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1.
Chemistry ; 30(19): e202304270, 2024 Apr 02.
Artículo en Inglés | MEDLINE | ID: mdl-38285527

RESUMEN

With peptides increasingly favored as drugs, natural product motifs, namely the tryptathionine staple, found in amatoxins and phallotoxins, and the 2,2'-bis-indole found in staurosporine represent unexplored staples for unnatural peptide macrocycles. We disclose the efficient condensation of a 5-hydroxypyrroloindoline with either a cysteine-thiol or a tryptophan-indole to form a tryptathionine or 2-2'-bis-indole staple. Judicious use of protecting groups provides for chemoselective stapling using α-MSH, which provides a basis for investigating both chemoselectivity and affinity. Both classes of stapled peptides show nanomolar Ki's, with one showing a sub-nanomolar Ki value.


Asunto(s)
Péptidos Cíclicos , alfa-MSH/análogos & derivados , Cisteína , Indoles
2.
Adv Exp Med Biol ; 1408: 291-308, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37093434

RESUMEN

Prostate-specific membrane antigen (PSMA) is expressed in epithelial cells of the prostate gland and is strongly upregulated in prostatic adenocarcinoma, with elevated expression correlating with metastasis, progression, and androgen independence. Because of its specificity, PSMA is a major target of prostate cancer therapy; however, detectable levels of PSMA are also found in other tissues, especially in salivary glands and kidney, generating bystander damage of these tissues. Antibody target therapy has been used with relative success in reducing tumor growth and prostate specific antigen (PSA) levels. However, since antibodies are highly stable in plasma, they have prolonged time in circulation and accumulate in organs with an affinity for antibodies such as bone marrow. For that reason, a second generation of PSMA targeted therapeutic agents has been developed. Small molecules and minibodies have had promising clinical trial results, but concerns about their specificity had arisen with side effects due to accumulation in salivary glands and kidneys. Herein we study the specificity of small molecules and minibodies that are currently being clinically tested. We observed a high affinity of these molecules for PSMA in prostate, kidney and salivary gland, suggesting that their effect is not prostate specific. The search for specific prostate target agents must continue so as to optimally treat patients with prostate cancer, while minimizing deleterious effects in other PSMA expressing tissues.


Asunto(s)
Neoplasias de la Próstata , Masculino , Humanos , Neoplasias de la Próstata/patología , Antígenos de Superficie/metabolismo , Antígeno Prostático Específico
3.
J Labelled Comp Radiopharm ; 66(4-6): 130-137, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36813569

RESUMEN

Organotrifluoroborates have gained acceptance as radioprosthetic groups for radiofluorination. Of these, the zwitterionic prosthetic group "AMBF3 " with a quaternary dimethylammonium ion dominates the trifluoroborate space. Herein, we report on imidazolium-methylene trifluoroborate (ImMBF3 ) as an alternative radioprosthetic group and report on its properties in the context of a PSMA-targeting EUK ligand that was previously been conjugated to AMBF3 . The ImMBF3 is readily synthesized from imidazole and conjugated via CuAAC "click" chemistry to give a structure similar to PSMA-617. 18 F-labeling proceeded in one step per our previous reports and imaged in LNCaP-xenograft bearing mice. The [18 F]-PSMA-617-ImMBF3 tracer proved to be less polar (LogP7.4 = -2.95 ± 0.03) while showing a significantly lower solvolytic rate (t1/2 = 8100 min) and slightly higher molar activity (Am) at 174 ± 38 GBq/µmol. Tumor uptake was measured at 13.7 ± 4.8%ID/g and a tumor:muscle ratio of 74.2 ± 35.0, tumor:blood ratio of 21.4 ± 7.0, tumor:kidney ratio of 0.29 ± 0.14, and tumor:bone ratio of 23.5 ± 9.5. In comparison with previously reported PSMA-targeting EUK-AMBF3 conjugates, we have altered the LogP7.4 value, tuned the solvolytic half-life of the prosthetic, and increased radiochemical conversion while achieving similar tumor uptake, contrast ratios, and molar activities compared with AMBF3 bioconjugates.


Asunto(s)
Próstata , Neoplasias de la Próstata , Masculino , Humanos , Animales , Ratones , Próstata/patología , Tomografía de Emisión de Positrones/métodos , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/patología , Radiofármacos , Radioisótopos de Flúor/química , Línea Celular Tumoral
4.
Angew Chem Int Ed Engl ; 62(16): e202215371, 2023 Apr 11.
Artículo en Inglés | MEDLINE | ID: mdl-36720697

RESUMEN

Tetrafluoroborate (BF4 - ) has long been used as a spectator counter anion. Herein, we report an unprecedented salt metathesis between a variety of BF4 - salts and a series of organoboronic acids yielding the corresponding organotrifluoroborates. We identified conditions for fast and efficient fluoridation (<1 h) with minimal workup. Fundamentally, this work discloses the proclivity of BF4 - to exchange fluoride atoms with organoboronates, highlighting the lability of BF4 - .

5.
Mol Pharm ; 18(1): 187-197, 2021 01 04.
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.


Asunto(s)
Fluoruros/metabolismo , Radioisótopos de Flúor/metabolismo , Tomografía de Emisión de Positrones/métodos , Radiofármacos/metabolismo , Receptores CXCR4/metabolismo , Animales , Células CHO , Línea Celular , Complejos de Coordinación/metabolismo , Cricetulus , Masculino , Ratones , Ratones Endogámicos NOD , Neoplasias/diagnóstico por imagen , Neoplasias/metabolismo , Péptidos/metabolismo , Péptidos Cíclicos/metabolismo , Distribución Tisular/efectos de los fármacos
6.
J Org Chem ; 79(11): 5365-8, 2014 Jun 06.
Artículo en Inglés | MEDLINE | ID: mdl-24826787

RESUMEN

Facile based promoted deboronation of electron-deficient arylboronate esters was observed for arylboronates containing two ortho electron-withdrawing group (EWG) substituents. Among 30 representative boronates, only the diortho-substituted species underwent facile C-B fission in aqueous basic conditions (200 mM hydroxide). These results provide fundamental insight into deboronative mechanisms with implications for cross-coupling reactions, regioselective deuteration/tritiation for isotopic labeling, and the design of new (18)F-trifluoroborate radioprosthetics.

7.
RSC Med Chem ; 11(5): 569-576, 2020 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-33479658

RESUMEN

In pursuit of 18F-labeled nucleosides for positron emission tomography (PET) imaging, we report on the chemical and radiochemical synthesis of two thymidine (dT) analogs, dT-C5-AMBF3 and dT-N3-AMBF3, that are radiofluorinated by isotope exchange (IEX) and studied as PET imaging agents in mice with tumor xenografts. dT-C5-AMBF3 shows preferential, and tumor-specific, uptake over dT-N3-AMBF3. This work provides a new synthetic method in order to access new nucleoside tracers for PET imaging.

9.
Nucl Med Biol ; 40(8): 959-66, 2013 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-24090672

RESUMEN

INTRODUCTION: Arylboronates afford rapid aqueous (18)F-labeling via the creation of a highly polar (18)F-aryltrifluoroborate anion ((18)F-ArBF3(-)). HYPOTHESIS: Radiosynthesis of an (18)F-ArBF3(-) can be successfully applied to a clinically relevant peptide. To test this hypothesis, we labeled dimeric-cylcoRGD, [c(RGDfK)]2E because a) it is molecularly complex and provides a challenging substrate to test the application of this technique, and b) [c(RGDfK)]2E has already been labeled via several (18)F-labeling methods which provide for a preliminary comparison. GOAL: To validate this labeling method in the context of a complex and clinically relevant tracer to show tumor-specific uptake ex vivo with representative PET images in vivo. METHODS: An arylborimidine was conjugated to [c(RGDfK)]2E to give the precursor [c(RGDfK)]2E-ArB(dan), which was aliquoted and stored at -20 °C. Aliquots of 10 or 25 nmol, containing only micrograms of precursor, were labeled using relatively low levels of (18)F-activity. Following purification eight mice (pre-blocked/unblocked) with U87M xenograft tumors were injected with [c(RGDfK)]2E-(18)F-ArBF3(-) (n = 4) for ex vivo tissue dissection. Two sets of mice (pre-blocked/unblocked) were also imaged with PET-CT (n = 2). RESULTS: The [c(RGDfK)]2E-ArB(dan) is converted within 15 min to [c(RGDfK)]2E-(18)F-ArBF3(-) in isolated radiochemical yields of ~10% (n = 3) at a minimum effective specific activity of 0.3 Ci/µmol. Biodistribution shows rapid clearance to the bladder via the kidney resulting in high tumor-to-blood and tumor-to-muscle ratios of >9 and >6 respectively while pre-blocking with [c(RGDfK)]2E showed high tumor specificity. PET imaging showed good contrast between tumor and non-target tissues confirming the biodistribution data. CONCLUSION: An arylborimidine-RGD peptide is rapidly (18)F-labeled in one step, in good yield, at useful specific activity. Biodistribution studies with blocking controls show tumor specificity, which is corroborated by PET images. Advances in Knowledge and Implications for patient Care: Despite many antecedent examples of labeled RGD tracers, this work is the first to show direct aqueous labeling of bisRGD with an (18)F-ArBF3(-). Labeling occurs in near record rapidity (45 min) at useful effective specific activities and competitive yields for high contrast tumor specific images. As bisRGD has been imaged in humans with several prosthetics, this work suggests potential clinical applications of tracers appended with an (18)F-ArBF3(-). More generally, the ability to label a molecularly complex tracer suggests that this method could be useful to label many other peptides. Furthermore, these results portend the development of kits that use only microgram quantities of lyophilized precursor for on demand labeling. The ability to perform one-step aqueous labeling in under an hour to provide tracers with high T:NT ratios has important implications for developing radiotracers for use in fundamental research and in preclinical tracer studies.


Asunto(s)
Dimerización , Radioisótopos de Flúor , Glioma/diagnóstico por imagen , Péptidos Cíclicos/química , Tomografía de Emisión de Positrones/métodos , Animales , Línea Celular Tumoral , Transformación Celular Neoplásica , Glioma/patología , Humanos , Marcaje Isotópico , Ratones , Tomografía Computarizada por Rayos X
10.
Nucl Med Biol ; 40(6): 841-9, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23810487

RESUMEN

INTRODUCTION: Positron Emission Tomography (PET) is a rapidly expanding, cutting edge technology for preclinical evaluation, cancer diagnosis and staging, and patient management. A one-step aqueous (18)F-labeling method, which can be applied to peptides to provide functional in vivo images, has been a long-standing challenge in PET imaging. Over the past few years, we have sought a rapid and mild radiolabeling method based on the aqueous radiosynthesis of in vivo stable aryltrifluoroborate (ArBF(3)(-)) conjugates. Recent access to production levels of (18)F-Fluoride led to a fluorescent-(18)F-ArBF(3)(-) at unprecedentedly high specific activities of 15Ci/µmol. However, extending this method to labeling peptides as imaging agents has not been explored. METHODS: In order to extend these results to a peptide of clinical interest in the context of production-level radiosynthesis, we applied this new technology for labeling RGD, measured its specific activity by standard curve analysis, and carried out a preliminary evaluation of its imaging properties. RESULTS: RGD was labeled in excellent radiochemical yields at exceptionally high specific activity (~14Ci/µmol) (n = 3). Preliminary tumor-specific images corroborated by ex vivo biodistribution data with blocking controls show statistically significant albeit relatively low tumor uptake along with reasonably high tumor:blood ratios (n = 3). CONCLUSIONS: Isotope exchange on a clinically useful (18)F-ArBF(3)(-) radiotracer leads to excellent radiochemical yields and exceptionally high specific activities while the anionic nature of the aryltrifluoroborate prosthetic results in very rapid clearance. Since rapid clearance of the radioactive tracer is generally desirable for tracer development, these results suggest new directions for varying linker arm composition to slightly retard clearance rather than enhancing it. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: This work is the first to use production levels of (18)F-activity to directly label RGD at specific activities that are an order of magnitude higher than most reports and thereby increases the distribution window for radiotracer production and delivery.


Asunto(s)
Boratos/química , Compuestos de Boro/química , Radioisótopos de Flúor/química , Glioblastoma/diagnóstico por imagen , Marcaje Isotópico/métodos , Péptidos Cíclicos/química , Tomografía de Emisión de Positrones , Animales , Línea Celular Tumoral , Transformación Celular Neoplásica , Química Clic , Glioblastoma/patología , Humanos , Ratones
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