Neuroinflammation and cyclooxygenase-2 (COX-2) upregulation are associated with the pathogenesis of degenerative brain diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), epilepsy, and a response to traumatic brain injury (TBI) or stroke. COX-2 is also induced in acute pain, depression, schizophrenia, various cancers, arthritis and in acute allograft rejection. Positron emission tomography (PET) imaging allows for the direct measurement of in vivo COX-2 upregulation and thereby enables disease staging, therapy evaluation and aid quantifying target occupancy of novel nonsteroidal anti-inflammatory drugs or NSAIDs. Thus far, no clinically useful radioligand is established for monitoring COX-2 induction in brain diseases due to the delay in identifying qualified COX-2-selective inhibitors entering the brain. This review examines radiolabeled COX-2 inhibitors reported in the past decade and identifies the most promising radioligands for development as clinically useful PET radioligands. Among the radioligands reported so far, the three tracers that show potential for clinical translation are, [11CTMI], [11C]MC1 and [18F]MTP. These radioligands demonstrated BBB permeablity and in vivo binding to constitutive COX-2 in the brain or induced COX-2 during neuroinflammation.

Immunotherapy has dramatically improved outcomes for some cancer patients; however, novel treatments are needed for more patients to achieve a long-lasting response. FAP-targeted molecular radiotherapy has shown efficacy in both preclinical and clinical models and has immunomodulatory effects. Here, we studied if combined immunotherapy and radiotherapy could increase antitumor efficacy in murine models of lung cancer and melanoma and interrogated the mechanisms by which these treatments attenuate tumor growth. Using LLC1 and B16F10 murine models of lung cancer and melanoma, respectively, we tested the efficacy of ¹⁷⁷Lu-FAPI-04 alone and in combination with immunotherapy. Alone, ¹⁷⁷Lu-FAPI-04 significantly reduced tumor growth in both models. In animals with melanoma, combined therapy resulted in tumor regression while lung tumor growth was attenuated, but tumors did not regress. Combined therapy significantly increased caspase-3 and decreased Ki67 compared with immunotherapy alone. Flow cytometry demonstrated that tumor-associated macrophages responded in a tumor-dependent manner which was distinct in animals treated with both therapies compared with either therapy alone. These data demonstrate that ¹⁷⁷Lu-FAPI-04 is an effective anticancer therapy for melanoma and lung cancer which mediates effects at least partially through induction of apoptosis and modulation of the immune response. Translational studies with immunotherapy and ¹⁷⁷Lu-FAPI-04 are needed to demonstrate the clinical efficacy of this combined regimen.

Glioblastoma (GBM) is the most common primary adult brain malignancy with an extremely poor prognosis and a median survival of fewer than two years. A key reason for this high mortality is that the blood–brain barrier (BBB) significantly restricts systemically delivered therapeutics to brain tumors. High-intensity focused ultrasound (HIFU) with microbubbles is a methodology being used in clinical trials to noninvasively permeabilize the BBB for systemic therapeutic delivery to GBM. Topotecan is a topoisomerase inhibitor used as a chemotherapeutic agent to treat ovarian and small cell lung cancer. Studies have suggested that topotecan can cross the BBB and can be used to treat brain metastases. However, pharmacokinetic data demonstrated that topotecan peak concentration in the brain extracellular fluid after systemic injection was ten times lower than in the blood, suggesting less than optimal BBB penetration by topotecan. We hypothesize that HIFU with microbubbles treatment can open the BBB and significantly increase topotecan concentration in the brain. We radiolabeled topotecan with ¹¹C and acquired static and dynamic positron emission tomography (PET) scans to quantify [¹¹C] topotecan uptake in the brains of normal mice and mice after HIFU treatment. We found that HIFU treatments significantly increased [¹¹C] topotecan brain uptake. Moreover, kinetic analysis of the [¹¹C] topotecan dynamic PET data demonstrated a substantial increase in [¹¹C] topotecan volume of distribution in the brain. Furthermore, we found a decrease in [¹¹C] topotecan brain clearance, confirming the potential of HIFU to aid in the delivery of topotecan through the BBB. This opens the potential clinical application of [¹¹C] topotecan as a tool to predict topotecan loco-regional brain concentration in patients with GBMs undergoing experimental HIFU treatments.

The human immune system is a complex system which protects against invaders and maintains tissue homeostasis. It is broadly divided into the innate and adaptive branches. Granzyme B is serine protease that plays an important role in both and can serve as a biomarker for cellular activation. Because of this, a granzyme B PET agent (GZP) has recently been developed and has been shown to be able to monitor response to immunotherapy. Here, we evaluated the utility of granzyme B PET imaging to assess the innate immune response. We subcutaneously administered LPS to mice to induce inflammation and performed granzyme B PET imaging after 24 and 120 h. We dissected out tissue in the region of injection and performed granzyme B immunofluorescence (IF) to confirm specificity of the GZP radiotracer. Granzyme B PET imaging demonstrated increased uptake in the region of LPS injection after 24 h, which normalized at 120 h. Granzyme B immunofluorescence showed specific staining in tissue from the 24 h time point compared to the PBS-injected control. These findings support the use of granzyme B PET for imaging innate immunity. In certain clinical contexts, the use of GZP PET imaging may be superior to currently available agents, and we therefore suggest further preclinical studies with the ultimate goal of translation to clinical use.

We have developed a novel fluorine-18 radiotracer, dipeptide 1, radiolabeled in two steps from mesylate 3. The initial radiolabeling is achieved in a short reaction time (10 min) and purified through solid-phase extraction (SPE) with modest radiochemical yields (rcy = 10 ± 2%, n = 5) in excellent radiochemical purity (rcp > 99%, n = 5). The de-protection of the tert-butyloxycarbonyl (Boc) and trityl group was achieved with mild heating under acidic conditions to provide ¹⁸F-tagged dipeptide 1. Preliminary analysis of ¹⁸F-dipeptide 1 was performed to confirm uptake by peptide transporters (PepTs) in human pancreatic carcinoma cell lines Panc1, BxPC3, and ASpc1, which are reported to express the peptide transporter 1 (PepT1). Furthermore, we confirmed in vivo uptake of ¹⁸F-dipeptide tracer 1 using microPET/CT in mice harboring subcutaneous flank Panc1, BxPC3, and Aspc1 tumors. In conclusion, we have established the radiolabeling of dipeptide 1 with fluoride-18, and demonstrated its potential as an imaging agent which may have clinical applications for the diagnosis of pancreatic carcinomas.

Purpose: Bladder cancer represents 3% of all new cancer diagnoses per year. We propose intravesical radionuclide therapy using the β-emitter 90 Y linked to DOTA-biotin-avidin ([ 90 Y]DBA) to deliver short-range radiation against non-muscle invasive bladder cancer (NMIBC). Material and methods: Image-guided biodistribution of intravesical DBA was investigated in an animal model by radiolabeling DBA with the 68 Ga and dynamic microPET imaging following intravesical infusion of [ 68 Ga]DBA for up to 4 hours and post-necropsy γ-counting of organs. The antitumor activity of [ 90 Y]DBA was investigated using an orthotopic MB49 murine bladder cancer model. Mice were injected with luciferase-expressing MB49 cells and treated via intravesical administration with 9.2 MBq of [ 90 Y]DBA or unlabeled DBA 3 days after the tumor implantation. Bioluminescence imaging was conducted after tumor implantation to monitor the bladder tumor growth. In addition, we investigated the effects of [ 90 Y]DBA radiation on urothelial histology with immunohistochemistry analysis of bladder morphology. Results: Our results demonstrated that DBA is contained in the bladder for up to 4 hours after intravesical infusion. A single dose of [ 90 Y]DBA radiation treatment significantly reduced growth of MB49 bladder carcinoma. Attaching 90 Y to the DOTA-avidin prevents its re-absorption into the blood and distribution throughout the rest of the body. Furthermore, immunohistochemistry demonstrated that [ 90 Y]DBA radiation treatment did not irreversibly damage the bladder urothelium, which appeared similar to the normal urothelium of healthy mice. Conclusion: Our data demonstrates the potential of intravesical [ 90 Y]DBA as a treatment for non-muscle invasive bladder cancer.