Topics in Medicinal Chemistry 34 Zhen Cheng   Editor Fluorescent Imaging in Medicinal Chemistry 34 Topics in Medicinal Chemistry SeriesEditors P.R.Bernstein,Philadelphia,USA A.L.Garner,AnnArbor,USA G.I.Georg,Minneapolis,USA J.A.Lowe,Stonington,USA N.A.Meanwell,Princeton,USA A.K.Saxena,Lucknow,India C.T.Supuran,SestoFiorentino,Italy A.Zhang,Pudong,China Aims and Scope Topics in Medicinal Chemistry (TMC) covers all relevant aspects of medicinal chemistryresearch,e.g.pathobiochemistryofdiseases,identificationandvalidation of (emerging) drug targets, structural biology, drugability of targets, drug design approaches,chemogenomics,syntheticchemistryincludingcombinatorialmethods, bioorganicchemistry,naturalcompounds,high-throughputscreening,pharmacolog- ical in vitro and in vivo investigations, drug-receptor interactions on the molecular level, structure-activity relationships, drug absorption, distribution, metabolism, elimination, toxicology and pharmacogenomics. Drug research requires interdisci- plinary team-work at the interface between chemistry, biology and medicine. To fulfil this need, TMC is intended for researchers and experts working in academia and in the pharmaceutical industry, and also for graduates that look for a carefully selected collection of high quality review articles on their respective field of expertise. Medicinal chemistry is both science and art. The science of medicinal chemistry offers mankind one of its best hopes for improving the quality of life. The art of medicinal chemistry continues to challenge its practitioners with the need for both intuition and experience to discover new drugs. Hence sharing the experience of drugresearchisuniquelybeneficialtothefieldofmedicinalchemistry. AllchaptersfromTopicsinMedicinalChemistryarepublishedOnlineFirstwithan individualDOI.Inreferences,TopicsinMedicinalChemistryisabbreviatedasTop MedChemandcitedasajournal. Moreinformationaboutthisseriesathttp://www.springer.com/series/7355 Zhen Cheng Editor Fluorescent Imaging in Medicinal Chemistry With contributions by (cid:1) (cid:1) (cid:1) (cid:1) (cid:1) (cid:1) Y. An A. Bi Z. Cheng Y. Du T. Gao J. Grimm (cid:1) (cid:1) (cid:1) (cid:1) (cid:1) (cid:1) S. He X. Jiang J. V. Jokerst T. Kim X. Liu Y. Liu (cid:1) (cid:1) (cid:1) (cid:1) J. F. Lovell T. F. Massoud N. Murthy A. Natarajan (cid:1) (cid:1) (cid:1) (cid:1) R. Paulmurugan M. Skubal E. P. Stater U. K. Sukumar (cid:1) (cid:1) (cid:1) (cid:1) (cid:1) R. Tamura C. Tang J. Tian D. Vernekohl L. Xing (cid:1) (cid:1) (cid:1) S. Yang X. Yang W. Zeng Y. Zhang Editor ZhenCheng StanfordUniversity Stanford,CA,USA ISSN1862-2461 ISSN1862-247X (electronic) TopicsinMedicinalChemistry ISBN978-3-030-46706-7 ISBN978-3-030-46707-4 (eBook) https://doi.org/10.1007/978-3-030-46707-4 ©SpringerNatureSwitzerlandAG2020 Thisworkissubjecttocopyright.AllrightsarereservedbythePublisher,whetherthewholeorpartofthe materialisconcerned,specificallytherightsoftranslation,reprinting,reuseofillustrations,recitation, broadcasting,reproductiononmicrofilmsorinanyotherphysicalway,andtransmissionorinformation storageandretrieval,electronicadaptation,computersoftware,orbysimilarordissimilarmethodology nowknownorhereafterdeveloped. Theuseofgeneraldescriptivenames,registerednames,trademarks,servicemarks,etc.inthispublication doesnotimply,evenintheabsenceofaspecificstatement,thatsuchnamesareexemptfromtherelevant protectivelawsandregulationsandthereforefreeforgeneraluse. Thepublisher,theauthors,andtheeditorsaresafetoassumethattheadviceandinformationinthisbook arebelievedtobetrueandaccurateatthedateofpublication.Neitherthepublishernortheauthorsorthe editorsgiveawarranty,expressedorimplied,withrespecttothematerialcontainedhereinorforany errorsoromissionsthatmayhavebeenmade.Thepublisherremainsneutralwithregardtojurisdictional claimsinpublishedmapsandinstitutionalaffiliations. ThisSpringerimprintispublishedbytheregisteredcompanySpringerNatureSwitzerlandAG. Theregisteredcompanyaddressis:Gewerbestrasse11,6330Cham,Switzerland Preface Fluorescent imaging techniques have broad and profound impact on numerous research fields including chemical biology, cancer biology, medical imaging, and pharmaceuticalsciences.Itprovidespowerfultoolstoreinforcemedicinalchemistry research,facilitatedrugdiscoveryanddevelopment,andhelpdiseasesdiagnosisand treatment. This book summarizes the most recent developments of fluorescent imagingtechniquesformedicinalchemistryresearchandbiomedicalapplications. In Chapter “Fluorescence Molecular Imaging of Medicinal Chemistry in Cancer”, some fundamental issues of fluorescence molecular imaging including imaging probe and imaging analysis methods are described, followed by an introduction to its medical applications in drug discovery. Then organic mole- cules-based fluorescent imaging probes and inorganic nanoprobes are presented in Chapter “Organic Fluorescent Probes for Diagnostics and Bio-Imaging” and Chapter “Inorganic Fluorescent Nanomaterials”, respectively. In Chapter “Advancements of Second Near-Infrared Biological Window Fluorophores: Mechanism, Synthesis, and Application In Vivo”, fluorescent imaging at long wavelengths (1,000–17,000 nm), namely near-infrared window II imaging, is introduced.Chapter“X-RayExcitedFluorescentMaterialsforMedicalApplication” coversanovelapproachtousingX-raytoilluminatematerialsandproducefluores- cence for medical imaging applications. In Chapter “Applications of Fluorescent Protein-Based SensorsinBioimaging”,fluorescent proteinsusedfor bioassays and their applications are reviewed. Chapter “Fluorescent Probes for Diagnostics of β-Galactosidase: From Micro to Macro” summarizes the fluorescent probes, nanomaterials, and biomolecules for the detection of an important enzyme (β- galactosidase) andtheirapplicationsin health monitoring.The last chapterfocuses onthecurrentstateoffluorescentimagingtechniques,especiallyendoscopicimag- ingandCerenkovluminescenceimagingforthediagnosisandtreatmentofdiseases inclinics. v vi Preface Through this book, it is hoped that more people will appreciate the role of fluorescentimaging,explorethisexcitingfield,anddevelopnewfluorescentimag- ingtechniquesforaddressingunmetmedicalneeds. Stanford,CA,USA ZhenCheng Contents FluorescenceMolecularImagingofMedicinalChemistryinCancer. . . 1 JieTian,YangDu,ChuTang,andYuAn OrganicFluorescentProbesforDiagnosticsandBio-Imaging. . . . . . . . 33 XingyueYang,JonathanF.Lovell,NirenMurthy,andYumiaoZhang InorganicFluorescentNanomaterials. . . . . . . . . . . . . . . . . . . . . . . . . . . 55 TaehoKimandJesseV.Jokerst AdvancementsofSecondNear-InfraredBiologicalWindow Fluorophores:Mechanism,Synthesis,andApplicationInVivo. . . . . . . 81 ShuqingHeandZhenCheng X-RayExcitedFluorescentMaterialsforMedicalApplication. . . . . . . . 125 DonVernekohlandLeiXing ApplicationsofFluorescentProtein-BasedSensorsinBioimaging. . . . . 149 UdayKumarSukumar,ArutselvanNatarajan,TarikF.Massoud, andRamasamyPaulmurugan FluorescentProbesforDiagnosticsofβ-Galactosidase:FromMicro toMacro. . . . . . . . .. . . . . . . . . .. . . . . . . . .. . . . . . . . . .. . . . . . . . .. . 185 AnyaoBi,XinchenJiang,TangGao,ShuqiYang,YiLiu,XiaohuiLiu, andWenbinZeng ThePresentandFutureofOpticalImagingTechnologiesintheClinic: DiagnosisandTherapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203 EvanP.Stater,MagdalenaSkubal,RyoTamura,andJanGrimm Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225 vii TopMedChem(2020)34:1–32 DOI:10.1007/7355_2019_86 ©SpringerNatureSwitzerlandAG2019 Publishedonline:29February2020 Fluorescence Molecular Imaging of Medicinal Chemistry in Cancer JieTian,YangDu,ChuTang,andYuAn Contents 1 Introduction................................................................................... 3 2 ImagingProbe................................................................................ 3 2.1 Fluorophores............................................................................ 4 2.2 TargetedLigandofFluorescentProbes................................................ 7 3 ImagingAnalysis............................................................................. 12 3.1 PhotonPropagationModel............................................................. 13 3.2 ForwardProblem-Solving.............................................................. 14 3.3 InverseProblem-Solving............................................................... 14 4 MedicalApplication.......................................................................... 15 4.1 IdentificationofTherapeuticTargets................................................... 16 4.2 CandidateDrugScreening.............................................................. 16 4.3 TrackingtheDrugBiodistributionandMetabolism................................... 17 J.Tian(*) CASKeyLaboratoryofMolecularImaging,TheStateKeyLaboratoryofManagementand ControlforComplexSystems,InstituteofAutomation,ChineseAcademyofSciences,Beijing, China BeijingKeyLaboratoryofMolecularImaging,Beijing,China UniversityofChineseAcademyofSciences,Beijing,China BeijingAdvancedInnovationCenterforBigData-BasedPrecisionMedicine,Beihang University,Beijing,China EngineeringResearchCenterofMolecularandNeuroImagingofMinistryofEducation,School ofLifeScienceandTechnology,XidianUniversity,Xi’an,Shaanxi,China e-mail:[email protected];[email protected];http://www.3dmed.net Y.DuandY.An CASKeyLaboratoryofMolecularImaging,TheStateKeyLaboratoryofManagementand ControlforComplexSystems,InstituteofAutomation,ChineseAcademyofSciences,Beijing, China BeijingKeyLaboratoryofMolecularImaging,Beijing,China UniversityofChineseAcademyofSciences,Beijing,China C.Tang EngineeringResearchCenterofMolecularandNeuroImagingofMinistryofEducation,School ofLifeScienceandTechnology,XidianUniversity,Xi’an,Shaanxi,China 2 J.Tianetal. 4.4 DeterminationofPharmacokineticsofDrugs.......................................... 18 4.5 FluorescenceProdrugConjugates...................................................... 19 5 FuturePerspectives........................................................................... 24 References......................................................................................... 25 Abstract The process of new drug discoveryand development isa lengthy, high- risk,andcostlytask.Fluorescentmolecularimaging(FMI)hastremendouspotential forimprovingtheefficiencyofdrugscreening,evaluatingdrugeffects,accelerating the process, and markedly reducing the cost of new drug development from initial targetvalidationandhigh-throughputscreeningidentificationcampaignstothefinal human translation phases. FMI can help evaluate the role of new candidate drugs under the influence of complex biological responses in living subjects and better understandthemechanismbetweendrugactivityanddisease,whichcanhelpselect candidatesthatseemmostlikelytosucceedorpreventthedevelopmentofdrugsthat seemtofailintheend.Hence,inthischapter,FMIwasdescribedforitsapplication indrugdiscovery,includingidentificationoftumor-specificmarkers,candidatedrug screening,determinationofpharmacokineticsofdrugs,andpreparationofprodrugs. Keywords Cancer,Drugdiscovery,Fluorescentmolecularimaging,Medicinal chemistry Abbreviations BBTD Benzobisthiadiazole BEM Boundaryelementmethod BLI Bioluminescenceimaging BODIPY Borondipyrromethene Cy Cyanine D-A-D Donor-acceptor-donorscaffold DE Diffusionequation FDM Finitedifferencemethod FEM Finiteelementmethod FITC Fluoresceinisothiocyanate FMI Fluorescencemolecularimaging FMT Fluorescencemoleculartomography GFP Greenfluorescentprotein HDACs Histonedeacetylases ICG Indocyaninegreen MM Meshlessmethod NIR Near-infrared ROS Reactiveoxygenspecies SBR Signal-to-backgroundratio