[99mTc]Tc-PentixaTec: development, extensive pre-clinical evaluation, and first human experience

Purpose The clinical success non-invasive imaging of CXCR4 expression using [(68) Ga]Ga-PentixaFor-PET warrants an expansion of the targeting concept towards conventional scintigraphy/SPECT with their lower cost and general availability. To this aim, we developed and comparatively evaluated a series of Tc-99m-labeled cyclic pentapeptides based on the PentixaFor scaffold.Methods Six mas(3)-conjugated CPCR4 analogs with different 4-aminobenzoic acid (Abz)-D-Ala-D-Arg-aa(3) linkers (L1-L6) as well as the corresponding HYNIC- and N-4-analogs of L6-CPCR4 were synthesized via standard SPPS. Competitive binding studies (IC50 and IC(50)inv) were carried out using Jurkat T cell lymphoma cells and [I-125]FC-131 as radioligand. Internalization kinetics were investigated using hCXCR4-overexpressing Chem-1 cells. Biodistribution studies and small animal SPECT/CT imaging (1 h p.i.) were carried out using Jurkat xenograft bearing CB17/SCID mice. Based on the preclinical results, [Tc-99m]Tc-N-4-L6-CPCR4 ([Tc-99m]Tc-PentixaTec) was selected for an early translation to the human setting. Five patients with hematologic malignancies underwent [Tc-99m]Tc-N-4-L6-CPCR4 SPECT/planar imaging with individual dosimetry.Results Of the six mas(3)-conjugated peptides, mas(3)-L6-CPCR4 (mas(3)-dap-r-a-Abz-CPCR4) showed the highest CXCR4 affinity (IC50 = 5.0 & PLUSMN; 1.3 nM). Conjugation with N-4 (N-4-L6-CPCR4) further improved hCXCR4 affinity to 0.6 & PLUSMN; 0.1 nM. [Tc-99m]Tc-N-4-L6-CPCR4 also showed the most efficient internalization (97% of total cellular activity at 2 h) and the highest tumor accumulation (8.6 & PLUSMN; 1.3% iD/g, 1 h p.i.) of the compounds investigated. Therefore, [Tc-99m]Tc-N-4-L6-CPCR4 (termed [Tc-99m]Tc-PentixaTec) was selected for first-in-human application. [Tc-99m]Tc-PentixaTec was well tolerated, exhibits a favorable biodistribution and dosimetry profile (2.1-3.4 mSv per 500 MBq) and excellent tumor/background ratios in SPECT and planar imaging.Conclusion The successive optimization of the amino acid composition of the linker structure and the N-terminal Tc-99m-labeling strategies (mas(3) vs HYNIC vs N-4) has provided [Tc-99m]Tc-PentixaTec as a novel, highly promising CXCR4-targeted SPECT agent for clinical application. With its excellent CXCR4 affinity, efficient internalization, high uptake in CXCR4-expressing tissues, suitable clearance/biodistribution characteristics, and favorable human dosimetry, it holds great potential for further clinical use

Towards personalized treatment of prostate cancer: PSMA I&T, a promising prostate-specific membrane antigen-targeted theranostic agent

Prostate-specific membrane antigen (PSMA) is a well-established target for nuclear imaging and therapy of prostate cancer (PCa). Radiolabeled small-molecule PSMA inhibitors are excellent candidates for PCa theranostics-they rapidly and efficiently localize in tumor lesions. However, high tracer uptake in kidneys and salivary glands are major concerns for therapeutic applications. Here, we present the preclinical application of PSMA I&T, a DOTAGA-chelated urea-based PSMA inhibitor, for SPECT/CT imaging and radionuclide therapy of PCa. 111In-PSMA I&T showed dose-dependent uptake in PSMA-expressing tumors, kidneys, spleen, adrenals, lungs and salivary glands. Coadministration of 2-(phosphonomethyl)pentane-1,5-dioic acid (2-PMPA) efficiently reduced PSMA-mediated renal uptake of 111In-PSMA I&T, with the highest tumor/kidney radioactivity ratios being obtained using a dose of 50 nmol 2-PMPA. SPECT/CT clearly visualized subcutaneous tumors and sub-millimeter intraperitoneal metastases; however, high renal and spleen uptake in control mice (no 2-PMPA) interfered with visualization of metastases in the vicinity of those organs. Coadministration of 2-PMPA increased the tumor-to-kidney absorbed dose ratio during 177Lu-PSMA I&T radionuclide therapy. Hence, at equivalent absorbed dose to the tumor (36 Gy), coinjection of 2-PMPA decreased absorbed dose to the kidneys from 30 Gy to 12 Gy. Mice injected with 177Lu-PSMA I&T only, showed signs of nephrotoxicity at 3 months after therapy, whereas mice injected with 177Lu-PSMA I&T + 2-PMPA did not. These data indicate that PSMA I&T is a promising theranostic tool for PCa. PSMA-specific uptake in kidneys can be successfully tackled using blocking agents such as 2-PMPA

From Theranostics to Immunotheranostics: the Concept

Immunotheranostics will be an important development in the future of nuclear medicine and medical oncology. It describes the synergy of theranostic procedures in nuclear medicine and immune oncology (IO) treatment. In brief, it takes advantage of molecular imaging and subsequent targeted modulation of the-in most cases immunosuppressive-tumor microenvironment (TME) by diagnostic and therapeutic radioisotopes. This is of high importance since only a fraction of patients receiving IO is currently being cured by this exciting therapy option. We therefore envision the concept of immunotheranostics as a powerful mean to augment the success of IO treatment in the future and thus the urgent need to further develop the interaction and joint action of nuclear medicine and medical oncology for substantially improved therapy outcome for cancer patients

New Developments in Peptide Receptor Radionuclide Therapy

Peptide Receptor Radionuclide Therapy (PRRT) is an established treatment for non-operable or metastatic neuroendocrine neoplasms that express highly and frequently somatostatin receptors. More generally, PRRT is an attractive therapy option for delivering cytotoxic radiation to tumor cells through specific binding of a radiolabeled peptide to a molecular target. The development of imaging companions gave rise to the concept of radiotheranostics, important for in vivo tumor detection, characterization, staging but also, and more importantly, for individual patient selection and treatment. The success of somatostatin receptor targeting paved the way for the clinical translation of other peptide-based radiopharmaceuticals targeting, e.g. the receptors Cholecystokinin 2 (CCK2), Gastrin Releasing Peptide (GRPR), Neurokinin-1 (NK-1) and C-X-C motif chemokine 4 (CXCR4). While historically the Auger-emitter 111In and the high-energy β--emitter 90Y were used, the vast majority of PRRT are currently performed with the medium-energy β--emitter 177Lu, while α-emitters are increasingly studied in various clinical applications.JRC.G.I.5-Advanced Nuclear Knowledg

Integration of DOTA as a bridging unit during solid-phase peptide synthesis

A method for the introduction of bifunctionalized 1,4,7,10-tetraazacyclododecane-N,N’,N’’,N’’’-tetraacetic acid (DOTA) into the bridging unit of peptide-based radiopharmaceuticals has been developed. The method is executed in the context of Fmoc-based solid-phase peptide synthesis (SPPS) using standard coupling reagents (HOAt, TBTU, DIPEA) and was optimized to maximize yields (>99% conversion) and suppress the formation of side products (<25%). The bifunctionalized DOTA chelator can be used to integrate radioactive or non-radioactive Ga3+-isotopes. This facilitates novel and structurally simple PET tracer designs and the combination of other functional moieties, such as dyes, with Ga-DOTA-chelates in one hybrid tracer