To be most effective anticancer drugs must penetrate tissue efficiently, reaching all the cancer cells that comprise the target population in a concentration sufficient to exert a therapeutic effect. Most research into the resistance of cancers to chemotherapy has concentrated on molecular mechanisms of resistance, whereas the role of limited drug distribution within tumours has been neglected. We summarize the evidence that indicates that the distribution of many anticancer drugs in tumour tissue is incomplete, and we suggest strategies that might be used either to improve drug penetration through tumour tissue or to select compounds based on their abilities to penetrate tissue, thereby increasing the therapeutic index.

Drug penetration in solid tumours

The role of fluorine in drug design and development is expanding rapidly as we learn more about the unique properties associated with this unusual element and how to deploy it with greater sophistication. The judicious introduction of fluorine into a molecule can productively influence conformation, pKa, intrinsic potency, membrane permeability, metabolic pathways, and pharmacokinetic properties. In addition, 18F has been established as a useful positron emitting isotope for use with in vivo imaging technology that potentially has extensive application in drug discovery and development, often limited only by convenient synthetic accessibility to labeled compounds. The wide ranging applications of fluorine in drug design are providing a strong stimulus for the development of new synthetic methodologies that allow more facile access to a wide range of fluorinated compounds. In this review, we provide an update on the effects of the strategic incorporation of fluorine in drug molecules and applications in po...

Applications of Fluorine in Medicinal Chemistry

Over the past decade, the most significant, conceptual advances in the field of fluorination were enabled most prominently by organo- and transition-metal catalysis. The most challenging transformation remains the formation of the parent C-F bond, primarily as a consequence of the high hydration energy of fluoride, strong metal-fluorine bonds, and highly polarized bonds to fluorine. Most fluorination reactions still lack generality, predictability, and cost-efficiency. Despite all current limitations, modern fluorination methods have made fluorinated molecules more readily available than ever before and have begun to have an impact on research areas that do not require large amounts of material, such as drug discovery and positron emission tomography. This Review gives a brief summary of conventional fluorination reactions, including those reactions that introduce fluorinated functional groups, and focuses on modern developments in the field.

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Introduction of Fluorine and Fluorine-Containing Functional Groups

Recent advances in catalysis have made the incorporation of fluorine into complex organic molecules easier than ever before, but selective, general and practical fluorination reactions remain sought after. Fluorination of molecules often imparts desirable properties, such as metabolic and thermal stability, and fluorinated molecules are therefore frequently used as pharmaceuticals or materials. But the formation of carbon-fluorine bonds in complex molecules is a significant challenge. Here we discuss reactions to make organofluorides that have emerged within the past few years and which exemplify how to overcome some of the intricate challenges associated with fluorination.

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Catalysis for fluorination and trifluoromethylation

The advent of modern C–H functionalization chemistries has enabled medicinal chemists to consider a synthetic strategy, late stage functionalization (LSF), which utilizes the C–H bonds of drug leads as points of diversification for generating new analogs. LSF approaches offer the promise of rapid exploration of structure activity relationships (SAR), the generation of oxidized metabolites, the blocking of metabolic hot spots and the preparation of biological probes. This review details a toolbox of intermolecular C–H functionalization chemistries with proven applicability to drug-like molecules, classified by regioselectivity patterns, and gives guidance on how to systematically develop LSF strategies using these patterns and other considerations. In addition, a number of examples illustrate how LSF approaches have been used to impact actual drug discovery and chemical biology efforts.

The medicinal chemist's toolbox for late stage functionalization of drug-like molecules

Molecular Imaging with PET

The therapeutic efficacy of antibodies can be substantially enhanced by conjugation of cytotoxic compounds such as chemotherapeutics and particle-emitting radionuclides. Intuitively one would assume that the therapeutic index would improve as the number of cytotoxic entities conjugated to the antibody increases. However, recent studies on auristatin–antibody conjugates in mice have demonstrated that a drug/antibody molar ratio of 4:1 results in optimal efficacy and in vivo tolerability. Unfortunately, conventional chemical strategies for protein modification are difficult to control and give rise to heterogeneous populations of immunoconjugates with variable stoichiometries, each of which has its own in vivo characteristics. The introduction of artificial, bio-orthogonal groups for site-specific and stoichiometric protein modification offers a potential solution to this problem. Such strategies are en vogue but are often laborious and still risk product heterogeneity. Transglutaminases (TGs, E.C. 2.3.2.13) catalyze acyltransfer reactions between the g-carboxamide group of glutamine (a side chain, which is otherwise chemically inert under physiological conditions) and the primary e-amino group of lysine, to form catabolically stable isopeptide bonds (Figure 1a). Most TGs are promiscuous with respect to the lysine substrate and accept even simple 5-aminopentyl groups as lysine surrogates. The criteria for a glutamine residue to be recognized by the enzyme, however, are muchmore stringent: it should be both located in a flexible region of the protein and flanked by specific amino acids. Given this inherent selectivity, we hypothesized that TG would be an alternative for the site-specific and stoichiometric functionalization of antibodies. For this study we used bacterial transglutaminase (BTG) because it is robust, inexpensive, and easy to handle. Our group is interested in radioimmunoconjugates for diagnostic and therapeutic applications, where low off-target accumulation of radioactivity is crucial. Earlier studies performed with radiolabeled monoclonal antibodies (mAbs) demonstrated that high numbers of metal chelators adversely affect the biological behavior of radioimmunoconjugates. Therefore, we tested the features of BTG for the preparation of immunoconjugates that are functionalized with different metal chelators and radiolabeled with different diagnostic and therapeutic radionuclides. Deferoxamine (DF, 1), an antidote for metal poisoning, has recently been identified as a suitable chelator for radionuclides such as Ga and Zr. During the course of our studies we recognized that without further derivatization deferoxamine is already a potent BTG substrate. Furthermore, the metal chelating system 4-(1,4,8,11tetraazacyclotetradec-1-yl)methyl benzoic acid (CPTA, 2) was derivatized with a 1,5-diaminopentane (cadaverine) spacer (Figure 1b; see the Supporting Information for details on the synthesis). To probe the scope of the new strategy we investigated other (model) substrates, which are of potential Figure 1. a) TG-mediated modification of Gln (Q) with a substrate containing lysine or a lysine surrogate. b) Substrates used in this study.

Site-specific and stoichiometric modification of antibodies by bacterial transglutaminase.

Fluorine-18 Click Radiosynthesis and Preclinical Evaluation of a New 18F-Labeled Folic Acid Derivative

Bombesin is a peptide exhibiting high affinity for the gastrin-releasing peptide receptor (GRPr), which is highly overexpressed on prostate cancer cells. In the present study, we developed an 18F-labeled bombesin analog, 18F-BAY 86-4367, which is currently being clinically tested for use in PET of prostate cancer. Methods: In vitro pharmacologic studies were performed to characterize the nonradioactive (19F) standard of the bombesin analog for binding affinity and selectivity for GRPr. The stability of 18F-BAY 86-4367 was determined in murine and human plasma. In vivo, the tumor-targeting potential and pharmacokinetic profile of the 18F tracer were analyzed with biodistribution experiments and PET studies of prostate tumor–bearing mice. Results: The nonradioactive (19F) standard of the bombesin analog showed subnanomolar and GRPr-selective binding affinity. The stability of the tracer in murine and human plasma was found to be high. In 2 prostate cancer xenograft models (PC-3 and LNCaP), 18F-BAY 86-4367 showed more specific and effective GRPr-based targeting in vivo than the benchmark radiotracers 18F-fluoroethylcholine and 18F-FDG. In addition, rapid tumor targeting and fast renal excretion (∼70%) and hepatobiliary excretion (∼10%) were identified in both xenograft models. Furthermore, PET studies provided clear and specific visualization of PC-3 tumors in mice. Conclusion: Favorable preclinical data showing specific and effective tumor targeting by 18F-BAY 86-4367 suggest that a clinical trial be undertaken to test its diagnostic utility in PET for prostate carcinoma patients.

https://jnm.snmjournals.org/content/52/2/270.full.pdf

Michael Honer

Papers

Molecular Imaging with PET

Site-specific and stoichiometric modification of antibodies by bacterial transglutaminase.

Molecular Imaging with PET

Fluorine-18 Click Radiosynthesis and Preclinical Evaluation of a New 18F-Labeled Folic Acid Derivative

18F-Labeled Bombesin Analog for Specific and Effective Targeting of Prostate Tumors Expressing Gastrin-Releasing Peptide Receptors