One-Pot Formal Carboradiofluorination of Alkenes: A Toolkit for Positron Emission Tomography Imaging Probe Development.

We report the first one-pot formal alkene carboradiofluorination reaction employing easily accessible alkenes as both prosthetic group precursors and coupling partners. The methodology features rapid sequential Markovnikov-selective iodofluorination and photoinduced Pd(0/I/II)-catalyzed alkyl Heck reaction as a mild and robust fluorine-18 (18F) radiochemical approach for positron emission tomography (PET) imaging probe development. A new class of prosthetic groups for PET imaging probe synthesis was isolated as iodofluorinated intermediates in moderate to excellent yields. The one-pot formal alkenylfluorination reaction was carried out to produce over 30 analogues of a wide range of bioactive molecules. Further application of the Pd(0/I/II) manifold in PET probe development was illustrated by the direct carbo(radio)fluorination of electron-rich alkenes. The methods were successfully translated to radiolabel a broad scope of medicinally relevant small molecules in generally good radiochemical conversion. The protocol was further optimized to accommodate no-carrier-added conditions with similar efficiency for future (pre)clinical translation. Moreover, the radiosynthesis of prosthetic groups was automated in a radiochemistry module to facilitate its practical use in multistep radiochemical reactions.

Effect of Chalcogenophenes on Chiroptical Activity of Twisted Tetracenes: Computational Analysis, Synthesis and Crystal Structure Thereof.

The synthesis of multiply substituted acenes is still a relevant research problem, considering their applications and future potential. Here we present an elegant synthetic protocol to afford tetra-peri-substituted naphthalene and tetracene from their tetrahalo derivatives by a Pd(0)-catalyzed C-C cross-coupling method in a single step. The newly synthesized tetracenes were characterized by NMR, HRMS, UV-vis spectrophotometry, and single-crystal X-ray diffraction (SCXRD). In addition, the first systematic computational study of the effect of chalcogenophenyl substitutions on the chiroptical properties of twistacenes was reported here. The gas phase computational studies using density functional theory (DFT) on a series of chalcogenophene-substituted tetracenes revealed that their chiroptical activity could be systematically increased via the atomistic tuning of peripheral substituents.

Theranostic Small-Molecule Prodrug Conjugates for Targeted Delivery and Controlled Release of Toll-like Receptor 7 Agonists.

We previously reported the design and synthesis of a small-molecule drug conjugate (SMDC) platform that demonstrated several advantages over antibody-drug conjugates (ADCs) in terms of in vivo pharmacokinetics, solid tumor penetration, definitive chemical structure, and adaptability for modular synthesis. Constructed on a tri-modal SMDC platform derived from 1,3,5-triazine (TZ) that consists of a targeting moiety (Lys-Urea-Glu) for prostate-specific membrane antigen (PSMA), here we report a novel class of chemically identical theranostic small-molecule prodrug conjugates (T-SMPDCs), [18/19F]F-TZ(PSMA)-LEGU-TLR7, for PSMA-targeted delivery and controlled release of toll-like receptor 7 (TLR7) agonists to elicit de novo immune response for cancer immunotherapy. In vitro competitive binding assay of [19F]F-TZ(PSMA)-LEGU-TLR7 showed that the chemical modification of Lys-Urea-Glu did not compromise its binding affinity to PSMA. Receptor-mediated cell internalization upon the PSMA binding of [18F]F-TZ(PSMA)-LEGU-TLR7 showed a time-dependent increase, indicative of targeted intracellular delivery of the theranostic prodrug conjugate. The designed controlled release of gardiquimod, a TLR7 agonist, was realized by a legumain cleavable linker. We further performed an in vivo PET/CT imaging study that showed significantly higher uptake of [18F]F-TZ(PSMA)-LEGU-TLR7 in PSMA+ PC3-PIP tumors (1.9 ± 0.4% ID/g) than in PSMA- PC3-Flu tumors (0.8 ± 0.3% ID/g) at 1 h post-injection. In addition, the conjugate showed a one-compartment kinetic profile and in vivo stability. Taken together, our proof-of-concept biological evaluation demonstrated the potential of our T-SMPDCs for cancer immunomodulatory therapies.

PSMA-Targeting Imaging and Theranostic Agents-Current Status and Future Perspective.

In the past two decades, extensive efforts have been made to develop agents targeting prostate-specific membrane antigen (PSMA) for prostate cancer imaging and therapy. To date, represented by two recent approvals of [68Ga]Ga-PSMA-11 and [18F]F-DCFPyL by the United States Food and Drug Administration (US-FDA) for positron emission tomography (PET) imaging to identify suspected metastases or recurrence in patients with prostate cancer, PSMA-targeting imaging and theranostic agents derived from small molecule PSMA inhibitors have advanced to clinical practice and trials of prostate cancer. The focus of current development of new PSMA-targeting agents has thus shifted to the improvement of in vivo pharmacokinetics and higher specific binding affinity with the aims to further increase the detection sensitivity and specificity and minimize the toxicity to non-target tissues, particularly the kidneys. The main strategies involve systematic chemical modifications of the linkage between the targeting moiety and imaging/therapy payloads. In addition to a summary of the development history of PSMA-targeting agents, this review provides an overview of current advances and future promise of PSMA-targeted imaging and theranostics with focuses on the structural determinants of the chemical modification towards the next generation of PSMA-targeting agents.

Validation of SV2A-Targeted PET Imaging for Noninvasive Assessment of Neuroendocrine Differentiation in Prostate Cancer.

Neuroendocrine prostate cancer (NEPC) is an aggressive and lethal variant of prostate cancer (PCa), and it remains a diagnostic challenge. Herein we report our findings of using synaptic vesicle glycoprotein 2 isoform A (SV2A) as a promising marker for positron emission tomography (PET) imaging of neuroendocrine differentiation (NED). The bioinformatic analyses revealed an amplified SV2A gene expression in clinical samples of NEPC versus castration-resistant PCa with adenocarcinoma characteristics (CRPC-Adeno). Importantly, significantly upregulated SV2A protein levels were found in both NEPC cell lines and tumor tissues. PET imaging studies were carried out in NEPC xenograft models with 18F-SynVesT-1. Although 18F-SynVesT-1 is not a cancer imaging agent, it showed a significant uptake level in the SV2A+ tumor (NCI-H660: 0.70 ± 0.14 %ID/g at 50-60 min p.i.). The SV2A blockade resulted in a significant reduction of tumor uptake (0.25 ± 0.03 %ID/g, p = 0.025), indicating the desired SV2A imaging specificity. Moreover, the comparative PET imaging study showed that the DU145 tumors could be clearly visualized by 18F-SynVesT-1 but not 68Ga-PSMA-11 nor 68Ga-DOTATATE, further validating the role of SV2A-targeted imaging for noninvasive assessment of NED in PCa. In conclusion, we demonstrated that SV2A, highly expressed in NEPC, can serve as a promising target for noninvasive imaging evaluation of NED.

Origin of Optoelectronic Contradictions in 3,4-Cycloalkyl[c]-chalcogenophenes: A Computational Study.

The planar morphology of the backbone significantly contributes to the subtle optoelectronic features of π-conjugated polymers. On the other hand, the atomistic tuning of an otherwise identical π-backbone could also impact optoelectronic properties systematically. In this manuscript, we compare a series of 3,4-cycloalkylchalcogenophenes by tuning them atomistically using group-16 elements. Additionally, the effect of systematically extending these building blocks in the form of oligomers and polymers is studied. The size of the 3,4-substitution affected the morphology of the oligomers. In addition, the heteroatoms contributed to a further alteration in their geometry and resultant optoelectronic properties. The chalcogenophenes, containing smaller 3,4-cycloalkanes, resulted in lower bandgap oligomers or polymers compared to those with larger 3,4-cycloalkanes. Natural bonding orbital (NBO) calculations were performed to understand the disparity alongside the contour maps of frontier molecular orbitals (FMO).

A Theranostic Small-Molecule Prodrug Conjugate for Neuroendocrine Prostate Cancer.

After androgen deprivation therapy, a significant number of prostate cancer cases progress with a therapy-resistant neuroendocrine phenotype (NEPC). This represents a challenge for diagnosis and treatment. Based on our previously reported design of theranostic small-molecule prodrug conjugates (T-SMPDCs), herein we report a T-SMPDC tailored for targeted positron emission tomography (PET) imaging and chemotherapy of NEPC. The T-SMPDC is built upon a triazine core (TZ) to present three functionalities: (1) a chelating moiety (DOTA: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) for PET imaging when labeled with 68Ga (t1/2 = 68 min) or other relevant radiometals; (2) an octreotide (Octr) that targets the somatostatin receptor 2 (SSTR2), which is overexpressed in the innervated tumor microenvironment (TME); and (3) fingolimod, FTY720-an antagonist of sphingosine kinase 1 that is an intracellular enzyme upregulated in NEPC. Polyethylene glycol (PEG) chains were incorporated via conventional conjugation methods or a click chemistry reaction forming a 1,4-disubstituted 1,2,3-triazole (Trz) linkage for the optimization of in vivo kinetics as necessary. The T-SMPDC, DOTA-PEG3-TZ(PEG4-Octr)-PEG2-Trz-PEG3-Val-Cit-pABOC-FTY720 (PEGn: PEG with n repeating ethyleneoxy units (n = 2, 3, or 4); Val: valine; Cit: citrulline; pABOC: p-amino-benzyloxycarbonyl), showed selective SSTR2 binding and mediated internalization of the molecule in SSTR2 high cells. Release of FTY720 was observed when the T-SMPDC was exposed to cathepsin B, and the released FTY720 exerted cytotoxicity in cells. In vivo PET imaging showed significantly higher accumulation (2.1 ± 0.3 %ID/g; p = 0.02) of [68Ga]Ga-DOTA-PEG3-TZ(PEG4-Octr)-PEG2-Trz-PEG3-Val-Cit-pABOC-FTY720 in SSTR2high prostate cancer xenografts than in the SSTR2low xenografts (1.5 ± 0.4 %ID/g) at 13 min post-injection (p.i.) with a rapid excretion through the kidneys. Taken together, these proof-of-concept results validate the design concept of the T-SMPDC, which may hold a great potential for targeted diagnosis and therapy of NEPC.

BODIPY-Based Molecules for Biomedical Applications.

BODIPY (4,4-difluoro-4-bora-3a,4a-diaza-s-indacene) derivatives have attracted attention as probes in applications like imaging and sensing due to their unique properties like (1) strong absorption and emission in the visible and near-infrared regions of the electromagnetic spectrum, (2) strong fluorescence and (3) supreme photostability. They have also been employed in areas like photodynamic therapy. Over the last decade, BODIPY-based molecules have even emerged as candidates for cancer treatments. Cancer remains a significant health issue world-wide, necessitating a continuing search for novel therapeutic options. BODIPY is a flexible fluorophore with distinct photophysical characteristics and is a fascinating drug development platform. This review provides a comprehensive overview of the most recent breakthroughs in BODIPY-based small molecules for cancer or disease detection and therapy, including their functional potential.

Persistent radical anion polymers based on naphthalenediimide and a vinylene spacer.

Persistent n-doped conjugated polymers were achieved by doping the electron accepting PDNDIV and PFNDIV polymers with ionic (TBACN) or neutral (TDAE) dopants. The great electron affinities, as indicated by the low LUMO levels of PDNDIV (-4.09 eV) and PFNDIV (-4.27 eV), facilitated the chemical reduction from either TBACN or TDAE. The low-lying LUMOs of the neutral polymers PDNDIV and PFNDIV were achieved by incorporation of vinylene spacers between the electron poor NDI units to increase the conjugation length without the use of an electron donor, and this was lowered further by an electron-withdrawing fluorinated N-substituent on the NDI moiety. The polymer radical anions were found to persist for several days under ambient conditions by EPR spectroscopy. A distinguishing and noteworthy feature of these polymers is that they can be consecutively reduced by up to four electrons in acetonitrile. Conductivity measurements demonstrate the prospective impact of PDNDIV and PFNDIV for organic electronics.

Radical-Cascade Avenue for 3,4-Fused-Ring-Substituted Thiophenes.

A single-step intramolecular radical cascade reaction of diynes and thioacetic acid in the presence of a catalytic amount of azobis(isobutyronitrile) as a radical initiator has been developed to synthesize thiophenes. This method allows easy and effective construction of a thiophene scaffold having 3,4-fused-ring substitution and unsubstituted 2,5-positions for further functionalization and polymerization. Using this method, derivatives of cyclopenta[ c]thiophene, 3,4-ethylenedioxythiophene, and thiophene-containing spirocyclic compound have been synthesized.

Selenium-Containing Fused Bicyclic Heterocycle Diselenolodiselenole: Field Effect Transistor Study and Structure-Property Relationship.

The first application of the diselenolodiselenole (C4Se4) heterocycle as an active organic field effect transistor materials is demonstrated here. C4Se4 derivatives (2a-2d) were obtained by using a newly developed straightforward diselenocyclization protocol, which includes the reaction of diynes with selenium powder at elevated temperature. C4Se4 derivatives exhibit strong donor characteristics and planar structure (except 2d). The atomic force microscopic analysis and thin-film X-ray diffraction pattern of compounds 2a-2d indicated the formation of distinct crystalline films that contain large domains. A scanning electron microscopy study of compound 2b showed development of symmetrical grains with an average diameter of 150 nm. Interestingly, 2b exhibited superior hole mobility, approaching 0.027 cm(2) V(-1) s(-1) with a transconductance of 9.2 µS. This study correlate the effect of π-stacking, Se···Se intermolecular interaction, and planarity with the charge transport properties and performance in the field effect transistor devices. We have shown that the planarity in C4Se4 derivatives was achieved by varying the end groups attached to the C4Se4 core. In turn, optoelectronic properties can also be tuned for all these derivatives by end-group variation.

Diselenolodiselenole: a selenium containing fused heterocycle for conjugated systems.

The synthesis of new conjugated building blocks, diselenolodiselenole (C4Se4) derivatives, is described for the first time. The structural and optoelectronic properties of C4Se4-derivatives are tuned by varying end-capping aromatic substituents. In cyclic voltammetry, all C4Se4-derivatives show two reversible oxidation peaks.