Hancheng Cai

Medulloblastoma is the most common malignant brain tumor of childhood. Despite major advances, long-term survival is hindered by relapse and leptomeningeal spread, necessitating the development of novel diagnostic and therapeutic approaches. Abnormal tryptophan metabolism, via the immunomodulatory indoleamine-2,3-dioxygenase (IDO)/ tryptophan-2,3 dioxygenase (TDO)-mediated kynurenine pathway (KP), has been demonstrated in tumors, and is emerging as a valid target for immunotherapy as well as non-invasive tumor imaging. Previously, a positron emission tomography (PET) tracer, α-[11C] methyl-L-tryptophan ([11C] AMT), has been successfully used to evaluate the increased tryptophan metabolism and uptake through KP in patients with glioma. Nevertheless, the short half-life of the carbon-11 isotope has limited the broad applications of [11C] AMT in clinical research and diagnostics. In this study, using a novel PET tracer, 1-(2-[18F]fluoroethyl)-L-tryptophan (L-1-[18F]FETrp) with similar pathophysiological and metabolic properties as [11C] AMT, we assessed the tryptophan metabolism in a transgenic mouse model of the Sonic hedgehog (Shh) subgroup of medulloblastoma. In Smo-Smo mice, preliminary PET imaging data showed increased accumulation of L-1-[18F]FETrp in tumors as compared to normal brain tissue. Immunofluorescence and molecular analysis of tumor tissues obtained from Smo-Smo mice indicated increased expression of TDO2, but not IDO1. Both TDO2 and IDO1 are tissue-specific first step and rate-limiting enzymes of the KP of tryptophan metabolism. Thus, our preclinical studies in Smo-Smo mice indicate that L-1-[18F]FETrp may be a suitable tracer for PET imaging of medulloblastoma tumors and could provide valuable information for noninvasive assessment of immunotherapy response and move towards targeted therapy for medulloblastoma in the future.

Positron emission tomography (PET) imaging of receptor integrin α_vβ₃ expression may play a key role in the early detection of cancer and cardiovascular diseases, monitoring disease progression, evaluating therapeutic response, and aiding anti‐angiogenic drugs discovery and development. The last decade has seen the development of new PET tracers for in vivo imaging of integrin α_vβ₃ expression along with advances in PET chemistry. In this review, we will focus on the radiochemistry development of PET tracers based on arginine–glycine–aspartic acid (RGD) peptide, present an overview of general strategies for preparing RGD‐based PET tracers, and review the recent advances in preparations of ¹⁸F‐labeled, ⁶⁴Cu‐labeled, and ⁶⁸Ga‐labeled RGD tracers, RGD‐based PET multivalent probes, and RGD‐based PET multimodality probes for imaging receptor integrin α_vβ₃ expression.

¹¹C-Doxepin is an established positron emission tomography (PET) probe for imaging the histamine H1 receptor, which is associated with various neurological disorders and allergic diseases. A fully automated current Good Manufacturing Practices (cGMP)-compliant radiosynthesis is therefore desirable in order to facilitate clinical PET studies. We report here a fully automated production method for ¹¹C-doxepin using a multipurpose PET module for clinical use. ¹¹C-Doxepin was radiosynthesized by N-[¹¹C]methylation of nordoxepin using [¹¹C]methyl iodide in DMF solvent, and then purified by HPLC, and finally reformulated with solid phase extraction (SPE) using a cGMP-compliant automated multipurpose PET module developed in house. The final product was analyzed and subjected to quality control according to current US Pharmacopeia requirements. The radiochemical yield (decay corrected) of ¹¹C-doxepin for clinical use was 47.0 ± 5.2% (n = 12) based on [¹¹C]methyl iodide, moreover the radiochemical purity of ¹¹C-doxepin was more than 97.5% with 1,200 ± 500 Ci/mmol specific activity(end of production). The total production time of ¹¹C-doxepin was 37 min from end of bombardment (EOB) with the final product passing all tests under cGMP requirements for clinical use. A simplified and reliable fully automated production of ¹¹ C-doxepin for clinical use was developed, allowing the synthesis of the tracer with high yield using a cGMP-compliant module and procedure. The success of this approach could make the PET tracer ¹¹ C-doxepin more accessible for clinical studies.