A variety of peptides labeled with the positron emitting radionuclide fluorine-18 have shown promise as tracers for use in positron emission tomography (PET) for the detection of malignancies. Peptides can be produced with a formidable versatility allowing them to target a vast diversity of uniquely expressed or overexpressed receptors associated with pathological conditions. The quantitative nature of PET gives the opportunity to stage and monitor the progress of the disease. The pharmacokinetics of peptides are compatible with the half-life of fluorine-18 (110 min), allowing the generation of high quality PET images within the time frame of 1-3 hours or longer. The production of high energy gamma emitting radiopharmaceuticals puts certain constraints and requirements on the production method. These are to a large extent dictated by the short half-life of the 18F and the need for appropriate shielding of the operator. For large scale productions, a fully automated production process is a requirement. Compared to low molecular weight fluorine-18 labeled tracers, the production of 18F-labeled peptides entails specific challenges. As opposed to small organic molecules where direct labeling with no-carrier added 18-fluoride is feasible, peptides do not normally allow for such a direct labeling approach. Therefore, peptides are for all practical purposes labeled by 18F-prosthetic groups, also called bifunctional labeling agents, making their synthesis relatively complicated. During the last decade, various methodologies have been developed for the introduction of 18F-fluoride into peptides. The strategies employed for the labeling of peptides with 18F all represent their own advantages and inconveniences, still some are more flexible than others. In this review, the aim is to provide an overview and discuss the strategies currently used for labeling of peptides with 18F for PET.

The decapeptide gonadotropin-releasing hormone, also referred to as luteinizing hormone-releasing hormone with the sequence (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH₂) plays an important role in regulating the reproductive system. It stimulates differential release of the gonadotropins FSH and LH from pituitary tissue. To date, treatment of hormone-dependent diseases targeting the GnRH receptor, including peptide GnRH agonist and antagonists are now available on the market. The inherited issues associate with peptide agonists and antagonists have however, led to significant interest in developing orally active, small molecule, non-peptide antagonists. In this review, we will summarize all developed small molecule GnRH antagonists along with the most recent clinical data and therapeutic applications.

The discovery of endogenous peptide ligands for morphine binding sites occurred in parallel with the identification of three subclasses of opioid receptor (OR), traditionally designated as μ, δ, and κ, along with the more recently defined opioid-receptor-like (ORL1) receptor. Early efforts in opioid receptor radiochemistry focused on the structure of the prototype agonist ligand, morphine, although N-[methyl-¹¹C]morphine, -codeine and -heroin did not show significant binding in vivo. [¹¹C]Diprenorphine ([¹¹C]DPN), an orvinol type, non-selective OR antagonist ligand, was among the first successful PET tracers for molecular brain imaging, but has been largely supplanted in research studies by the μ-preferring agonist [¹¹C]carfentanil ([¹¹C]Caf). These two tracers have the property of being displaceable by endogenous opioid peptides in living brain, thus potentially serving in a competition-binding model. Indeed, many clinical PET studies with [¹¹C]DPN or [¹¹C]Caf affirm the release of endogenous opioids in response to painful stimuli. Numerous other PET studies implicate μ-OR signaling in aspects of human personality and vulnerability to drug dependence, but there have been very few clinical PET studies of μORs in neurological disorders. Tracers based on naltrindole, a non-peptide antagonist of the δ-preferring endogenous opioid enkephalin, have been used in PET studies of δORs, and [¹¹C]GR103545 is validated for studies of κORs. Structures such as [¹¹C]NOP-1A show selective binding at ORL-1 receptors in living brain. However, there is scant documentation of δ-, κ-, or ORL1 receptors in healthy human brain or in neurological and psychiatric disorders; here, clinical PET research must catch up with recent progress in radiopharmaceutical chemistry.

Patients with melanoma have a high risk of developing brain metastasis, which is associated with a dismal prognosis. During early stages of metastasis development, the blood–brain barrier (BBB) is likely intact, which inhibits sufficient drug delivery into the metastatic lesions. We investigated the ability of the peptide, K16ApoE, to permeabilize the BBB for improved treatment with targeted therapies preclinically. Dynamic contrast enhanced MRI (DCE-MRI) was carried out on NOD/SCID mice to study the therapeutic window of peptide-mediated BBB permeabilization. Further, both in vivo and in vitro assays were used to determine K16ApoE toxicity and to obtain mechanistic insight into its action on the BBB. The therapeutic impact of K16ApoE on metastases was evaluated combined with the mitogen-activated protein kinase pathway inhibitor dabrafenib, targeting BRAF mutated melanoma cells, which is otherwise known not to cross the intact BBB. Our results from the DCE-MRI experiments showed effective K16ApoE-mediated BBB permeabilization lasting for up to 1 hour. Mechanistic studies showed a dose-dependent effect of K16ApoE caused by induction of endocytosis. At concentrations above IC₅₀, the peptide additionally showed nonspecific disturbances on plasma membranes. Combined treatment with K16ApoE and dabrafenib reduced the brain metastatic burden in mice and increased animal survival, and PET/CT showed that the peptide also facilitated the delivery of compounds with molecular weights as large as 150 kDa into the brain. To conclude, we demonstrate a transient permeabilization of the BBB, caused by K16ApoE, that facilitates enhanced drug delivery into the brain. This improves the efficacy of drugs that otherwise do not cross the intact BBB.