Selecting robust silicon photonic designs after Bayesian optimization without extra simulations.

Optimization methods are frequently exploited in the design of silicon photonic devices. In this paper, we demonstrate that pushing the objective function to its minimum during optimization often results in devices that gradually become more sensitive to perturbations of design variables. The dominant strategy of selecting the design with the smallest objective function can lead to fabrication failure or yield loss due to manufacturing process variations.

Synthesis and Evaluation of Novel Ga-Labeled [D-Phe,LeuψThz]bombesin(6-14) Analogs for Cancer Imaging with Positron Emission Tomography.

Gastrin-releasing peptide receptor (GRPR) is overexpressed in various cancers and is a promising target for cancer diagnosis and therapy. However, the high pancreas uptake and/or metabolic instability observed for most reported GRPR-targeted radioligands might limit their clinical applications. Our group recently reported a GRPR-targeted antagonist tracer, [Ga]Ga-TacsBOMB2 ([Ga]Ga-DOTA-Pip-D-Phe-Gln-Trp-Ala-Val-Gly-His-LeuψThz-NH), which showed a minimal pancreas uptake in a preclinical mouse model.

Development, preclinical evaluation and preliminary dosimetry profiling of SB03178, a first-of-its-kind benzo[h]quinoline-based fibroblast activation protein-α-targeted radiotheranostic for cancer imaging and therapy.

Fibroblast activation protein-α (FAP) is a marker of cancer-associated fibroblasts (CAFs) that constitute a significant portion of most carcinomas. Since it plays a critical role in tumor growth and metastasis, its timely detection to identify tumor lesions in early developmental stages using targeted radiopharmaceuticals has gained significant impetus. In the present work, two novel FAP-targeted precursors SB03178 and SB04033 comprising of an atypical benzo[h]quinoline construct were synthesized and either chelated to diagnostic radionuclide gallium-68 or therapeutic radionuclide lutetium-177, with ≥90% radiochemical purities and 22-76% decay-corrected radiochemical yields.

Unnatural amino acid substitutions to improve in vivo stability and tumor uptake of Ga-labeled GRPR-targeted TacBOMB2 derivatives for cancer imaging with positron emission tomography.

Background: Overexpressed in various solid tumors, gastrin-releasing peptide receptor (GRPR) is a promising cancer imaging marker and therapeutic target. Although antagonists are preferable for the development of GRPR-targeted radiopharmaceuticals due to potentially fewer side effects, internalization of agonists may lead to longer tumor retention and better treatment efficacy. In this study, we systematically investigated unnatural amino acid substitutions to improve in vivo stability and tumor uptake of a previously reported GRPR-targeted agonist tracer, [Ga]Ga-TacBOMB2 (Ga-DOTA-Pip-D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-Thz-NH).

Lys-urea-Aad, Lys-urea-Cmc and Lys-urea-Cms as potential pharmacophores for the design of PSMA-targeted radioligands to reduce off-target uptake in kidneys and salivary glands.

High kidney and salivary gland uptake is a common feature of prostate-specific membrane antigen (PSMA)-targeted radioligands derived from the lysine-urea-glutamic acid (Lys-urea-Glu) pharmacophore. In this study we investigated if radioligands derived from lysine-urea-2-aminoadipic acid (Lys-urea-Aad), lysine-urea--carboxylmethylcysteine (Lys-urea-Cmc) and lysine-urea--carboxylmethylserine (Lys-urea-Cms) pharmacophores with/without an albumin binder could retain good PSMA-targeting capability but with minimized kidney and salivary gland uptake. HTK03177 and HTK03187 were obtained by replacing Aad in the previously reported Lys-urea-Aad-derived HTK03149 with Cmc and Cms, respectively.

Inference of process variations in silicon photonics from characterization measurements.

Understanding process variations and their impact in silicon photonics remains challenging. To achieve high-yield manufacturing, a key step is to extract the magnitude and spatial distribution of process variations in the actual fabrication, which is usually based on measurements of replicated test structures. In this paper, we develop a Bayesian-based method to infer the distribution of systematic geometric variations in silicon photonics, without requiring replication of identical test structures.

Synthesis and Evaluation of Tc-Labeled PSMA-Targeted Tracers Based on the Lys-Urea-Aad Pharmacophore for Detecting Prostate Cancer with Single Photon Emission Computed Tomography.

Prostate-specific membrane antigen (PSMA) is a well-validated prostate cancer marker but reported PSMA-targeted tracers derived from the Lys-urea-Glu pharmacophore including the clinically validated [Tc]Tc-EDDA/HYNIC-iPSMA have high off-target uptake in kidneys, spleen, and salivary glands. In this study, we synthesized and evaluated three novel Tc-labeled PSMA-targeted tracers and investigated if the tracers derived from the Lys-urea-Aad pharmacophore could have minimized uptake in off-target organs/tissues. In vitro competition binding assays showed that compared with HYNIC-iPSMA, the three novel ligands had slightly weaker PSMA binding affinity (average K = 3.

Synthesis and Preclinical Evaluation of Novel Ga-Labeled ()-Pyrrolidin-2-yl-boronic Acid-Based PET Tracers for Fibroblast Activation Protein-Targeted Cancer Imaging.

Fibroblast activation protein (FAP) is a membrane-tethered serine protease overexpressed in the reactive stromal fibroblasts of >90% human carcinomas, which makes it a promising target for developing radiopharmaceuticals for the imaging and therapy of carcinomas. Here, we synthesized two novel ()-pyrrolidin-2-yl-boronic acid-based FAP-targeted ligands: SB02055 (DOTA-conjugated ()-(1-((6-(3-(piperazin-1-yl)propoxy)quinoline-4-carbonyl)glycyl)pyrrolidin-2-yl)boronic acid) and SB04028 (DOTA-conjugated (()-1-((6-(3-(piperazin-1-yl)propoxy)quinoline-4-carbonyl)-D-alanyl)pyrrolidin-2-yl)boronic acid). Ga- and Ga-complexes of both ligands were evaluated in preclinical studies and compared to previously reported Ga/Ga-complexed PNT6555.

Multimodality Imaging of Aortic Valve Calcification and Function in a Murine Model of Calcific Aortic Valve Disease and Bicuspid Aortic Valve.

Calcific aortic valve disease (CAVD) is a prevailing disease with increasing occurrence and no known medical therapy. mice have a high prevalence of bicuspid aortic valve (BAV), spontaneous aortic valve calcification, and aortic stenosis (AS). F-NaF PET/CT can detect the aortic valve calcification process in humans.

Impact of process variations on splitter-tree-based integrated optical phased arrays.

We consider the impact of intra-wafer systematic spatial variation, pattern density mismatch, and line edge roughness on splitter-tree-based integrated optical phased arrays. These variations can substantially affect the emitted beam profile in the array dimension. We study the effect on different architecture parameters, and the analysis is shown to be consistent with experimental results.

Synthesis and Evaluation of Ga-Labeled (2,4)-4-Fluoropyrrolidine-2-Carbonitrile and (4)-Thiazolidine-4-Carbonitrile Derivatives as Novel Fibroblast Activation Protein-Targeted PET Tracers for Cancer Imaging.

Fibroblast activation protein α (FAP-α) is a cell-surface protein overexpressed on cancer-associated fibroblasts that constitute a substantial component of tumor stroma and drive tumorigenesis. FAP is minimally expressed by most healthy tissues, including normal fibroblasts. This makes it a promising pan-cancer diagnostic and therapeutic target.

Ga-Labeled [Thz]Bombesin(7-14) Analogs: Promising GRPR-Targeting Agonist PET Tracers with Low Pancreas Uptake.

With overexpression in various cancers, the gastrin-releasing peptide receptor (GRPR) is a promising target for cancer imaging and therapy. However, the high pancreas uptake of reported GRPR-targeting radioligands limits their clinical application. Our goal was to develop Ga-labeled agonist tracers for detecting GRPR-expressing tumors with positron emission tomography (PET), and compare them with the clinically validated agonist PET tracer, [Ga]Ga-AMBA.

Synthesis and Preclinical Evaluation of Three Novel Ga-Labeled Bispecific PSMA/FAP-Targeting Tracers for Prostate Cancer Imaging.

Tumor heterogeneity limits the efficacy and reliability of monospecific radiopharmaceuticals in prostate cancer diagnosis and therapy. To overcome this limitation and improve lesion detection sensitivity, we developed and evaluated three bispecific radiotracers that can target both prostate-specific membrane antigen (PSMA) and fibroblast activation protein (FAP), which are the two key proteins overexpressed in prostate cancer. Three FAP-targeting ligands with various linker lengths were synthesized through multistep organic synthesis, and then connected to the PSMA-targeting motif.

Toward Ga and Cu Positron Emission Tomography Probes: Is Hdedpa-,'-pram the Missing Link for dedpa Conjugation?

Hdedpa-,'-pram (HL), a new chelator derived from the hexadentate ligand 1,2-bis[[(6-carboxypyridin-2-yl)methyl]amino]ethane (Hdedpa), which incorporates 3-propylamine chains anchored to the secondary amines of the ethylenediamine core of the latter, has emerged as a very promising scaffold for preparing Ga- and Cu-based positron emission tomography probes. This new platform is cost-effective and easy to prepare, and the two pendant primary amines make it versatile for the preparation of bifunctional chelators by conjugation and/or click chemistry. Reported herein, we have also included the related Hdedpa-,'-prpta (HL) platform as a simple structural model for its conjugated systems.

What a difference a methylene makes: replacing Glu with Asp or Aad in the Lys-urea-Glu pharmacophore of PSMA-targeting radioligands to reduce kidney and salivary gland uptake.

The aim of this study was to investigate the effect of replacing Glu in the Lys-urea-Glu PSMA-targeting pharmacophore of [Ga]Ga-HTK03041 with a close analog on the uptake of kidneys, salivary glands and PSMA-expressing tumor xenografts. HTK03161, HTK03149 and HTK03189A/B were obtained by replacing Glu in HTK03041 with Asp, Aad (L-2-aminoadipic acid) and Api (2-aminopimelic acid), respectively. PSMA binding affinities were measured by competition binding assays.

Reducing the Kidney Uptake of High Contrast CXCR4 PET Imaging Agents via Linker Modifications.

Purpose: The C-X-C chemokine receptor 4 (CXCR4) is highly expressed in many subtypes of cancers, notably in several kidney-based malignancies. We synthesized, labeled, and assessed a series of radiotracers based on a previous high contrast PET imaging radiopharmaceutical [Ga]Ga-BL02, with modifications to its linker and metal chelator, in order to improve its tumor-to-kidney contrast ratio.

Methods: Based on the design of BL02, a piperidine-based cationic linker (BL06) and several anionic linkers (tri-Aad (BL17); tri-D-Glu (BL20); tri-Asp (BL25); and tri-cysteic acid (BL31)) were substituted for the triglutamate linker.

Ga-Labeled [LeuψThz]Bombesin(7-14) Derivatives: Promising GRPR-Targeting PET Tracers with Low Pancreas Uptake.

The gastrin-releasing peptide receptor (GRPR) is a G-protein-coupled receptor that is overexpressed in many solid cancers and is a promising target for cancer imaging and therapy. However, high pancreas uptake is a major concern in the application of reported GRPR-targeting radiopharmaceuticals, particularly for targeted radioligand therapy. To lower pancreas uptake, we explored Ga-complexed TacsBOMB2, TacsBOMB3, TacsBOMB4, TacsBOMB5, and TacsBOMB6 derived from a potent GRPR antagonist sequence, [LeuψThz]Bombesin(7-14), and compared their potential for cancer imaging with [Ga]Ga-RM2.

Synthesis and preliminary evaluation of octreotate conjugates of bioactive synthetic amatoxins for targeting somatostatin receptor (sstr2) expressing cells.

Targeted cancer therapy represents a paradigm-shifting approach that aims to deliver a toxic payload selectively to target-expressing cells thereby sparing normal tissues the off-target effects associated with traditional chemotherapeutics. Since most targeted constructs rely on standard microtubule inhibitors or DNA-reactive molecules as payloads, new toxins that inhibit other intracellular targets are needed to realize the full potential of targeted therapy. Among these new payloads, α-amanitin has gained attraction as a payload in targeted therapy.

Targeting Refractory Mantle Cell Lymphoma for Imaging and Therapy Using C-X-C Chemokine Receptor Type 4 Radioligands.

Purpose: Mantle cell lymphoma (MCL) is associated with poor survival. The purpose of this study was to assess whether the C-X-C chemokine receptor type 4 (CXCR4) is a useful target for imaging and radioligand therapy of MCL, using a novel pair of radioligands, [68Ga]Ga and [177Lu]Lu-BL02.

Experimental Design: We performed a retrospective analysis of 146 patients with MCL to evaluate CXCR4 expression and its correlation with outcomes.

A Radiotracer for Molecular Imaging and Therapy of Gastrin-Releasing Peptide Receptor-Positive Prostate Cancer.

The gastrin-releasing peptide receptor (GRPR) is overexpressed in many solid malignancies, particularly in prostate and breast cancers, among others. We synthesized ProBOMB2, a novel bombesin derivative radiolabeled with Ga and Lu, and evaluated its ability to target GRPR in a preclinical model of human prostate cancer. ProBOMB2 was synthesized in solid phase using fluorenylmethoxycarbonyl chemistry.

High-Contrast CXCR4-Targeted F-PET Imaging Using a Potent and Selective Antagonist.

C-X-C chemokine receptor 4 (CXCR4) is highly expressed in cancers, contributing to proliferation, metastasis, and a poor prognosis. The noninvasive imaging of CXCR4 can enable the detection and characterization of aggressive cancers with poor outcomes. Currently, no F-labeled CXCR4 positron emission tomography (PET) radiotracer has demonstrated imaging contrast comparable to [Ga]Ga-Pentixafor, a CXCR4-targeting radioligand.

Lu-Labeled Albumin-Binder-Conjugated PSMA-Targeting Agents with Extremely High Tumor Uptake and Enhanced Tumor-to-Kidney Absorbed Dose Ratio.

The use of an albumin binder has been shown to improve tumor uptake of prostate-specific membrane antigen (PSMA)-targeting radiotherapeutic agents. The aim of this study was to develop improved radiotherapeutic agents that combine an optimized affinity-modifying group and optimized albumin binders to maximize the tumor-to-kidney absorbed dose ratio. Ga-labeled DOTA-conjugated lysine-ureido-glutamate-based PSMA-targeting agents bearing various affinity-modifying groups or albumin binders were synthesized and evaluated by PET/CT imaging and biodistribution studies in LNCaP tumor-bearing mice.

Evaluation of Met-Val-Lys as a Renal Brush Border Enzyme-Cleavable Linker to Reduce Kidney Uptake of Ga-Labeled DOTA-Conjugated Peptides and Peptidomimetics.

High kidney uptake is a common feature of peptide-based radiopharmaceuticals, leading to reduced detection sensitivity for lesions adjacent to kidneys and lower maximum tolerated therapeutic dose. In this study, we evaluated if the Met-Val-Lys (MVK) linker could be used to lower kidney uptake of Ga-labeled DOTA-conjugated peptides and peptidomimetics. A model compound, [Ga]Ga-DOTA-AmBz-MVK(Ac)-OH (AmBz: aminomethylbenzoyl), and its derivative, [Ga]Ga-DOTA-AmBz-MVK(HTK01166)-OH, coupled with the PSMA (prostate-specific membrane antigen)-targeting motif of the previously reported HTK01166 were synthesized and evaluated to determine if they could be recognized and cleaved by the renal brush border enzymes.

Selective Cyclized α-Melanocyte-Stimulating Hormone Derivative with Multiple -Methylations for Melanoma Imaging with Positron Emission Tomography.

In this study, we designed and evaluated a novel α-melanocyte-stimulating hormone derivative with four -methylations for melanocortin 1 receptor-targeted melanoma imaging with positron emission tomography (PET). The resulting peptide, DOTA-Pip-Nle-Cyclo[Asp--Me-His-d-Phe--Me-Arg--Me-Trp--Me-Lys]αMSH-NH (CCZ01099), showed high receptor selectivity, greatly improved stability, and rapid internalization. [Ga]Ga-CCZ01099 showed clear tumor visualization and excellent tumor-to-normal tissue contrast with PET imaging in a preclinical melanoma model.

Synthesis and Evaluation of [F]FEtLos and [F]AMBFLos as Novel F-Labelled Losartan Derivatives for Molecular Imaging of Angiotensin II Type 1 Receptors.

Losartan is widely used in clinics to treat cardiovascular related diseases by selectively blocking the angiotensin II type 1 receptors (ATRs), which regulate the renin-angiotensin system (RAS). Therefore, monitoring the physiological and pathological biodistribution of ATR using positron emission tomography (PET) might be a valuable tool to assess the functionality of RAS. Herein, we describe the synthesis and characterization of two novel losartan derivatives PET tracers, [F]fluoroethyl-losartan ([F]FEtLos) and [F]ammoniomethyltrifluoroborate-losartan ([F]AMBFLos).