Background Radiohybrid PSMA-targeted ligands (rhPSMA) have been introduced as a novel platform for theranostic applications. Among a variety of rhPSMA-ligands developed for radioligand therapy, two stereoisomers [ 177 Lu]Lu-rhPSMA-10.1 and -10.2 have been synthesized and initially characterized in preclinical experiments with the aim to provide an optimized binding profile to human serum albumin, a reduction of charge, and thus accelerated kidney excretion, and unaffected or even improved tumor uptake. As both isomers showed similar in vitro characteristics and tumor uptake at 24 h post injection in tumor bearing mice and in order to identify the isomer with the most favorable pharmacokinetics for radioligand therapy, we carried out in-depth biodistribution and dosimetry studies in tumor-bearing and healthy mice. Results rhPSMA-10.1 and -10.2 were radiolabeled with lutetium-177 according to the established procedures of other DOTA-based PSMA ligands and displayed a high and comparable stability in all buffers and human serum (> 97%, 24 h). Biodistribution studies revealed fast clearance from the blood pool (0.3–0.6%ID/g at 1 h) and other background tissues within 48 h. Distinctive differences were found in the kidneys, where [ 177 Lu]Lu-rhPSMA-10.1 displayed lower initial uptake and faster excretion kinetics compared to [ 177 Lu]Lu-rhPSMA-10.2 expressed by a 1.5-fold and ninefold lower uptake value at 1 h and 24 h in healthy animals, respectively. Tumor uptake was comparable and in the range of 8.6–11.6%ID/g for both isomers over 24 h and was maintained up to 168 h at a level of 2.2 ± 0.8 and 4.1 ± 1.4%ID/g for [ 177 Lu]Lu-rhPSMA-10.1 and [ 177 Lu]Lu-rhPSMA-10.2, respectively. Conclusion Our preclinical data on biodistribution and dosimetry indicate a more favorable profile of [ 177 Lu]Lu-rhPSMA-10.1 compared to [ 177 Lu]Lu-rhPSMA-10.2 for PSMA-targeted radioligand therapy. [ 177 Lu]Lu-rhPSMA-10.1 shows fast kidney clearance kinetics resulting in excellent tumor-to-organ ratios over a therapy relevant time course. Meanwhile, [ 177 Lu]Lu-rhPSMA-10.1 is currently being investigated in clinical phase I/II studies in patients with mCRPC (NCT05413850), in patients with high-risk localized PC (NCT06066437, Nautilus Trial) and after external beam radiotherapy (NCT06105918).

Ziel/Aim 177Lu-PSMA radioligand (RLT) therapy is a new treatment option for metastatic castration-resistant prostate cancer (mCRPC). Its low toxicity profile favors the use in elderly patients. Purpose of this study was to evaluate the safety and efficacy of 177Lu-PSMA-RLT in mCRPC patients≥80 years of age.

Ziel/Aim Die Erfassung der Tumorausdehnung und die exakte lokoregionäre Tumordetektion bei niedrigen biochemischen Rezidiven (BCR) nach radikaler Prostatektomie (RP) bei Prostatakarzinom (PCa) Patienten (Pat.) sind für eine individuelle Therapieplanung von besonderem Interesse. Das Ziel dieser Studie war die Analyse der Wertigkeit einer zur [F-18]siPSMA-14-PET/CT ergänzenden PET/mpMRT inklusive DCE (dynamic contrast enhanced) MRT des Beckens zur Verbesserung der lokalen Tumordetektion.

Ziel/Aim Radiohybride prostataspezifische Membranantigene (rhPSMA) Liganden stellen eine neue Gruppe theranostischer Radiopharmaka dar. Basierend auf in vitro Daten ist rhPSMA7.3 ein vielversprechender Kandidat. Ziel dieser retrospektiven Analyse war ein Vergleich prätherapeutischer Dosimetrien von Lu-177-rhPSMA-7.3 (rh) und Lu-177-PSMA-I&T (I&T) für eine mögliche Endoradiotherapie.

1328 Aim: The novel PSMA-specific PET-Tracer [F-18]siPSMA-14 showed promising biodistribution and tumour uptake in prostate cancer (PCa) bearing mice. Our aim was to analyze its clinical performance in primary- (PS) and restaging (RS) of PCa patients by analyzing biodistribution, detection rates and interobserver variability at 90min p.i.. Methods: In 134 patients with PCa (69.7 ± 7.5 years; GS 6-9; median (range) PSA 2.36 (0.08-1898) ng/ml) [F-18]siPSMA-14 PET/CT was performed for PS (40%, 54/134) or RS (60%, 80/134). Images were acquired 90min p.i. of 374.2 ± 8.1 MBq without forced diuresis. Findings in different lesion localizations (prostatic lesions (PL), lymphatic lesions (LN), bone lesions (B), visceral lesions (P)) were rated using a 5-scale-system ranging from C1 (definitely benign) to C5 (definitely malignant). Images were evaluated by two nuclear medicine physicians and radiologists (R1, R2). Agreement between R1 and R2 was measured by Cohens-Kappa. Biodistribution measurements were performed using SUVmean in a fixed size region of interest (ROI) to assess the physiological and pathological tracer accumulation. For contrast evaluation target/non target ratios (TTR) were measured by comparing tumour- and background uptake. Results: In consensus reading, the detection rate was 94% (51/54) and 86% (69/80) in PS and RS respectively. In subgroups with PSA values of 0-0.5, 0.5-1, 1-5 and >5 ng/ml detection rates were 68% (19/28), 89% (17/19), 94% (30/32) und 98% (54/55). Interobserver agreement for PL, LN, P was high with Kappa-values of 0.85, 0.75, 0.86 and with 0.51 moderate for B. TTR for PL (n = 88), LN (n = 68), B (n = 51), P (n = 3) were high with 9.3, 11.6, 14.3, 14.6; PL-uptake ranged above urinary bladder uptake with an average SUVmean ratio of 1.7. Conclusions: [F-18]siPSMA-14-PET/CT performs comparably concerning detection rates to other PSMA-binding radiopharmaceuticals with high interobserver agreement and excellent contrast. A major advantage is good performance and image quality adjacent to the urinary bladder even without forced diuresis which is of high relevance for detection of loco-regional tumour recurrence.

Ziel/Aim Lu-177-PSMA is increasingly used in mCRPC. Based on dosimetry results the kidneys are an organ at risk potentially limiting the number of cycles applied. We aimed to investigate the effect of Lu-177-PSMA on kidney function in patients who underwent at least 4 cycles with a minimum follow-up time of 12 months.

Ziel/Aim Wir analysierten den neuen PET-Tracer [F-18]siPSMA14 in einem heterogenen Patientenkollektiv zur Überprüfung der Untersuchervariabilität in der klinischen Routine.

1660 Background: Arterial inflammation is the hallmark of atherogenesis and its complications. People living with human immunodeficiency virus (PLHIV) infection have an excess risk of atherosclerotic cardiovascular disease (ASCVD). 18F-FDG PET/CT is the most used modality to image arterial inflammation in ASCVD. There are several challenges with the use of 18F-FDG PET/CT for this purpose. In this study, we aimed to perform a head-to-head comparison of 18F-FDG PET/CT and [68Ga]Ga-pentixafor PET/CT for quantification of arterial inflammation in PLHIV.\n Methods: We prospectively recruited HIV-infected patients to undergo 18F-FDG PET/CT and [68Ga]Ga-pentixafor PET/CT within two weeks of each other. All recruited patients had been living with HIV infection for a minimum of 24 months and had completely suppressed HIV viremia on antiretroviral therapy. We obtained the maximum standardized uptake value (SUVmax) of arterial tracer uptake from the ascending aorta and carotid artery. We obtained the mean standardized uptake value (SUVmean) from the lumen of the superior vena cava and internal jugular vein for background correction. We computed the target-background-ratio for the ascending aorta and carotid artery by dividing the arterial SUVmax by the venous SUVmean. We used Bland and Altman plots to measure the level of agreement between tracer quantification parameters obtained on both scans.\n Results: A total of 12 patients were included with a mean age of 44.67 ± 7.62 years. The mean duration of HIV infection was 71.08 ± 37 months with a mean CD+ T-cell count of 522.17 ± 260.33 cells/µL, respectively. The mean activity of administered 18F-FDG was significantly higher than that of [68Ga]Ga-pentixafor (7.84 ± 1.17mCi and 4.70 ± 2.12mCi, p\u003c0.001). The median interval between the two scans was 2 days (range=1-11 days). We found a high level of agreement between the 18F-FDG PET-derived quantification variables and the [68Ga]Ga-pentixafor PET-derived variables in the aortic and carotid arterial beds with 91% to 100% of all measurements within the limits of agreement. There was a positive correlation between 18F-FDG PET and [68Ga]Ga-pentixafor PET-derived quantification variables obtained in the ascending aorta while similar parameters obtained in the carotid bed mostly showed negative correlation.\n Conclusions: There is a good level of agreement in the arterial tracer quantification variables obtained on 18F-FDG PET/CT and [68Ga]Ga-pentixafor PET/CT in PLHIV. This suggests that [68Ga]Ga-pentixafor may be used in the place of 18F-FDG PET/CT for the quantification of arterial inflammation.

Ziel/Aim After acute myocardial infarction (MI), tissue inflammation plays a crucial role mediating cardiac repair. Here, we investigated effects of macrophage depletion on early myocardial inflammation and later functional outcome.

1054 Objectives: In addition to previous approaches aiming to improve the metabolic stability and pharmacokinetics of GRPR antagonists by C- or N-terminal modifications, we investigated in this study the introduction of unnatural amino acids (homoserine [Hse], citrulline [Cit], β-(3-benzo­thienyl)alanine [Bta] and α-methyl tryptophan [α-Me-Trp]) at the metabolically unstable Gln7-Trp8 sequence within the typically used Gastrin-releasing peptide receptor (GRPR) antagonist RM2 (DOTA-Pip5-D-Phe6-Gln7-Trp8-Ala9-Val10-Gly11-His12-Sta13-Leu14-NH2). The results of the development and evaluation of the five novel candidates for diagnosis and therapy of GRPR-based malignancies are given. Methods: All RM2-based compounds were synthesized by standard Fmoc-based solid-phase peptide synthesis (SPPS). Labeling with 177Lu was carried out at 95 °C within 10 min (1.0 M sodium acetate buffer, pH = 5.5, 0.1 M sodium ascorbate). GRPR affinity (IC50) and internalization (37 °C, 60 min) were determined using PC-3 cells. In addition, the lipophilicities (expressed as n-octanol/PBS partition coefficient; logD7.4) were determined and metabolic stabilities in vitro in human as well as murine plasma (3 d, 37 °C) were examined. Biodistribution studies were carried out at 1 h and 24 h p.i. on PC-3 tumor-bearing CB17-SCID mice. Results: Similar to the production of parent compound, the new RM2 derivatives were easily accessible by SPPS, resulting in 6-11% HPLC purified labeling precursor. Each of 177Lu-labeled compounds revealed suitable hydrophilicity (logD7.4) (177Lu-RM2: - 2.51 ± 0.02, 177Lu-Hse7-RM2: - 2.25 ± 0.06, 177Lu-Cit7-RM2: - 3.22 ± 0.15, 177Lu-Bta8-RM2: - 1.81 ± 0.02, 177Lu-α-Me-Trp8-RM2 = AMTG: - 2.28 ± 0.06 and 177Lu-DOTAGA-α-Me-Trp8-RM2 = AMTG2: - 2.51 ± 0.11. The GRPR affinity (IC50 [nM]) of the new compounds was high to moderate (Lu-RM2: 3.45 ± 0.18, Lu-Hse7-RM2: 19.7 ± 1.6; Lu-Cit7-RM2: 11.6 ± 2.1; Lu-Bta8-RM2: 4.63 ± 0.23; Lu-AMTG: 3.04 ± 0.08; Lu-AMTG2: 4.74 ± 0.23). Furthermore, internalization studies at 1 h confirmed antagonistic behavior for all evaluated compounds (specific internalization of 177Lu-RM2: 2.92 ± 0.20%; 177Lu-Hse7-RM2: 1.40 ± 0.16%; 177Lu-Bta8-RM2: 2.26 ± 0.18% and 177Lu-AMTG: 3.03 ± 0.18%). Compared to 177Lu-RM2, improved tumor-to-background (T/B) ratios at 1 h p.i. in mice was found in all organs for 177Lu-Hse7-RM2 and 177Lu-Bta8-RM2, whereas 177Lu-AMTG and 177Lu-AMTG2 showed enhanced T/B ratios in most organs (especially in blood and muscle) at 24 h p.i. Interestingly, studies on the metabolic stability of 177Lu-RM2 and 177Lu-AMTG in vitro in human and murine plasma revealed similar stability of both derivatives after 3 d (67% and 59%, respectively) in murine plasma, whereas stability in human plasma was significantly higher for 177Lu-AMTG after 3 d of incubation at 37 °C (36% and 92%, for 177Lu-RM2 and 177Lu-AMTG, respectively). Conclusion: Based on its high affinity, excellent biodistribution and improved metabolic stability, the novel GRPR-targeted antagonist AMTG as well as AMTG2 could be promising candidates for diagnosis and therapy of GRPR-expressing malignancies. In addition, Hse7-RM2 and Bta8-RM2 could be appropriate ligands for diagnostic purposes.

Pentamethine cyanine (Cy5) fluomphores have proven to be versatile imaging agents (i.e., tracers) for a range of micro- and macroscopic imaging applications, including image-guided surgery. In this study the relationship between the structure of asymmetric Cy5 fluorophores and their photophysical properties was studied. To this end, seven Cy5 analogues, bearing orthogonal N-indole substituents (H, SC3-, or benzene), were synthesised and evaluated. In-depth analysis revealed that introduction of sulfonates enhanced the fluorescence brightness and photostability, while reducing the lipophilicity, serum binding and stacking tendency. The addition of benzene moieties induced a bathochromic shift of 10-20 nm, increased the lipophilicity (LogP = -1.56-1.23) and serum binding (67.3-93.8% bound), as well as negatively impacted the brightness (0.74-42.9 . 10(3) M-1 cm(-1)), photostability (24.4-90.6% remaining), and stacking tendency. Chemical stability was uninfluenced by the substitution pattern. Additionally, the generation of a c[RGDyK]-based hybrid tracer based on one of these fluomphores in combination with a diethylenetriaminepentaacetic acid (DTPA) chelate and an In-111-isotope was reported. This compound was evaluated in vitro using alpha(v)beta(3)-overexpressing Ge beta 3 cells and in vivo using a 4T1 mouse tumour model. Overall, the presented results imply that alterations of the asymmetrical orthogonal Cy5 fluomphore structure have impact on the (photo)physical properties. Furthermore, the orthogonal Cy5 fluorophore framework can readily be applied in tracer development.

Prostate-specific membrane antigen (PSMA) SPECT imaging in prostate cancer (PCa) could be a valuable alternative in regions where access to PSMA-PET imaging is restricted. [99mTc]Tc-PSMA-I&S is a new 99mTc-labeled PSMA-targeting SPECT agent, initially developed for radio-guided surgery. We report on the diagnostic use of [99mTc]Tc-PSMA-I&S-SPECT/CT in PCa. [99mTc]Tc-PSMA-I&S-SPECT/CT was performed and evaluated in 210 outpatients with PCa at a single center. Patients were imaged for biochemical recurrence (BCR, n = 152, mean PSA 8.7 ng/ml), for primary staging of high-risk PCa (n = 12, mean PSA 393 ng/ml), and restaging in advanced recurrent PCa (n = 46, mean PSA 101.3 ng/ml). Number and location of positive lesions were determined for the different subgroups. For BCR, detection rates were calculated, defined as the proportion of scans with at least one PSMA-positive lesion. PSMA positive lesions were detected in 65.2% of all 210 patients. Tumor tissue was mainly detected in lymph nodes (59%), in the bone (42%), and in the prostate (fossa) (28%). In the subgroup of patients referred for detection of BCR the detection rate increased from 20% at a PSA level < 1 ng/ml to 82.9% and 100% at PSA levels > 4 ng/ml and > 10 ng/ml, respectively. In the subgroup of high-risk patients referred for primary staging, 42% demonstrated metastatic disease. Restaging of advanced recurrent PCa revealed detectability of PSMA positive tumor lesions in 85% of the scans. [99mTc]Tc-PSMA-I&S-SPECT/CT was useful in PSMA-targeted imaging of PCa at various clinical stages. At low PSA levels (< 4 ng/ml), detection rates of [99mTc]Tc-PSMA-I&S-SPECT/CT in BCR are clearly inferior to data reported for PET-imaging and should thus only be considered for lesion detection if imaging with PET is unavailable. However, at higher PSA levels (> 4 ng/ml) [99mTc]Tc-PSMA-I&S-SPECT/CT provides high detection rates in BCR. [99mTc]Tc-PSMA-I&S-SPECT/CT can also be used for primary staging and for restaging of advanced recurrent PCa. However, further studies are needed to assess the clinical value in these indications.

647 Objectives: In cardiovascular disease, there is tight interaction between the heart and kidneys, which is the foundation of cardiorenal syndrome (CRS), contributes to adverse outcome, and forms a basis for targeted drug intervention. We speculated that whole-body molecular imaging provides insights into inflammatory heart-kidney interaction after myocardial infarction (MI) and predicts adverse renal outcome. Methods: CXCR4-directed PET datasets of 96 acute MI patients following revascularization (median 3.4 days) were evaluated for Ga-68-pentixafor tracer retention. Glomerular filtration rate (GFR) was measured at baseline and follow-up. Renal event (RE) was defined as rapid renal disease progression (GFR loss >5 ml/min/1.73m2 within one year). Results: CXCR4 signal derived from renal parenchyma correlated with the MI territory signal (R=0.25, P<0.05) and remote myocardium signal (R=0.39, P<0.0001), suggesting an inflammatory link between heart and kidneys. At time of PET, GFR did not correlate with CXCR4 signal in any organ (R≤0.04, n.s.). During follow-up, GFR was available in 48/96 subjects (50%) and declined from 83.3±18.2 to 79.8±19.2 ml/min/1.73m2. In 16/48 (33.3%), RE occurred mean 80.5 days post-MI. GFR at baseline (AUC=0.49, p=0.47) and PET-derived signal from the infarct (AUC=0.55, p=0.29) and kidneys (AUC=0.58, p=0.16) failed to be significant for RE prediction in a ROC analysis. Subjects with RE, however, had elevated baseline CXCR4 signal in remote myocardium (SUVpeak, 1.6 ± 0.38 vs 1.37 ± 0.32 for no RE; p=0.02). Ga-68-pentixafor uptake in remote myocardium reached significance in ROC analysis (AUC=0.68, p=0.02) and a cutoff of 1.475 yielded a sensitivity of 75% and specificity of 66%. For patients above the cutoff, the probability for RE was 81.9% (Hazard Ratio, 4.53; p=0.04). Using the ROC-derived cutoff, Kaplan-Meier analysis revealed a significant distinction between high-risk vs. low-risk individuals (p<0.05). Conclusions: After acute MI, inflammatory molecular signatures appear to contribute to CRS development, with a particular role for non-directly injured, remote myocardial involvement. Cardiac Ga-68-pentixafor PET may identify risk of adverse renal outcome after MI, thereby suggesting a potential future role for imaging-guided, renoprotective strategies early after the acute event. Acknowledgement. This project was supported by PRACTIS - Clinician Scientist Program, funded by the German Research Foundation (DFG, ME 3696/3-1) and the clinical research group KFO311.