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The peptide is an important class of biological targeting molecule; herein, a new bifunctional octadentate non-macrocyclic H4octapa, tBu4octapa-alkyl-NHS, which is compatible with solid-phase peptide synthesis and thus useful for radiopeptide preparation, has been synthesized. To preserve denticity, the alkyl-N-hydroxylsuccinimide linker was covalently attached to the methylene–carbon on one of the acetate arms, yielding a chiral carbon center. According to density-functional theory (DFT) calculations using [Lu(octapa-alkyl-benzyl-ester)]− as a simulation model, the chirality has minimal effects on the complex geometry; regardless of the S-/R-stereochemistry, DFT calculations revealed two possible geometric isomers, distorted bicapped trigonal antiprism (DBTA) and distorted square antiprism (DSA), due to the asymmetry in the chelator. To evaluate the biological behavior of the new bifunctionalization, two well-studied PSMA (prostate-specific membrane antigen)-targeting peptidomimetics of varying hydrophobicity were chosen as proof-of-principle targeting vector molecules. Radiolabeling both bioconjugates with lutetium-177 was highly efficient at room temperature in 15 min at micromolar chelator concentration pH = 7. Both the in vitro serum challenge and the lanthanum(III) challenge studies revealed complex lability, and notably, progressive bone accumulation was only observed with the more hydrophobic linker (i.e. H4octapa-alkyl-PSMA617). This in vivo result informs potential alterations exerted by the linker on the complex geometry and stability, with an appropriate biological targeting vector adopted for such evaluations. [ABSTRACT FROM AUTHOR]

The gastrin‐releasing peptide receptor (GRPR) is overexpressed in prostate cancer and other solid malignancies. Following up on our work on [68Ga]Ga‐ProBOMB1 that had better imaging characteristics than [68Ga]Ga‐NeoBOMB1, we investigated the effects of substituting 68Ga for 177Lu to determine if the resulting radiopharmaceuticals could be used with a therapeutic aim. We radiolabeled the bombesin antagonist ProBOMB1 (DOTA‐pABzA‐DIG‐D‐Phe‐Gln‐Trp‐Ala‐Val‐Gly‐His‐Leu‐ψ‐Pro‐NH2) with lutetium‐177 and compared it with [177Lu]Lu‐NeoBOMB1 (obtained in 54.2 ± 16.5% isolated radiochemical yield with >96% radiochemical purity and 440.8 ± 165.1 GBq/μmol molar activity) for GRPR targeting. Lu‐NeoBOMB1 had better binding affinity for GRPR than Lu‐ProBOMB1 (Ki values: 2.26 ± 0.24 and 30.2 ± 3.23nM). [177Lu]Lu‐ProBOMB1 was obtained in 53.7 ± 5.4% decay‐corrected radiochemical yield with 444.2 ± 193.2 GBq/μmol molar activity and >95% radiochemical purity. In PC‐3 prostate cancer xenograft mice, tumor uptake of [177Lu]Lu‐ProBOMB1 was 3.38 ± 1.00, 1.32 ± 0.24, and 0.31 ± 0.04%ID/g at 1, 4, and 24 hours pi. However, the uptake in tumor was lower than [177Lu]Lu‐NeoBOMB1 at all time points. [177Lu]Lu‐ProBOMB1 was inferior to [177Lu]Lu‐NeoBOMB1, which had better therapeutic index for the organs receiving the highest doses. [ABSTRACT FROM AUTHOR]

Abstract: 2‐Nitroimidazole‐based hypoxia imaging tracers such as 18F‐FMISO are normally imaged at late time points (several hours post‐injection) due to their slow clearance from background tissues. Here, we investigated if a hydrophilic zwitterion‐based ammoniomethyl‐trifluoroborate derivative of 2‐nitroimidazole, 18F‐AmBF3‐Bu‐2NI, could have the potential to image tumor hypoxia at earlier time points. AmBF3‐Bu‐2NI was prepared in 4 steps. 18F labeling was conducted via 18F‐19F isotope exchange reaction, and 18F‐AmBF3‐Bu‐2NI was obtained in 14.8 ± 0.4% (n = 3) decay‐corrected radiochemical yield with 24.5 ± 5.2 GBq/μmol specific activity and >99% radiochemical purity. Imaging and biodistribution studies in HT‐29 tumor‐bearing mice showed that 18F‐AmBF3‐Bu‐2NI cleared quickly from blood and was excreted via the hepatobiliary and renal pathways. However, the tumor was not visualized in PET images until 3 hours post‐injection due to low tumor uptake (0.54 ± 0.13 and 0.19 ± 0.04%ID/g at 1 and 3 hours post‐injection, respectively). The low tumor uptake is likely due to the highly hydrophilic motif of ammoniomethyl‐trifluoroborate that prevents free diffusion of 18F‐AmBF3‐Bu‐2NI across the cell membrane. Our results suggest that highly hydrophilic 18F‐labeled ammoniomethyl‐trifluoroborate derivatives might not be suitable for imaging intracellular targets including nitroreductase, a common tumor hypoxia imaging target. [ABSTRACT FROM AUTHOR]

The gastrin-releasing peptide receptor (GRPR) is overexpressed in a variety of cancers and represents a promising target for diagnosis and therapy. However, the extremely high accumulation in the pancreas observed for most of the clinically evaluated GRPR-targeted radiopharmaceuticals could limit their applications. In this study, we synthesized one GRPR antagonist (ProBOMB5) and two GRPR agonists (LW02056 and LW02057) by replacing the 4-thiazolidinecarboxylic acid (Thz 14 ) residue in our previously reported GRPR-targeted tracers with Pro 14 . The 68 Ga and 177 Lu labeling were conducted in HEPES (2 M, pH 5.0) buffer and acetate (0.1 M, pH 4.5) buffer, respectively, and the radiolabeled products were obtained in a 24-57% decay-corrected radiochemical yield and >92% radiochemical purity. The binding affinities ( K i ) of Ga-ProBOMB5, Ga-LW02056, Ga-LW02057, and Lu-ProBOMB5 were measured via in vitro competition binding assays and were 12.2 ± 1.89, 14.7 ± 4.81, 13.8 ± 2.24, and 13.6 ± 0.25 nM, respectively. The PET imaging and ex vivo biodistribution studies were conducted in PC-3 tumor-bearing mice at 1 h post injection. [ 68 Ga]Ga-ProBOMB5, [ 68 Ga]Ga-LW02056, and [ 68 Ga]Ga-LW02057 enabled clear tumor visualization in PET images. The tumor uptake values of [ 68 Ga]Ga-ProBOMB5, [ 68 Ga]Ga-LW02056, and [ 68 Ga]Ga-LW02057 were 12.4 ± 1.35, 8.93 ± 1.96, and 7.64 ± 0.55%ID/g, respectively, and their average pancreas uptake values were minimal (0.60-1.37%ID/g). Longitudinal SPECT imaging and ex vivo biodistribution studies were also conducted for [ 177 Lu]Lu-ProBOMB5 and clinically validated [ 177 Lu]Lu-RM2. Despite comparable tumor uptake at 1 h post injection ([ 177 Lu]Lu-ProBOMB5:8.09 ± 1.70%ID/g; [ 177 Lu]Lu-RM2:7.73 ± 0.96%ID/g), a faster clearance from PC-3 tumor xenografts was observed for [ 177 Lu]Lu-ProBOMB5, leading to a lower radiation-absorbed dose delivered to tumors. Our data demonstrate that [ 68 Ga]Ga-ProBOMB5 is a promising tracer for clinical translation for detecting GRPR-expressing tumor lesions. However, further optimizations are needed for [ 177 Lu]Lu-ProBOMB5 to prolong tumor retention for therapeutic applications.

Gastrin-releasing peptide receptor (GRPR), overexpressed in many solid tumors, is a promising imaging marker and therapeutic target. Most reported GRPR-targeted radioligands contain a C -terminal amide. Based on the reported potent antagonist D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-NHOH, we synthesized C -terminal hydroxamate-derived [ 68 Ga]Ga-LW02075 ([ 68 Ga]Ga-DOTA-pABzA-DIG-D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-NHOH) and [ 68 Ga]Ga-LW02050 ([ 68 Ga]Ga-DOTA-Pip-D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-NHOH), and compared them with the closely related and clinically validated [ 68 Ga]Ga-SB3 ([ 68 Ga]Ga-DOTA-pABzA-DIG-D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-NHEt). Binding affinities (K i ) of Ga-SB3, Ga-LW02075, and Ga-LW02050 were 1.20 ± 0.31, 1.39 ± 0.54, and 8.53 ± 1.52 nM, respectively. Both Ga-LW02075 and Ga-LW02050 were confirmed to be GRPR antagonists by calcium release assay. Imaging studies showed that PC-3 prostate cancer tumor xenografts were clearly visualized at 1 h post injection by [ 68 Ga]Ga-SB3 and [ 68 Ga]Ga-LW02050 in PET images, but not by [ 68 Ga]Ga-LW02075. Ex vivo biodistribution studies conducted at 1 h post injection showed that the tumor uptake of [ 68 Ga]Ga-LW02050 was comparable to that of [ 68 Ga]Ga-SB3 (5.38 ± 1.00 vs. 6.98 ± 1.36 %ID/g), followed by [ 68 Ga]Ga-LW02075 (3.97 ± 1.71 %ID/g). [ 68 Ga]Ga-SB3 had the highest pancreas uptake (37.3 ± 6.90 %ID/g) followed by [ 68 Ga]Ga-LW02075 (17.8 ± 5.24 %ID/g), while the pancreas uptake of [ 68 Ga]Ga-LW02050 was only 0.53 ± 0.11 %ID/g. Our data suggest that [ 68 Ga]Ga-LW02050 is a promising PET tracer for detecting GRPR-expressing cancer lesions.

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 68 Ga and 177 Lu, and evaluated its ability to target GRPR in a preclinical model of human prostate cancer. Methods: ProBOMB2 was synthesized in solid phase using fluorenylmethoxycarbonyl chemistry. The chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid was coupled to the N terminus and separated from the GRPR-targeting sequence by a cationic 4-amino-(1-carboxymethyl)-piperidine spacer. Binding affinity for both human and murine GRPR was determined using a cell-based competition assay, whereas a calcium efflux assay was used to measure the agonist and antagonist properties of the derivatives. ProBOMB2 was radiolabeled with 177 Lu and 68 Ga. SPECT and PET imaging and biodistribution studies were conducted using male immunocompromised mice bearing GRPR-positive PC-3 human prostate cancer xenografts. Results: Ga-ProBOMB2 and Lu-ProBOMB2 bound to PC-3 cells with an inhibition constant of 4.58 ± 0.67 and 7.29 ± 1.73 nM, respectively. 68 Ga-ProBOMB2 and 177 Lu-ProBOMB2 were radiolabeled with a radiochemical purity greater than 95%. Both radiotracers were excreted primarily via the renal pathway. PET images of PC-3 tumor xenografts were visualized with excellent contrast at 1 and 2 h after injection with 68 Ga-ProBOMB2, and there was very low off-target organ accumulation. 177 Lu-ProBOMB2 enabled clear visualization of PC-3 tumor xenografts by SPECT imaging at 1, 4, and 24 h after injection 177 Lu-ProBOMB2 displayed higher tumor uptake than 68 Ga-ProBOMB2 at 1 h after injection. 177 Lu-ProBOMB2 tumor uptake at 1, 4, and 24 h after injection was 14.9 ± 3.1, 4.8 ± 2.1, and 1.7 ± 0.3 percentage injected dose per gram of tissue, respectively. Conclusion: 68 Ga-ProBOMB2 and 177 Lu-ProBOMB2 are promising radiotracers with limited pancreas uptake, good tumor uptake, and favorable pharmacokinetics for imaging and therapy of GRPR-expressing tumors., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

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. Methods: 68 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. The optimized affinity-modifying group and albumin binders were combined, and the resulting derivatives were radiolabeled with 177 Lu and evaluated by SPECT/CT imaging and biodistribution studies in LNCaP tumor-bearing mice. Radiation dosimetry was calculated using the OLINDA/EXM software. Results: Affinity-modifying group optimization revealed that 68 Ga-HTK03041 bearing a tranexamic acid-9-anthrylalanine affinity-modifying group had the highest tumor uptake (23.1 ± 6.11 percentage injected dose [%ID]/g at 1 h after injection). Albumin binder optimization showed that 68 Ga-HTK03055 and 68 Ga-HTK03086 bearing the N -(4-( p -chlorophenyl)butanoyl)-Gly and N -(4-( p -methoxyphenyl)butanoyl)-Gly motifs, respectively, had relatively faster tumor accumulation (∼30 %ID/g at 3 h after injection) and lower average kidney uptake (<55 %ID/g at both 1 and 3 h after injection). Combining the tranexamic acid-9-anthrylalanine affinity-modifying group with N -(4-( p -chlorophenyl)butanoyl)-Gly and N -(4-( p -methoxyphenyl)butanoyl)-Gly albumin-binding motifs generated HTK03121 and HTK03123, respectively. 177 Lu-HTK03121 and 177 Lu-HTK03123 had extremely high peak uptake (104 ± 20.3 and 70.8 ± 23.7 %ID/g, respectively) in LNCaP tumor xenografts, and this peak was sustained up to 120 h after injection. Dosimetry calculation showed that compared with 177 Lu-PSMA-617, 177 Lu-HTK03121 and 177 Lu-HTK03123 delivered 18.7- and 12.7-fold higher absorbed dose to tumor but only 6.4- and 6.3-fold higher absorbed dose to kidneys, leading to 2.9- and 2.0-fold improvement in the tumor-to-kidney absorbed dose ratios. Conclusion: With greatly enhanced tumor uptake and tumor-to-kidney absorbed dose ratio, 177 Lu-HTK03121 and 177 Lu-HTK03123 have the potential to improve treatment efficacy using significantly lower quantities of 177 Lu and are promising candidates for clinical translation to treat metastatic castration-resistant prostate cancer., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

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 68 Ga-labeled DOTA-conjugated peptides and peptidomimetics. A model compound, [ 68 Ga]Ga-DOTA-AmBz-MVK(Ac)-OH (AmBz: aminomethylbenzoyl), and its derivative, [ 68 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. Additionally, positron emission tomography (PET) imaging, ex vivo biodistribution and in vivo stability studies were conducted in mice to evaluate their pharmacokinetics. [ 68 Ga]Ga-DOTA-AmBz-MVK(Ac)-OH was effectively cleaved specifically by neutral endopeptidase (NEP) of renal brush border enzymes at the Met-Val amide bond, and the radio-metabolite [ 68 Ga]Ga-DOTA-AmBz-Met-OH was rapidly excreted via the renal pathway with minimal kidney retention. [ 68 Ga]Ga-DOTA-AmBz-MVK(HTK01166)-OH retained its PSMA-targeting capability and was also cleaved by NEP, although less effectively when compared to [ 68 Ga]Ga-DOTA-AmBz-MVK(Ac)-OH. The kidney uptake of [ 68 Ga]Ga-DOTA-AmBz-MVK(HTK01166)-OH was 30% less compared to that of [ 68 Ga]Ga-HTK01166. Our data demonstrated that derivatives of [ 68 Ga]Ga-DOTA-AmBz-MVK-OH can be cleaved specifically by NEP, and therefore, MVK can be a promising cleavable linker for use to reduce kidney uptake of radiolabeled DOTA-conjugated peptides and peptidomimetics.

The peptide is an important class of biological targeting molecule; herein, a new bifunctional octadentate non-macrocyclic H4octapa, tBu4octapa-alkyl-NHS, which is compatible with solid-phase peptide synthesis and thus useful for radiopeptide preparation, has been synthesized. To preserve denticity, the alkyl-N-hydroxylsuccinimide linker was covalently attached to the methylene-carbon on one of the acetate arms, yielding a chiral carbon center. According to density-functional theory (DFT) calculations using [Lu(octapa-alkyl-benzyl-ester)]- as a simulation model, the chirality has minimal effects on the complex geometry; regardless of the S-/R-stereochemistry, DFT calculations revealed two possible geometric isomers, distorted bicapped trigonal antiprism (DBTA) and distorted square antiprism (DSA), due to the asymmetry in the chelator. To evaluate the biological behavior of the new bifunctionalization, two well-studied PSMA (prostate-specific membrane antigen)-targeting peptidomimetics of varying hydrophobicity were chosen as proof-of-principle targeting vector molecules. Radiolabeling both bioconjugates with lutetium-177 was highly efficient at room temperature in 15 min at micromolar chelator concentration pH = 7. Both the in vitro serum challenge and the lanthanum(iii) challenge studies revealed complex lability, and notably, progressive bone accumulation was only observed with the more hydrophobic linker (i.e. H4octapa-alkyl-PSMA617). This in vivo result informs potential alterations exerted by the linker on the complex geometry and stability, with an appropriate biological targeting vector adopted for such evaluations.

We report a single-molecule radiotracer that can be labeled independently with 18 F-fluoride or radiometals ( 64 Cu, 177 Lu) in a single step. A prostate-specific membrane antigen (PSMA)-targeting ligand, armed with both an organotrifluoroborate and a metal-chelator (DOTA), was designed to optionally afford 18 F-, 64 Cu- or 177 Lu-labeled products that were injected into mice bearing prostate cancer (LNCaP) xenografts. PET/CT images and ex vivo biodistribution data show high, specific tumor uptake irrespective of which radionuclide is used, thereby demonstrating a new approach to combining, in a single molecule, 18 F-labeling capabilities for PET imaging with radiometalation for potential imaging and therapeutic applications., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

44 Sc is an attractive positron-emitting radionuclide for PET imaging; herein, a new complex of the Sc 3+ ion with nonmacrocyclic chelator H 4 pypa was synthesized and characterized with high-resolution electrospray-ionization mass spectrometry (HR-ESI-MS), as well as different nuclear magnetic resonance (NMR) spectroscopic techniques ( 1 H, 13 C, 1 H- 13 C HSQC, 1 H- 13 C HMBC, COSY, and NOESY). In aqueous solution (pH = 7), [Sc(pypa)] - presented two isomeric forms, the structures of which were predicted using density functional theory (DFT) calculation with a small energy difference of 22.4 kJ/mol, explaining their coexistence. [Sc(pypa)] - was found to have superior thermodynamic stability (pM = 27.1) compared to [Sc(AAZTA)] - (24.7) and [Sc(DOTA)] - (23.9). In radiolabeling, [ 44 Sc][Sc(pypa)] - formed efficiently at RT in 15 min over a range of pH (2-5.5), resulting in a complex that is highly stable (>99%) in mouse serum over at least six half-lives of scandium-44. Similar labeling efficiency was observed with the PSMA (prostate-specific membrane antigen)-targeting H 4 pypa-C7-PSMA617 at pH = 5.5 (RT, 15 min), confirming negligible disturbance from the bifunctionalization on scandium-44 scavenging. Moreover, the kinetic inertness of the radiocomplex was proved in vivo. Surprisingly, the molar activity was found to have profound influence on the pharmacokinetics of the radiotracers where lower molar activity drastically reduced the background accumulations, particularly, kidney, and thus, yielded a much higher tumor-to-background contrast.

The gastrin-releasing peptide receptor (GRPR) is overexpressed in prostate cancer and other solid malignancies. Following up on our work on [ 68 Ga]Ga-ProBOMB1 that had better imaging characteristics than [ 68 Ga]Ga-NeoBOMB1, we investigated the effects of substituting 68 Ga for 177 Lu to determine if the resulting radiopharmaceuticals could be used with a therapeutic aim. We radiolabeled the bombesin antagonist ProBOMB1 (DOTA-pABzA-DIG-D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-ψ-Pro-NH 2 ) with lutetium-177 and compared it with [ 177 Lu]Lu-NeoBOMB1 (obtained in 54.2 ± 16.5% isolated radiochemical yield with >96% radiochemical purity and 440.8 ± 165.1 GBq/μmol molar activity) for GRPR targeting. Lu-NeoBOMB1 had better binding affinity for GRPR than Lu-ProBOMB1 (K i values: 2.26 ± 0.24 and 30.2 ± 3.23nM). [ 177 Lu]Lu-ProBOMB1 was obtained in 53.7 ± 5.4% decay-corrected radiochemical yield with 444.2 ± 193.2 GBq/μmol molar activity and >95% radiochemical purity. In PC-3 prostate cancer xenograft mice, tumor uptake of [ 177 Lu]Lu-ProBOMB1 was 3.38 ± 1.00, 1.32 ± 0.24, and 0.31 ± 0.04%ID/g at 1, 4, and 24 hours pi. However, the uptake in tumor was lower than [ 177 Lu]Lu-NeoBOMB1 at all time points. [ 177 Lu]Lu-ProBOMB1 was inferior to [ 177 Lu]Lu-NeoBOMB1, which had better therapeutic index for the organs receiving the highest doses., (© 2019 John Wiley & Sons, Ltd.)

C-X-C chemokine receptor type 4 (CXCR4) is overexpressed in hematological and solid malignancies. LY2510924 is a potent peptide antagonist of CXCR4. A derivative of LY2510924, BL01, was evaluated for theranostic applications targeting CXCR4. Methods: BL01 was synthesized by solid phase approach. A Lys(ivDde) residue was added at the C-terminus of LY2510924 (cyclo[Phe-Tyr-Lys(iPr)-d-Arg-2-Nal-Gly-d-Glu]-Lys(iPr)-NH 2 ). A DOTA chelator was conjugated to the side chain of the deprotected exogenous Lys residue. The binding affinity of Ga/Lu-BL01 was determined by competitive radioligand binding assays. BL01 was radiolabeled with 68 GaCl 3 or 177 LuCl 3 . Biodistribution studies were performed in mice bearing Daudi Burkitt's lymphoma tumor xenografts at selected time points. PET imaging studies were performed with [ 68 Ga]Ga-BL01, with blocking experiments performed with preinjection of LY2510924. The stability of [ 68 Ga]Ga/[ 177 Lu]Lu-BL01 was assessed in mouse plasma. Results: Ga-BL01 and Lu-BL01 have nanomolar affinity for CXCR4. [ 68 Ga]Ga-BL01 was obtained in 58 ± 5% decay-corrected radiochemical yields and >99% radiochemical purity with a molar activity of 40 ± 11 GBq/μmol, while [ 177 Lu]Lu-BL01 was obtained in 65 ± 6% decay-corrected radiochemical yields and >99% radiochemical purity with a molar activity of 120 ± 21 GBq/μmol. [ 68 Ga]Ga-BL01 and [ 177 Lu]Lu-BL01 were excreted primarily through the renal pathway. Daudi xenografts were clearly delineated in PET images with good contrast. On the basis of biodistribution data, tumor uptake of [ 68 Ga]Ga-BL01 was 10.2 ± 2.56% injected dose per gram (%ID/g) at 1 h postinjection (p.i.). Spleen (12.6 ± 2.36 %ID/g) and lungs (13.2 ± 2.98 %ID/g), organs that express CXCR4, had high uptake as well. Preinjection of LY2510924 reduced average uptake of [ 68 Ga]Ga-BL01 in tumors by 88%, demonstrating target specificity. The uptake of [ 68 Ga]Ga-BL01 in tumor increased to 15.3 ± 1.86 %ID/g at 2 h p.i., with improved contrast. [ 177 Lu]Lu-BL01 has similar pharmacokinetics as [ 68 Ga]Ga-BL01 at 1 h p.i. The highest uptake was observed in tumor (14.0 ± 1.11 %ID/g), followed by the lungs (13.0 ± 1.27 %ID/g) and spleen (11.6 ± 1.78 %ID/g). The tumor uptake increased to 16.2 ± 2.69 %ID/g at 4 h p.i., before declining slightly to 10.1 ± 1.41 %ID/g at 24 h p.i. Both compounds were stable in vivo, as no metabolites were observed at 5 min p.i. Conclusions: [ 68 Ga]Ga-BL01 and [ 177 Lu]Lu-BL01 are a promising theranostic pair for imaging and endoradiotherapy of CXCR4-expressing malignancies.

After the identification of the high-affinity glutamate-ureido scaffold, the design of several potent 18 F- and 68 Ga-labeled tracers has allowed spectacular progress in imaging recurrent prostate cancer by targeting the prostate-specific membrane antigen (PSMA). We evaluated a series of PSMA-targeting probes that are 18 F-labeled in a single step for PET imaging of prostate cancer. Methods: We prepared 8 trifluoroborate constructs for prostate cancer imaging, to study the influence of the linker and the trifluoroborate prosthetic on pharmacokinetics and image quality. After 1-step labeling by 19 F- 18 F isotopic exchange, the radiotracers were injected in mice bearing LNCaP xenografts, with or without blocking controls, to assess specific uptake. PET/CT images and biodistribution data were acquired at 1 h after injection and compared with 18 F-DCFPyL on the same mouse strain and tumor model. Results: All tracers exhibited nanomolar affinities, were labeled in good radiochemical yields at high molar activities, and exhibited high tumor uptake in LNCaP xenografts with clearance from nontarget organs. Most derivatives with a naphthylalanine linker showed significant gastrointestinal excretion. A radiotracer incorporating this linker with a dual trifluoroborate-glutamate labeling moiety showed high tumor uptake, low background activity, and no liver or gastrointestinal track accumulation. Conclusion: PSMA-targeting probes with trifluoroborate prosthetic groups represent promising candidates for prostate cancer imaging because of facile labeling while affording high tumor uptake values and contrast ratios that are similar to those obtained with 18 F-DCFPyL., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

Here, we present the synthesis and characterization of a new potentially nonadentate chelator H 4 pypa and its bifunctional analogue t Bu 4 pypa-C7-NHS conjugated to prostate-specific membrane antigen (PSMA)-targeting peptidomimetic (Glu-urea-Lys). H 4 pypa is very functionally versatile and biologically stable. Compared to the conventional chelators (e.g., DOTA, DTPA), H 4 pypa has outstanding affinities for both 111 In (EC, t 1/2 ≈ 2.8 days) and 177 Lu (β - ,γ, t 1/2 ≈ 6.64 days). Its radiolabeled complexes were achieved at >98% radiochemical yield, RT within 10 min, at a ligand concentration as low as 10 -6 M, with excellent stability in human serum over at least 5-7 days (<1% transchelation). The thermodynamic stabilities of the [M(pypa)] - complexes (M 3+ = In 3+ , Lu 3+ , La 3+ ) were dependent on the ionic radii, where the smaller In 3+ has the highest pM value (30.5), followed by Lu 3+ (22.6) and La 3+ (19.9). All pM values are remarkably higher than those with DOTA, DTPA, H 4 octapa, H 4 octox, and H 4 neunpa. Moreover, the facile and versatile bifunctionalization enabled by the p-OH group in the central pyridyl bridge of the pypa scaffold (compound 14) allows incorporation of a variety of linkers for bioconjugation through easy nucleophilic substitution. In this work, an alkyl linker was selected to couple H 4 pypa to a PSMA-targeting pharmacophore, proving that the bioconjugation sacrifices neither the tumor-targeting nor the chelation properties. The biodistribution profiles of 111 In- and 177 Lu-labeled tracers are different, but promising, with the 177 Lu analogue particularly outstanding.

We evaluated the ability of monosodium glutamate (MSG) to reduce salivary and kidney uptake of a prostate-specific membrane antigen (PSMA) radioligand without affecting tumor uptake. Methods: LNCaP tumor-bearing mice were intraperitoneally injected with MSG (657, 329, or 164 mg/kg) or phosphate-buffered saline (PBS). Fifteen minutes later, the mice were intravenously administered 68 Ga-PSMA-11. PET/CT imaging and biodistribution studies were performed 1 h after administration. Results: Tumor uptake (percentage injected dose per gram [%ID]) was not statistically different between groups, at 8.42 ± 1.40 %ID in the 657 mg/kg group, 7.19 ± 0.86 %ID in the 329 mg/kg group, 8.20 ± 2.44 %ID in the 164 mg/kg group, and 8.67 ± 1.97 %ID in the PBS group. Kidney uptake was significantly lower in the 657 mg/kg group (85.8 ± 24.2 %ID) than in the 329 mg/kg (159 ± 26.2 %ID), 164 mg/kg (211 ± 27.4 %ID), and PBS groups (182 ± 33.5 %ID) ( P < 0.001). Salivary gland uptake was lower in the 657 mg/kg (3.72 ± 2.12 %ID) and 329 mg/kg (5.74 ± 0.62 %ID) groups than in the PBS group (10.04 ± 2.52 %ID) ( P < 0.01). Conclusion: MSG decreased salivary and kidney uptake of 68 Ga-PSMA-11 in a dose-dependent manner, whereas tumor uptake was unaffected., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.)

We designed and evaluated a novel albumin-binder-conjugated 177 Lu-PSMA-617 derivative, 177 Lu-HTK01169, with an extended blood retention time to maximize the radiation dose delivered to prostate tumors expressing prostate-specific membrane antigen (PSMA). PSMA-617 and HTK01169 that contained N-[4-( p-iodophenyl)butanoyl]-Glu as an albumin-binding motif were synthesized using the solid-phase approach. Binding affinity to PSMA was determined by in vitro competition-binding assay. 177 Lu labeling was performed in acetate buffer (pH 4.5) at 90 °C for 15 min. SPECT/CT imaging, biodistribution, and endoradiotherapy studies were conducted in mice bearing PSMA-expressing LNCaP tumor xenografts. Radiation dosimetry was calculated using OLINDA software. Lu-PSMA-617 and Lu-HTK01169-bound PSMA with high affinity ( K i values = 0.24 and 0.04 nM, respectively). SPECT imaging and biodistribution studies showed that 177 Lu-PSMA-617 and 177 Lu-HTK01169 were excreted mainly via the renal pathway. With fast blood clearance (0.68%ID/g at 1 h postinjection), the tumor uptake of 177 Lu-PSMA-617 peaked at 1 h postinjection (15.1%ID/g) and gradually decreased to 7.91%ID/g at 120 h postinjection. With extended blood retention (16.6 and 2.10%ID/g at 1 and 24 h, respectively), the tumor uptake of 177 Lu-HTK01169 peaked at 24 h postinjection (55.9%ID/g) and remained at the same level by the end of the study (120 h). Based on dosimetry calculations, 177 Lu-HTK01169 delivered an 8.3-fold higher radiation dose than 177 Lu-PSMA-617 to LNCaP tumor xenografts. For the endoradiotherapy study, the mice treated with 177 Lu-PSMA-617 (18.5 MBq) all reached humane end point (tumor volume >1000 mm 3 ) by Day 73 with a median survival of 58 days. Mice treated with 18.5, 9.3, 4.6, or 2.3 MBq of 177 Lu-HTK01169 had a median survival of >120, 103, 61, and 28 days, respectively. With greatly enhanced tumor uptake and treatment efficacy compared to 177 Lu-PSMA-617 in preclinical studies, 177 Lu-HTK01169 warrants further investigation for endoradiotherapy of prostate cancer.

68 Ga-PSMA-11 is currently the most popular prostate-specific membrane antigen (PSMA) radioligand used in the clinic to detect prostate cancer and metastases. However, the high uptake of 68 Ga-PSMA-11 in kidneys can create halo-artifacts resulting in lower detection sensitivity for lesions adjacent to the kidneys. In this study, we developed two 68 Ga-labeled PSMA-targeted tracers, 68 Ga-HTK01166 and 68 Ga-HTK01167, based on 68 Ga-PSMA-617 with the goal of improving tumor-to-kidney ratio compared to 68 Ga-PSMA-11. The 2-naphthylalanine (2-Nal) in PSMA-617 was replaced with 2-indanylglycine (Igl) or 3,3-diphenylalanine (Dip) to synthesize HTK01166 and HTK01167, respectively. Binding affinities ( K i ) of Ga-PSMA-11, Ga-PSMA-617, Ga-HTK01166, and Ga-HTK01167 to PSMA were 3.13 ± 0.40, 1.23 ± 0.08, 5.74 ± 2.48, and 25.7 ± 9.84 nM, respectively, as determined by in vitro competition binding assays. 68 Ga labeling was performed in HEPES buffer with microwave heating, and 68 Ga-labeled PSMA-11, PSMA-617, HTK01166, and HTK01167 were obtained in 46-69% average decay-corrected radiochemical yield with >99% radiochemical purity and 62.9-152 GBq/μmol average specific activity. PET imaging and biodistribution studies were performed in mice bearing PSMA-expressing LNCap prostate cancer xenografts. All tracers enabled clear visualization of tumors in PET images with excellent tumor-to-background contrast. The uptake values (%ID/g) for tumor and kidneys at 1 h postinjection were 8.91 ± 0.86 and 204 ± 70.6 for 68 Ga-PSMA-11, 16.7 ± 2.30 and 29.2 ± 5.14 for 68 Ga-PSMA-617, 14.1 ± 4.40 and 147 ± 59.6 for 68 Ga-HTK01166, and 7.79 ± 1.65 and 4.30 ± 1.80 for 68 Ga-HTK01167. The tumor-to-kidney ratios for 68 Ga-labeled PSMA-11, PSMA-617, HTK01166, and HTK01167 were 0.05 ± 0.02, 0.63 ± 0.10, 0.10 ± 0.02, and 1.98 ± 0.63, respectively. Compared with 68 Ga-PSMA-617, 68 Ga-HTK01166 showed comparable tumor uptake and almost 5-fold higher kidney uptake, whereas 68 Ga-HTK01167 exhibited lower tumor and kidney uptake. Compared with 68 Ga-PSMA-11, 68 Ga-HTK01167 had similar tumor uptake and tumor-to-blood contrast ratio (23.8 ± 6.71 vs 20.4 ± 4.98) but higher tumor-to-background contrast ratios for other background organs especially for kidneys. Our data indicate that substitution of 2-Nal in PSMA-617 with other lipophilic amino acid can modulate PSMA binding affinity and their pharmacokinetics in vivo.

Bioassay-guided fractionation of the methanolic extract of the stem of Pisonia umbellifera (Nyctaginaceae) afforded the three new compounds, secopisonic acid (1), 6,8-dimethylisogenistein (2), and (+)- ENT-ficusol (3), and four first isolates from nature, pisoninol I (4), pisoninol II (5), pisoquinoline (6), and pisodienone (7), together with fifteen known compounds. Their structures were elucidated by analysis of spectroscopic data. Seven of these isolates, 3, 7, 12, 16, 18, 20, and 21 showed antitubercular activities against Mycobacterium tuberculosis H37R (V) in vitro, with MIC values ≤ 50 µg/mL., (© Georg Thieme Verlag KG Stuttgart · New York.)