The Radiotracer [¹¹C]OMAR was developed for positron emission tomography (PET) imaging of cannabinoid type-1 receptors (CB1R). The objectives of the present study were to evaluate kinetic analysis methods, determine test–retest reliability, and assess gender differences in receptor availability. Dynamic PET data were acquired in 10 human subjects, and analyzed with one-tissue (1T) and two-tissue (2T) compartment models and by the Logan and multilinear analysis (MA1) methods to estimate regional volume of distribution ( V_T). The 2T model inclusive of a vascular component (2T_V) and MA1 were the preferred techniques. Test–retest reliability of V_Twas good (mean absolute deviation ~ 9%; intraclass correlation coefficient ~ 0.7). Tracer parent fraction in plasma was lower in women ( P < 0.0001). Cerebral uptake normalized by body weight and injected dose was higher in men by 17% ( P < 0.0001), but V_Twas significantly greater in women by 23% ( P < 0.0001). These findings show that [¹¹C]OMAR binding can be reliably quantified by the 2T model or MA1 method and demonstrate the utility of this tracer for in vivo imaging of CB1R. In addition, results from the present study indicate that gender difference in receptor binding should be taken into consideration when [¹¹C]OMAR is used to quantify CB1R availability in neuropsychiatric disorders.

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:⁶⁸Ga-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 ¹⁷⁷Lu 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 ⁶⁸Ga-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 ⁶⁸Ga-HTK03055 and ⁶⁸Ga-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. ¹⁷⁷Lu-HTK03121 and ¹⁷⁷Lu-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 ¹⁷⁷Lu-PSMA-617, ¹⁷⁷Lu-HTK03121 and ¹⁷⁷Lu-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, ¹⁷⁷Lu-HTK03121 and ¹⁷⁷Lu-HTK03123 have the potential to improve treatment efficacy using significantly lower quantities of ¹⁷⁷Lu and are promising candidates for clinical translation to treat metastatic castration-resistant prostate cancer. Visual Abstract

Theranostics is the integration of diagnostic information with pharmaceuticals to increase effectiveness and safety of cancer treatments. Nuclear medicine provides a non-invasive means to visualize drug target expression across primary and metastatic sites, and assess pharmacokinetics and efficacy of companion therapeutic agents. This is significant given the increasing recognition of the importance of clonal heterogeneity in treatment response and resistance. Carbonic anhydrase IX (CA-IX) has been advocated as an attractive diagnostic and therapeutic biomarker for targeting hypoxia in solid malignancies. CA-IX confers cancer cell survival under low oxygen tension, and is associated with increased propensity for metastasis. As such, CA-IX is overexpressed in a broad spectrum of cancers. Different classes of antigen recognition molecules targeting CA-IX including monoclonal antibodies, peptides, small molecule inhibitors, and antibody mimetics have been radiolabeled for imaging and therapeutic applications. cG250, a chimeric monoclonal antibody, has been labeled with an assortment of radionuclides (¹²⁴I, ¹¹¹In, ⁸⁹Zr, ¹³¹I, ⁹⁰Y, and ¹⁷⁷Lu) and is the most extensively investigated CA-IX radiopharmaceutical. In recent years, there have been tremendous advancements made by the research community in developing alternatives to cG250. Although still in preclinical settings, several small molecule inhibitors and antibody mimetics hold great promise in improving the management of aggressive and resistant cancers.