IMMH-010 is an ester prodrug of YPD-29B, a potent programmed cell death ligand 1 (PD-L1) inhibitor. The metabolism of IMMH-010 was investigated and compared in various species. Four metabolites of IMMH-010 were identified, and the major metabolite was the parent compound, YPD-29B, which was mainly catalyzed by carboxylesterase 1 (CES1). We observed IMMH-010 metabolism in the plasma of various species. IMMH-010 was rapidly metabolized to YPD-29B in rat and mouse plasma, whereas it remained stable in human and monkey plasma. In the liver S9 fractions of human, monkey, dog, and rat, IMMH-010 was quickly transformed to YPD-29B with no obvious differences among species. In addition, the transformation ratio of IMMH-010 to YPD-29B was low in rat and human intestines, which indicated that the intestine was not an important site for IMMH-010 hydrolysis. Moreover, we demonstrated the remarkable antitumor efficacy of IMMH-010 in B16F10 melanoma and MC38 colon carcinoma xenograft mouse models. We also compared the pharmacokinetic profiles of IMMH-010 in rodents and primates. After oral administration of IMMH-010, the general exposure of active metabolite YPD-29B was slightly lower in primates than in rodents, suggesting that data should be extrapolated cautiously from rodents to humans.

Background: Glucuronidation is an essential metabolic pathway for a variety of drugs. IMM-H004 is a novel neuroprotective agent against ischemic stroke, and its glucuronide metabolite IMM-H004G exhibits similar pharmacological activity. Despite possessing a higher molecular weight and polarity, brain exposure of IMM-H004G is much higher than that of IMM-H004. This study aimed to investigate the brain metabolism and transport mechanisms of IMM-H004 and IMM-H004G. Methods: First, the possibility of IMM-H004 glucuronidation in the brain was evaluated in several human brain cell lines and rat homogenate. Subsequently, the blood–brain barrier carrier-mediated transport mechanism of IMM-H004 and IMM-H004G was studied using overexpression cell models. In addition, intracerebroventricular injection, in situ brain perfusion model, and microdialysis/microinjection techniques were performed to study the distribution profiles of IMM-H004 and IMM-H004G. Results: IMM-H004 could be metabolized to IMM-H004G in both rat brain and HEB cells mediated by UGT1A7. However, IMM-H004G could not be hydrolyzed back into IMM-H004. Furthermore, the entry and efflux of IMM-H004 in the brain were mediated by the pyrilamine-sensitive H⁺/OC antiporter and P-gp, respectively, while the transport of IMM-H004G from the blood to the brain was facilitated by OATP1A2 and OATP2B1. Ultimately, stronger concentration gradients and OATP-mediated uptake played a critical role in promoting greater brain exposure of IMM-H004G. Conclusions: The active glucuronide metabolite of the brain protectant IMM-H004 with poor blood–brain barrier permeability demonstrates a high partition in the rat brain via multiple mechanisms, and our findings deepen the understanding of the mechanisms underlying the blood–brain barrier metabolism and transport of active glucuronide conjugates.

Microwave photonics offers a promising solution to the increasing demand for high-frequency and broadband signals in battlefield communications. We propose a method for receiving broadband microwave signals with image-reject processing. The approach involves two main processes: signal reception and image-reject processing. In signal reception, the input broadband signal with a frequency span from DC to 40 GHz is multicast to three-tone signal optical carriers using a Mach-Zehnder modulator (MZM) biased at its minimum transmission bias point (MITB). Then, by using a three-tone local oscillator (LO) optical carriers to align with the corresponding modulation sidebands of the signal optical carriers, the input signal at any center frequency and with a bandwidth of 10 GHz can be demodulated after one capture. Hence, the full bandwidth of 40 GHz can be received by capturing the signal four times. In image-reject processing, the modulation sidebands of the signal carriers and the corresponding LO carriers are injected into an optical coherent receiver to achieve IQ demodulation. The generated in-phase (I) and quadrature (Q) signals are digitized and processed to suppress image interference. A numerical simulation is carried out to validate the proposed scheme. The simulation result indicates that the proposed scheme is capable of receiving broadband signals with a bandwidth of 40 GHz and its instantaneous bandwidth is equal to 10 GHz. Besides, the sensitivity and the dynamic range of the proposed system are equal to -85 dBm and 109.9 dB·Hz2/3, respectively. The proposed scheme is promising for enhancing the receive bandwidth and the sensitivity in electromagnetic spectrum sensing applications.