Lu]Lu-NeoBOMB1 (obtained in 54.2 ± 16.5% isolated radiochemical yield with >96% radiochemical purity and 440.8 ± 165.1 GBq/µmol molar activity) for GRPR targeting. Lu-NeoBOMB1 had better binding affinity for GRPR than Lu-ProBOMB1 (Ki values: 2.26 ± 0.24 and 30.2 ± 3.23nM). [177 Lu]Lu-ProBOMB1 was obtained in 53.7 ± 5.4% decay-corrected radiochemical yield with 444.2 ± 193.2 GBq/µmol molar activity and >95% radiochemical purity. In PC-3 prostate cancer xenograft mice, tumor uptake of [177 Lu]Lu-ProBOMB1 was 3.38 ± 1.00, 1.32 ± 0.24, and 0.31 ± 0.04%ID/g at 1, 4, and 24 hours pi. However, the uptake in tumor was lower than [177 Lu]Lu-NeoBOMB1 at all time points. [177 Lu]Lu-ProBOMB1 was inferior to [177 Lu]Lu-NeoBOMB1, which had better therapeutic index for the organs receiving the highest doses.

16.
Sci Rep ; 9(1): 13575, 2019 09 19.
Artículo en Inglés | MEDLINE | ID: mdl-31537869

RESUMEN

Since metastatic melanoma is deadly, early diagnosis thereof is crucial for managing the disease. We recently developed α-melanocyte-stimulating hormone (αMSH) derivatives, [68Ga]Ga-CCZ01048 and [18F]CCZ01064, that target the melanocortin 1 receptor (MC1R) for mouse melanoma imaging. In this study, we aim to evaluate [18F]CCZ01064 as well as a novel dual-ammoniomethyl-trifluoroborate (AmBF3) derivative, [18F]CCZ01096, for targeting human melanoma xenograft using µPET imaging. The peptides were synthesized on solid phase using Fmoc chemistry. Radiolabeling was achieved in a one-step 18F-19F isotope-exchange reaction. µPET imaging and biodistribution studies were performed in NSG mice bearing SK-MEL-1 melanoma xenografts. The MC1R density on the SK-MEL-1 cell line was determined to be 972 ± 154 receptors/cell (n = 4) via saturation assays. Using [18F]CCZ01064, moderate tumor uptake (3.05 ± 0.47%ID/g) and image contrast were observed at 2 h post-injection. Molar activity was determined to play a key role. CCZ01096 with two AmBF3 motifs showed comparable sub-nanomolar binding affinity to MC1R and much higher molar activity. This resulted in improved tumor uptake (6.46 ± 1.42%ID/g) and image contrast (tumor-to-blood and tumor-to-muscle ratios were 30.6 ± 5.7 and 85.7 ± 11.3, respectively) at 2 h post-injection. [18F]CCZ01096 represents a promising αMSH-based µPET imaging agent for human melanoma and warrants further investigation for potential clinical translation.


Asunto(s)
Radioisótopos de Flúor/química , Melanoma/diagnóstico por imagen , Fragmentos de Péptidos/administración & dosificación , alfa-MSH/análogos & derivados , Animales , Línea Celular Tumoral , Estabilidad de Medicamentos , Humanos , Melanoma/metabolismo , Ratones , Estructura Molecular , Trasplante de Neoplasias , Fragmentos de Péptidos/síntesis química , Fragmentos de Péptidos/química , Fragmentos de Péptidos/farmacocinética , Tomografía de Emisión de Positrones , Receptor de Melanocortina Tipo 1/metabolismo , alfa-MSH/química
17.
Mol Pharm ; 16(11): 4688-4695, 2019 11 04.
Artículo en Inglés | MEDLINE | ID: mdl-31545614

RESUMEN

C-X-C chemokine receptor type 4 (CXCR4) is overexpressed in hematological and solid malignancies. LY2510924 is a potent peptide antagonist of CXCR4. A derivative of LY2510924, BL01, was evaluated for theranostic applications targeting CXCR4. Methods: BL01 was synthesized by solid phase approach. A Lys(ivDde) residue was added at the C-terminus of LY2510924 (cyclo[Phe-Tyr-Lys(iPr)-d-Arg-2-Nal-Gly-d-Glu]-Lys(iPr)-NH2). A DOTA chelator was conjugated to the side chain of the deprotected exogenous Lys residue. The binding affinity of Ga/Lu-BL01 was determined by competitive radioligand binding assays. BL01 was radiolabeled with 68GaCl3 or 177LuCl3. Biodistribution studies were performed in mice bearing Daudi Burkitt's lymphoma tumor xenografts at selected time points. PET imaging studies were performed with [68Ga]Ga-BL01, with blocking experiments performed with preinjection of LY2510924. The stability of [68Ga]Ga/[177Lu]Lu-BL01 was assessed in mouse plasma. Results: Ga-BL01 and Lu-BL01 have nanomolar affinity for CXCR4. [68Ga]Ga-BL01 was obtained in 58 ± 5% decay-corrected radiochemical yields and >99% radiochemical purity with a molar activity of 40 ± 11 GBq/µmol, while [177Lu]Lu-BL01 was obtained in 65 ± 6% decay-corrected radiochemical yields and >99% radiochemical purity with a molar activity of 120 ± 21 GBq/µmol. [68Ga]Ga-BL01 and [177Lu]Lu-BL01 were excreted primarily through the renal pathway. Daudi xenografts were clearly delineated in PET images with good contrast. On the basis of biodistribution data, tumor uptake of [68Ga]Ga-BL01 was 10.2 ± 2.56% injected dose per gram (%ID/g) at 1 h postinjection (p.i.). Spleen (12.6 ± 2.36 %ID/g) and lungs (13.2 ± 2.98 %ID/g), organs that express CXCR4, had high uptake as well. Preinjection of LY2510924 reduced average uptake of [68Ga]Ga-BL01 in tumors by 88%, demonstrating target specificity. The uptake of [68Ga]Ga-BL01 in tumor increased to 15.3 ± 1.86 %ID/g at 2 h p.i., with improved contrast. [177Lu]Lu-BL01 has similar pharmacokinetics as [68Ga]Ga-BL01 at 1 h p.i. The highest uptake was observed in tumor (14.0 ± 1.11 %ID/g), followed by the lungs (13.0 ± 1.27 %ID/g) and spleen (11.6 ± 1.78 %ID/g). The tumor uptake increased to 16.2 ± 2.69 %ID/g at 4 h p.i., before declining slightly to 10.1 ± 1.41 %ID/g at 24 h p.i. Both compounds were stable in vivo, as no metabolites were observed at 5 min p.i. Conclusions: [68Ga]Ga-BL01 and [177Lu]Lu-BL01 are a promising theranostic pair for imaging and endoradiotherapy of CXCR4-expressing malignancies.


Asunto(s)
Linfoma de Burkitt/radioterapia , Radioisótopos de Galio/uso terapéutico , Radiofármacos/uso terapéutico , Receptores CXCR4/metabolismo , Animales , Linfoma de Burkitt/metabolismo , Línea Celular , Radioisótopos de Galio/farmacocinética , Xenoinjertos , Pulmón/metabolismo , Pulmón/efectos de la radiación , Masculino , Ratones , Ratones Endogámicos NOD , Péptidos Cíclicos/farmacocinética , Péptidos Cíclicos/farmacología , Radioquímica/métodos , Radiofármacos/farmacocinética , Bazo/metabolismo , Bazo/efectos de la radiación , Nanomedicina Teranóstica/métodos , Distribución Tisular
18.
Bioconjug Chem ; 30(5): 1539-1553, 2019 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-31009566

RESUMEN

Here, we present the synthesis and characterization of a new potentially nonadentate chelator H4pypa and its bifunctional analogue tBu4pypa-C7-NHS conjugated to prostate-specific membrane antigen (PSMA)-targeting peptidomimetic (Glu-urea-Lys). H4pypa is very functionally versatile and biologically stable. Compared to the conventional chelators (e.g., DOTA, DTPA), H4pypa has outstanding affinities for both 111In (EC, t1/2 ≈ 2.8 days) and 177Lu (ß-,γ, t1/2 ≈ 6.64 days). Its radiolabeled complexes were achieved at >98% radiochemical yield, RT within 10 min, at a ligand concentration as low as 10-6 M, with excellent stability in human serum over at least 5-7 days (<1% transchelation). The thermodynamic stabilities of the [M(pypa)]- complexes (M3+ = In3+, Lu3+, La3+) were dependent on the ionic radii, where the smaller In3+ has the highest pM value (30.5), followed by Lu3+ (22.6) and La3+ (19.9). All pM values are remarkably higher than those with DOTA, DTPA, H4octapa, H4octox, and H4neunpa. Moreover, the facile and versatile bifunctionalization enabled by the p-OH group in the central pyridyl bridge of the pypa scaffold (compound 14) allows incorporation of a variety of linkers for bioconjugation through easy nucleophilic substitution. In this work, an alkyl linker was selected to couple H4pypa to a PSMA-targeting pharmacophore, proving that the bioconjugation sacrifices neither the tumor-targeting nor the chelation properties. The biodistribution profiles of 111In- and 177Lu-labeled tracers are different, but promising, with the 177Lu analogue particularly outstanding.


Asunto(s)
Antígenos de Superficie/química , Quelantes/química , Glutamato Carboxipeptidasa II/química , Radioisótopos de Indio/química , Lutecio/química , Humanos , Masculino , Prueba de Estudio Conceptual , Próstata/metabolismo , Radiofármacos/química
19.
Bioconjug Chem ; 30(4): 1210-1219, 2019 04 17.
Artículo en Inglés | MEDLINE | ID: mdl-30896929

RESUMEN

DOTA is commonly used for radiometal chelation in molecular imaging. Yet in the absence of a radiometal, DOTA is hypothesized to promote renal clearance of 18F-labeled peptide tracers. In light of an increasing interest in the use of F18 for PET, here the effect of DOTA is evaluated for the first time with an 18F-labeled tracer and is found to significantly improve the quality of images acquired through positron emission tomography (PET). We chose to image the peptide LLP2A that recognizes the transmembrane protein very-late antigen 4 (VLA-4) that is overexpressed by many cancers. Since it is known that [18F]RBF3-PEG2-LLP2A derivatives gave low tumor uptake values and significant GI tract accumulation, this ligand thus represents an ideal means of testing the additive effects of a DOTA group on clearance while permitting a facile, user-friendly, one-step 18F-labeling. A newly designed RBF3-LLP2A bioconjugate with an appended DOTA moiety increased tumor uptake nearly 3-fold and reduced GI accumulation by more than 10-fold. The DOTA-AMBF3-PEG2-LLP2A was radiolabeled by isotope exchange and was purified by semiprep HPLC and C18 cartridge elution. Male C57BL/6J mice bearing B16-F10 melanoma tumors that overexpress the VLA-4 target were used to evaluate [18F]DOTA-AMBF3-PEG2-LLP2A using a combination of static and dynamic PET scans, biodistribution studies, and blocking controls at 1 h post injection (p.i.). The precursor peptide was synthesized and 18F-labeled to provide formulations with mean (±SD) radiochemical purities of 95.9 ± 1.8%, in radiochemical yields of 4.8 ± 2.9% having molar activities of 131.7 ± 50.3 GBq/µmol. In vivo static PET images of [18F]DOTA-AMBF3-PEG2-LLP2A provided clear tumor visualization, and biodistribution studies showed that tumor uptake was 9.46 ± 2.19% injected dose per gram of tissue (%ID/g) with high tumor/muscle and tumor/blood contrast ratios of ∼8 and ∼10, respectively. Blocking confirmed the specificity of [18F]DOTA-AMBF3-PEG2-LLP2A to VLA-4 in the tumor and the bone marrow. Dynamic PET showed clearance of [18F]DOTA-AMBF3-PEG2-LLP2A mainly via the renal pathway, wherein accumulation in the intestines was reduced 10-fold compared to our previously investigated LLP2A's, while spleen uptake was at levels similar to previously reported LLP2A-chelator radiotracers. [18F]DOTA-AMBF3-PEG2-LLP2A represents a promising VLA-4 radiotracer and provides key evidence as to how a DOTA appendage can significantly reduce GI uptake in favor of urinary excretion. Implications for the development of dual-isotope theranostics that exploit the use fluorine-18 for imaging and DOTA to chelate therapeutic metal cations for therapy are discussed.


Asunto(s)
Quelantes/química , Radioisótopos de Flúor/química , Compuestos Heterocíclicos con 1 Anillo/química , Riñón/metabolismo , Melanoma Experimental/diagnóstico por imagen , Radiofármacos/química , Animales , Quelantes/metabolismo , Radioisótopos de Flúor/metabolismo , Compuestos Heterocíclicos con 1 Anillo/metabolismo , Melanoma Experimental/metabolismo , Ratones , Ratones Endogámicos C57BL , Tomografía de Emisión de Positrones/métodos , Radiofármacos/metabolismo
20.
ACS Omega ; 4(1): 1470-1478, 2019 Jan 31.
Artículo en Inglés | MEDLINE | ID: mdl-30775647

RESUMEN

The gastrin-releasing peptide receptor (GRPR), a G protein-coupled receptor, is overexpressed in solid malignancies and particularly in prostate cancer. We synthesized a novel bombesin derivative, [68Ga]Ga-ProBOMB1, evaluated its pharmacokinetics and potential to image GRPR expression with positron emission tomography (PET), and compared it with [68Ga]Ga-NeoBOMB1. ProBOMB1 (DOTA-pABzA-DIG-d-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-ψ(CH2N)-Pro-NH2) was synthesized by solid-phase peptide synthesis. The polyaminocarboxylate chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) was coupled to the N-terminal and separated from the GRPR-targeting sequence by a p-aminomethylaniline-diglycolic acid (pABzA-DIG) linker. The binding affinity to GRPR was determined using a cell-based competition assay, whereas the agonist/antagonist property was determined with a calcium efflux assay. ProBOMB1 was radiolabeled with 68GaCl3. PET imaging and biodistribution studies were performed in male immunocompromised mice bearing PC-3 prostate cancer xenografts. Blocking experiments were performed with coinjection of [d-Phe6,Leu-NHEt13,des-Met14]bombesin(6-14). Dosimetry calculations were performed with OLINDA software. ProBOMB1 and the nonradioactive Ga-ProBOMB were obtained in 1.1 and 67% yield, respectively. The K i value of Ga-ProBOMB1 for GRPR was 3.97 ± 0.76 nM. Ga-ProBOMB1 behaved as an antagonist for GRPR. [68Ga]Ga-ProBOMB1 was obtained in 48.2 ± 10.9% decay-corrected radiochemical yield with 121 ± 46.9 GBq/µmol molar activity and >95% radiochemical purity. Imaging/biodistribution studies showed that the excretion of [68Ga]Ga-ProBOMB1 was primarily through the renal pathway. At 1 h postinjection (p.i.), PC-3 tumor xenografts were clearly delineated in PET images with excellent contrast. The tumor uptake for [68Ga]Ga-ProBOMB1 was 8.17 ± 2.57 percent injected dose per gram (% ID/g) and 9.83 ± 1.48% ID/g for [68Ga]Ga-NeoBOMB1, based on biodistribution studies at 1 h p.i. This corresponded to tumor-to-blood and tumor-to-muscle uptake ratios of 20.6 ± 6.79 and 106 ± 57.7 for [68Ga]Ga-ProBOMB1 and 8.38 ± 0.78 and 39.0 ± 12.6 for [68Ga]Ga-NeoBOMB1, respectively. Blockade with [d-Phe6,Leu-NHEt13,des-Met14]bombesin(6-14) significantly reduced the average uptake of [68Ga]Ga-ProBOMB1 in tumors by 62%. The total absorbed dose was lower for [68Ga]Ga-ProBOMB1 in all organs except for bladder compared with [68Ga]Ga-NeoBOMB1. Our data suggest that [68Ga]Ga-ProBOMB1 is an excellent radiotracer for imaging GRPR expression with PET. [68Ga]Ga-ProBOMB1 achieved a similar uptake as [68Ga]Ga-NeoBOMB1 in tumors, with enhanced contrast and lower whole-body absorbed dose.

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