When we critically assess the reason for the current dominance of 68 Ga-labeled peptides and peptide-like ligands in radiopharmacy and nuclear medicine, we have to conclude that the major advantage of such radiopharmaceuticals is the apparent lack of suitable 18 F-labeling technologies with proven clinical relevance. To prepare and to subsequently perform a clinical proof-of-concept study on the general suitability of silicon-fluoride-acceptor (SiFA)-conjugated radiopharmaceuticals, we developed inhibitors of the prostate-specific membrane antigen (PSMA) that are labeled by isotopic exchange (IE). To compensate for the pronounced lipophilicity of the SiFA unit, we used metal chelates, conjugated in close proximity to SiFA. Six different radiohybrid PSMA ligands (rhPSMA ligands) were evaluated and compared with the commonly used 18 F-PSMA inhibitors 18 F-DCFPyL and 18 F-PSMA-1007. Methods: All inhibitors were synthesized by solid-phase peptide synthesis. Human serum albumin binding was measured by affinity high-performance liquid chromatography, whereas the lipophilicity of each tracer was determined by the n-octanol/buffer method. In vitro studies (IC 50 , internalization) were performed on LNCaP cells. Biodistribution studies were conducted on LNCaP tumor-bearing male CB-17 SCID mice. Results: On the laboratory scale (starting activities, 0.2-9.0 GBq), labeling of 18 F-rhPSMA-5 to -10 by IE was completed in , 20 min (radiochemical yields, 58% ± 9%; radiochemical purity, .97%) with molar activities of 12-60 GBq/μmol. All rhPSMAs showed low nanomolar affinity and high internalization by PSMA-expressing cells when compared with the reference radiopharmaceuticals, medium-to-low lipophilicity, and high human serum albumin binding. Biodistribution studies in LNCaP tumorbearing mice revealed high tumor uptake, sufficiently fast clearance kinetics from blood, low hepatobiliary excretion, fast renal excretion, and very low uptake of 18 F activity in bone. Conclusion: The novel 18 F-rhPSMA radiopharmaceuticals developed under the radiohybrid concept show equal or better targeting characteristics than the established 18 F-PSMA tracers 18 F-DCFPyL and 18 F-PSMA-1007. The unparalleled simplicity of production, the possibility to produce the identical 68 Ga-labeled 19 F-68 Ga-rhPSMA tracers, and the possibility to extend this concept to true theranostic radiohybrid radiopharmaceuticals, such as F-Lu-rhPSMA, are unique features of these radiopharmaceuticals.

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Subcutaneous administration results in equivalent bortezomib plasma exposure to intravenous administration, together with comparable blood 20S proteasome inhibition pharmacodynamic effects. These findings, together with the non-inferior efficacy of subcutaneous versus intravenous bortezomib demonstrated in MMY-3021, support the use of bortezomib via the subcutaneous route across the settings of clinical use in which the safety and efficacy of intravenous bortezomib has been established.

Non-invasive PET imaging of CXCR4 expression in cancer and inflammation as well as CXCR4-targeted radioligand therapy (RLT) have recently found their way into clinical research by the development of the theranostic agents [ 68 Ga]PentixaFor (cyclo(D-Tyr 1 -D-[NMe]Orn 2 (AMBS-[ 68 Ga]DOTA)-Arg 3 -Nal 4 -Gly 5 ) = [ 68 Ga]DOTA-AMBS-CPCR4) and [ 177 Lu/ 90 Y]PentixaTher (cyclo(D-3-iodo-Tyr 1 -D-[NMe]Orn 2 (AMBS-[ 177 Lu/ 90 Y]DOTA)-Arg 3 -Nal 4 -Gly 5 ) = [ 177 Lu/ 90 Y]DOTA-AMBS- iodo CPCR4). Although convincing clinical results have already been obtained with both agents, this study was designed to further investigate the required structural elements for improved ligand-receptor interaction for both peptide cores (CPCR4 and iodo CPCR4). To this aim, a series of DOTA-conjugated CPCR4- and iodo CPCR4-based ligands with new linker structures, replacing the AMBA-linker in PentixaFor and PentixaTher, were synthesized and evaluated. Methods: The in vitro investigation of the novel compounds alongside with the reference peptides PentixaFor and PentixaTher encompassed the determination of hCXCR4 and mCXCR4 affinity (IC 50 ) of the respective nat Ga-, nat Lu-, nat Y- and nat Bi-complexes in Jurkat and Eμ-myc 1080 cells using [ 125 I]FC-131 and [ 125 I]CPCR4.3 as radioligands, respectively, as well as the evaluation of the internalization and externalization kinetics of selected 68 Ga- and 177 Lu-labeled compounds in hCXCR4-transfected Chem-1 cells. Comparative small animal PET imaging studies (1h p.i.) as well as in vivo biodistribution studies (1, 6 and 48h p.i.) were performed in Daudi (human B cell lymphoma) xenograft bearing CB17 SCID mice. Results: Based on the affinity data and cellular uptake studies, [ 68 Ga/ 177 Lu]DOTA-r-a-ABA-CPCR4 and [ 68 Ga/ 177 Lu]DOTA-r-a-ABA- iodo CPCR4 (with r-a-ABA = D-Arg-D-Ala-4-aminobenzoyl-) were selected for further evaluation. Both analogs show app. 10-fold enhanced hCXCR4 affinity compared to the respective references [ 68 Ga]PentixaFor and [ 177 Lu]PentixaTher, four times higher cellular uptake in hCXCR4 expressing cells and...